Solid dots represent participants with CV; hollow dots represent participants without CV. Solid lines represent the best fit lines for participants with CV; dotted lines represent the best fit lines for participants without CV. Decreasing brain volume is associated with decreasing psychomotor speed scores in participants both with and without CV, but the slope is more severe for participants with CV. In models that include age and educational level as covariates, the P values for the interaction terms are .03 for the thalamus, .04 for the caudate, .009 for the putamen, .02 for the hippocampus, and .007 for the amygdala (after adjustments are made for multiple testing via the Holm step-down procedure).
eAppendix 1. Professional Fighters Brain Health Study
eAppendix 2. Cognitive and Mood Assessments
eAppendix 3. Imaging
eAppendix 4. Statistics
eFigure 1. Measurement of the Cavum Septum Pellucidum (CSP) in the Maximum Transverse Dimension and Measurement of the CSP and Cavum Vergae (CV) in the Maximum Longitudinal Dimension
eFigure 2. Example of a Cavum Septum Pellucidum and Cavum Vergae in a Fighter and Example of a Cavum Septum Pellucidum in a Fighter
eFigure 3. Scatterplot of Cavum Septum Pellucidum and Cavum Vergae (CSPV) Length and Processing Speed (PSS) Score and Psychomotor Speed (PsychoS) Score Among 251 Fighters With CSPV Length Available
eFigure 4. Example of a Patient With Increased Cavum Septum Pellucidum/Cavum Vergae Over Time
eFigure 5. Scatterplot of Cavum Septum Pellucidum and Cavum Vergae (CSPV) Length and Processing Speed (PSS) Score and Psychomotor Speed (PsychoS) Score With Only Active Fighters
eFigure 6. Scatterplot of Cavum Septum Pellucidum and Cavum Vergae (CSPV) Length and Processing Speed (PSS) Score and Psychomotor Speed (PsychoS) Score With Only Retired Fighters
eTable 1. Characteristics of Study Participants
eTable 2A. Cognitive Scores Among Fighters With and Without CSP and CV
eTable2B. Cognitive Scores Among Fighters With and Without WMC and CMH
eTable 3. Change in Psychomotor Speed With Increase in Various Brain Volumes Without and With CV
eTable 4. Association Between Fighter Exposure Score and Various Imaging Characteristics, Brain Volumes, and Cognitive Scores
eTable 5. Correlation Between Changes in CSPV Length and Changes in Various Cognitive/Behavioral Measures
eTable 6. Correlation Between Changes in CSPV Length and Changes in Various Brain Volumes
eTable 7. Characteristics of Active Versus Retired Fighters
eTable 8. Comparison of Imaging and Cognitive Variables in Active Fighters and Controls
eTable 9. Estimated Mean Differences for Various Brain Volumes Among Active Fighters With and Without CSP and CV
eTable 10. Estimated Change in Mean Brain Volumes With Each 1-mm Enlargement in CSPV Length in Active Fighters
eTable 11. Comparison of Imaging and Cognitive Variables in Retired Fighters and Controls
eTable 12. Estimated Mean Differences for Various Brain Volumes Among Retired Fighters With and Without CSP and CV
eTable 13. Estimated Change in Mean Brain Volumes With Each 1-mm Enlargement in CSPV Length in Retired Fighters
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Lee JK, Wu J, Bullen J, et al. Association of Cavum Septum Pellucidum and Cavum Vergae With Cognition, Mood, and Brain Volumes in Professional Fighters. JAMA Neurol. 2020;77(1):35–42. doi:10.1001/jamaneurol.2019.2861
Given the increased frequency of cavum septum pellucidum and cavum vergae in fighters who experience repetitive head trauma, is the presence of these imaging findings associated with lower cognitive and mood testing scores and reduced volumes of various brain structures?
This population-based cohort study demonstrated that fighters with cavum vergae or increased cavum septum pellucidum and cavum vergae length had decreased volumes in various brain structures and lower cognitive scores vs fighters without these imaging findings.
The presence of cavum septum pellucidum and cavum vergae was associated with lower regional brain volumes and cognitive performance in a cohort exposed to repetitive head trauma.
Many studies have investigated the imaging findings showing sequelae of repetitive head trauma, with mixed results.
To determine whether fighters (boxers and mixed martial arts fighters) with cavum septum pellucidum (CSP) and cavum vergae (CV) have reduced volumes in various brain structures or worse clinical outcomes on cognitive and mood testing.
Design, Setting, and Participants
This cohort study assessed participants from the Professional Fighters Brain Health Study. Data were collected from April 14, 2011, to January 17, 2018, and were analyzed from September 1, 2018, to May 23, 2019. This study involved a referred sample of 476 active and retired professional fighters. Eligible participants were at least 18 years of age and had at least a fourth-grade reading level. Healthy age-matched controls with no history of trauma were also enrolled.
Presence of CSP, CV, and their total (additive) length (CSPV length).
Main Outcomes and Measures
Information regarding depression, impulsivity, and sleepiness among study participants was obtained using the Patient Health Questionnaire depression scale, Barrett Impulsiveness Scale, and the Epworth Sleepiness Scale. Cognition was assessed using raw scores from CNS Vital Signs. Volumes of various brain structures were measured via magnetic resonance imaging.
A total of 476 fighters (440 men, 36 women; mean [SD] age, 30.0 [8.2] years [range, 18-72 years]) and 63 control participants (57 men, 6 women; mean [SD] age, 30.8 [9.6] years [range, 18-58 years]) were enrolled in the study. Compared with fighters without CV, fighters with CV had significantly lower mean psychomotor speed (estimated difference, –11.3; 95% CI, –17.4 to –5.2; P = .004) and lower mean volumes in the supratentorium (estimated difference, –31 191 mm3; 95% CI, –61 903 to –479 mm3; P = .05) and other structures. Longer CSPV length was associated with lower processing speed (slope, –0.39; 95% CI, –0.49 to –0.28; P < .001), psychomotor speed (slope, –0.43; 95% CI, –0.53 to –0.32; P < .001), and lower brain volumes in the supratentorium (slope, –1072 mm3 for every 1-mm increase in CSPV length; 95% CI, –1655 to –489 mm3; P < .001) and other structures.
Conclusions and Relevance
This study suggests that the presence of CSP and CV is associated with lower regional brain volumes and cognitive performance in a cohort exposed to repetitive head trauma.
Repetitive head trauma, particularly in the context of contact sports such as US football, is associated with various neurodegenerative disorders.1-6 Athletes in these sports sustain repetitive head trauma over the span of their careers, with resulting cognitive and structural changes that are increasingly being studied with imaging and cognitive testing.7-9Quiz Ref ID A wide range of structural brain changes on magnetic resonance imaging findings have been noted in contact sports athletes with histories of repetitive head trauma. These structural brain changes include increased frequency of cerebral microhemorrhages (CMHs),10,11 nonspecific white matter changes (WMCs),12 and the presence of cavum septum pellucidum (CSP) and cavum vergae (CV).13-16 Other investigations, however, have found no substantial structural abnormalities on imaging results in this population.17,18 These variable findings are confounded by small sample sizes and limited data regarding cognitive changes and clinical outcomes. In addition, few studies have provided longitudinal data on changes in brain structure and function as repetitive head trauma accumulates over time.
The Professional Fighters Brain Health Study (PFBHS) is a longitudinal cohort study of boxers and mixed martial arts fighters that is positioned to elucidate the importance of various structural brain changes caused by cumulative sports-related head trauma and to determine the potential association between structural findings and functional alterations. Changes in various cognitive domains have been reported in professional boxers.8,19 However, few longitudinal studies have explored the association between cognitive and brain structural changes. Quiz Ref IDPrevious analyses of data from the PFBHS have demonstrated an association between head trauma and imaging findings of smaller deep gray structures, specifically the caudate and amygdala, as well as decreased function, specifically involving processing speed.9 Increased motor impulsivity has also been reported along with decreased volumes of deep gray structures such as the caudate and thalamus in a subset of this cohort.20
Another recent study examined the frequency of CSP, CV, CMHs, and WMCs among professional fighters vs controls and observed a significantly increased frequency of CSP and CV in fighters21; these findings are similar to those reported in studies of US football players with chronic traumatic encephalopathy.14,17 However, as CSP and CV are also often described as normal variants in imaging studies, the clinical significance of this increased incidence of CSP and CV among fighters is poorly understood. In the present study, we sought to examine associations between CSP and CV, various intracranial volume measurements, and cognitive and mood outcomes.
The PFBHS is an ongoing observational cohort study of active and retired professional fighters and healthy age-matched controls. Data for this study were collected from April 14, 2011, to January 17, 2018. This study was approved by the Cleveland Clinic Institutional Review Board, and written informed consent was obtained from all study participants. See eAppendix 1 in the Supplement for further details regarding inclusion criteria for fighters and controls.
Quiz Ref IDInformation regarding depression, impulsivity, and sleepiness among study participants was obtained using the Patient Health Questionnaire depression scale, Barrett Impulsiveness Scale, and the Epworth Sleepiness Scale. Cognition was assessed using raw scores from CNS Vital Signs,22 a computerized test providing robust and reliable measurements of cognition in the clinical realms of verbal memory, processing speed, psychomotor speed, and reaction time. See eAppendix 2 in the Supplement for further details regarding these cognitive and mood assessments.
As part of the PFBHS, all fighters and control participants underwent brain imaging on a Verio 3-T magnetic resonance imaging scanner (Siemens). Volumetric segmentation was performed on the MPRAGE image data set using FreeSurfer, version 6.0 (http://surfer.nmr.mgh.harvard.edu/).23-34 For the current analysis, 4 of us (neuroradiology experience: J.W., 1 year; J.K.L., 3 years; S.E.J., 12 years; P.R., 26 years) measured the combined length of the CSP and CV (hereafter CSPV length) and the maximum transverse width. The mean measurements from all readers were used for the analysis (eFigure 1 in the Supplement). The readers were blinded to whether the images belonged to a fighter or a control participant. Longitudinal follow-up evaluation was performed by the same 4 neuroradiologists, who were not blinded to the time order of the scans. eFigure 2 in the Supplement shows an example of a CSP and CV. eAppendix 3 in the Supplement provides further details regarding the scan parameters and previous and current analysis techniques.
Statistical analysis was performed from September 1, 2018, to May 23, 2019. For each of the 13 cognitive and mood measures, a linear regression model was used to test the hypothesis that the scores would be different for all study participants with and without CSP. In each model, the score was the outcome variable, the CSP status was the variable of interest, and age, educational level, race, and ethnicity were included as covariates. The resulting 13 P values were adjusted for multiple comparisons using the Holm step-down procedure, applying a significance of .05. This entire process was repeated for the 3 remaining imaging characteristics (CV, WMCs, and CMHs). A similar approach was used to assess the association between imaging findings and the 7 brain volumes of interest (supratentorium, thalamus, corpus callosum, caudate, putamen, hippocampus, and amygdala). A subgroup analysis was repeated separately for active fighters only and retired fighters only.
The intraclass correlation coefficient (ICC) was used to characterize interreader reliability with respect to CSPV length and maximum transverse width of the CSP. Intraclass correlation coefficient estimates and their 95% CIs were calculated based on a single-rater, absolute-agreement, 2-way random effects model. The sample for these estimates consisted of measurements provided by 4 readers from 275 participants with CSP from a prior analysis. In multiple post hoc analyses, associations between CSPV length, fighting status (fighter vs control), and fighter exposure score9 were individually compared with various brain volumes and cognitive scores using a series of linear regression models.
The hypothesis that the association between brain volume and cognitive score would be different for fighters with CV than for fighters without CV was assessed by adding an interaction term (brain volume × CV status) to the model with psychomotor speed and processing speed, which were assessed separately. Follow-up data were also analyzed when available, and the Spearman correlation coefficient was calculated to quantify the association between changes in CSPV length and changes in cognitive measures and brain volumes. See eAppendix 4 in the Supplement for further details regarding these post hoc analyses.
The study population consisted of 476 fighters, with a mean (SD) age of 30.0 (8.2) years (range, 18-72 years); 440 of the fighters were men (92.4%) (eTable 1 in the Supplement). The mean (SD) number of years of education among fighters was 13 (3) (range, 2-25 years). The control population consisted of 63 participants, with a mean (SD) age of 30.8 (9.6) years (range, 18-58 years; P = .41); 57 of the controls (90.5%) were men (P = .46). The mean (SD) number of years of education among control participants was 14 (3) (range, 9-20; P = .15). The cognitive and mood scores among fighters with and without various imaging findings are shown in eTables 2A and 2B in the Supplement.
Agreement among the 4 readers was good with respect to CSPV length (ICC, 0.87; 95% CI, 0.84-0.89) and maximum transverse width of the CSP (ICC, 0.70; 95% CI, 0.64-0.75). Fighters had a significantly increased frequency of CSP (odds ratio, 4.64; 95% CI, 2.36-9.83; P < .001) and CV (odds ratio, 24.8; 95% CI, 3.26-31.94; P = .001), lower volumes in the thalamus (mean difference, –650 mm3; P = .02) and corpus callosum (mean difference, –402 mm3; P < .001), and lower processing speed (mean difference, –7.54; P < .001) and psychomotor speed (mean difference, –20.2; P < .001) vs controls (Table 1). Fighters had a higher volume in the putamen (mean difference, 919 mm3; P < .001) vs controls.
Fighters with WMCs had higher cognitive complexity scores on the Barrett Impulsiveness Scale vs fighters without WMCs (estimate, 0.9; 95% CI, 0.30-1.44; P = .04). No significant associations were found between presence or absence of CSP or CMHs and the various cognitive measures (Table 2). Fighters with CV had a significantly lower mean psychomotor speed (estimated difference, –11.3; 95% CI, –17.4 to –5.2; P = .004; Table 2) and lower mean brain volumes in the supratentorium (estimated difference, –31 191 mm3; 95% CI, –61 903 to –479 mm3; P = .05) and other structures vs fighters without CV (Table 3).
Longer CSPV was associated with lower processing speed (slope, –0.39; 95% CI, –0.49 to –0.28; P < .001) and psychomotor speed (slope, –0.43; 95% CI, –0.53 to –0.32; P < .001) scores (eFigure 3 in the Supplement). In addition, longer CSPV was associated with lower brain volumes in the supratentorium (slope, –1072 mm3 for every 1-mm increase in CSPV length; 95% CI, –1655 to –489 mm3; P < .001) and other structures (Table 4).
For the thalamus, caudate, putamen, hippocampus, and amygdala, a significant interaction was observed between presence or absence of CV and brain volume with respect to psychomotor speed. In these locations, decreasing volume was associated with decreasing psychomotor speed in fighters with or without CV, but the association was strongest in fighters with CV. No similar significant interaction was seen between corpus callosum volume and psychomotor speed or between the various deep brain structures and processing speed (Figure; eTable 3 in the Supplement). No significant associations were seen between fighter exposure score and the various imaging findings, brain volumes, or cognitive scores (eTable 4 in the Supplement).
A total of 125 fighters with CSP were followed up longitudinally. Median follow-up duration was 2.8 years (range, 0.8-5.7 years). The length of the CSPV increased a mean of 1.0 mm (range, –3.2 to 21.5 mm). Maximum transverse width of the CSP increased a mean of 0.2 mm (range, –0.45 to 2.3 mm) (an example is shown in eFigure 4 in the Supplement). No significant associations were seen between changes in CSP size and changes in brain volumes or cognitive scores, although this study was ultimately not designed to assess these associations (eTables 5 and 6 in the Supplement).
A subanalysis of active and retired fighters (437 active fighters vs 39 retired fighters; eTable 7 in the Supplement) demonstrated many of the same associations as were seen in the main analysis with regard to the control group, although corpus callosum volumes were more influenced in active fighters (eTable 8 in the Supplement) and thalamic volumes were more influenced in retired fighters (eTable 11 in the Supplement). For active fighters, the presence of CV was not associated with decreased intracranial volumes (eTable 9 in the Supplement), but associations between increased CSPV length and brain volumes (eTable 10 in the Supplement) and processing and psychomotor speeds (eFigure 5 in the Supplement) were seen. For retired fighters, associations seen in the main analysis with regard to CV, CSPV length, and CSPV length vs processing and psychomotor speed were no longer observed (eTables 12 and 13, eFigure 6 in the Supplement).
Quiz Ref IDIn this study, we found that, compared with control participants, fighters had an increased frequency of CSP and CV, impaired cognitive testing results, and decreased volumes in certain brain structures. Within the fighter group, those with CV and increased CSPV lengths demonstrated impaired cognitive testing results and volume loss in various central structures, although fighters with CSP did not. Such a link between cognitive testing scores and intracranial volumes as measured with conventional magnetic resonance imaging sequences has not previously been reported.
The exact mechanism underlying the development of CSP and CV is unknown. One theory is that direct traumatic injury causes tears in the septal leaflets, described in a postmortem examination of a boxer as multiple perforations of the septal leaflets with a lattice-like appearance.35 Subsequently, transient increased intracranial pressure, perhaps from direct trauma or Valsalva maneuvers when the fighter bears down before or during contact, may accentuate these tears and/or cause increased cerebrospinal fluid to accumulate. The development of devices designed to monitor intracranial pressure in real time could help elucidate this theory.36 Another potential mechanism for the development of CSP and CV is the accumulation of various proteins in the subarachnoid space owing to a breakdown of the blood-brain barrier, resulting in impaired cerebrospinal fluid resorption.37 Finally, ex vacuo expansion of the potential space in the septum pellucidum from central volume loss could also exacerbate CSP enlargement in cases of repetitive traumatic injury.14,38 Further evaluation of other potential risk factors, such as environmental and genetic factors, is needed. In addition, it is unclear why certain fighters develop CV and increased CSPV length and others do not. In this study, the fighter exposure score was not associated with the presence of CV, increased CSPV length, intracranial volumes, or cognitive measures. However, our analysis may have been limited because of the high number of hypotheses being tested, leading to increased adjusted P values. Again, further study is needed to explore these potential associations.
Specific brain structures are also affected by repetitive head trauma among fighters. Central structures such as the corpus callosum, thalamus, caudate, putamen, and hippocampus have extensive connections with cortical structures and with each other. Rotational movement of the head due to punches can result in shear strain and diffuse axonal injury in white matter tracts because of the relative fixation of the deep portion of the brain to the superficial aspect. These resultant injuries usually occur at junctions of gray matter and white matter and deep white matter structures.39 Most of these injuries are nonhemorrhagic, which is reflected in the low number of CMHs evident among susceptibility-weighted imaging findings in our cohort.21 However, injury to these white matter tracts can cause Wallerian degeneration and volume loss in various central structures.40-43 In addition, torsional forces can produce fluid waves in the lateral ventricles that may directly injure adjacent structures that are relatively immobile.44 These 2 hypotheses may explain the volume loss that was seen in fighters with CV and increased CSPV length in our study. This analysis also demonstrated that fighters with WMCs had higher cognitive complexity scores than did fighters without WMCs, and fighters had higher putamen volumes than did control participants. Further study is needed to determine whether these findings are of any clinical significance.
The decreased volume of multiple brain structures in fighters with increased CSPV length may explain the decreases in psychomotor speed and processing speed seen in this analysis. Psychomotor speed, which is a measure of the time needed to complete fine motor tasks requiring precise movement, coordination, and dexterity, is often considered one of the most commonly affected areas of cognition after repetitive head trauma.45 Our study demonstrated that decreased volumes in certain brain structures were associated with decreased psychomotor speed; this association was even stronger in fighters with CV. This study also assessed the association of head trauma with processing speed, which is a measure of the time needed to complete mental tasks that involve comprehension of an instruction and the subsequent reaction; this measure includes components of visual, auditory, and motor functions. The tasks comprised in processing speed involve multiple brain networks. Thus, reduced processing speed may reflect a global disruption such as widespread disturbance of white matter tracts,46,47 as might be seen with repetitive head trauma in fighters.43,48 For instance, decreased processing speed has been associated with a history of multiple concussions.49 However, these associations may be nonlinear, and certain thresholds of volume loss may be necessary to affect cognitive measures; this would account for our finding that presence of CV and increased CSPV length were associated with decreased psychomotor and processing speeds, whereas presence of CSP was not.
In this analysis, mood and behavioral measures were not associated with structural changes. Perhaps cognitive domains are more likely to be affected by cumulative head trauma, or perhaps these domains are more easily measured in the setting of cumulative trauma. In addition, a limited set of mood measures was used in this study; these factors can be difficult to assess accurately as they are self-reported and can vary over time.
Our follow-up analysis also did not demonstrate an association between increased CSPV length and decreased intracranial volumes or cognitive measures; the reasons for this result are unclear. Perhaps the length of follow-up was not sufficient or the degree of change in CSPV length was too small to discern associated changes in regional volumes or cognitive scores. In addition, several fighters demonstrated decreases in CSPV length during follow-up; again, the reasons for this finding are unclear. Longer-term follow-up with this cohort may help to elucidate these results.
Finally, in the separate subanalysis we performed to assess differences between retired fighters and active fighters, some of the associations we observed in our primary analysis were nullified. However, separating the fighters in this way underpowered both groups because of the small number of retired fighters in the study. In addition, the retired fighter group was significantly different from the active fighter group in terms of age and fighting exposure.
This study had several important strengths. A large cohort of well-characterized fighters was included in this analysis. In addition, all fighters underwent imaging on the same magnetic resonance imaging machine, with images reviewed by several expert neuroradiologists with many years of experience. Furthermore, there will be continued follow-up of this cohort to document further changes in imaging findings or alterations in cognitive and mood assessments.
Quiz Ref IDThis study also had several limitations. Because this was primarily a cross-sectional study, causality could not be ascertained. Moreover, it would be premature to suggest that the presence or increased size of CV is an indicator of a specific pathologic process such as chronic traumatic encephalopathy; there is no way to know whether any individuals in the cohort harbored pathologic characteristics of chronic traumatic encephalopathy. Fighters were also self-selected, which may have introduced bias. Finally, the computerized neuropsychiatric tests used in this study are limited in scope and may be influenced by the effort of the participant.
Repetitive traumatic injury in fighters with the imaging findings of CV and increased CSPV length is associated with decreased volumes of various brain structures and impaired cognitive measures. When CSP and CV are identified on routine clinical imaging in fighters, they can be viewed as a risk factor for clinical traumatic brain injury and may warrant further clinical analysis. Continued follow-up in this cohort will be important to evaluate longer-term changes and to determine whether the pathologic process of chronic traumatic encephalopathy will become evident.
Accepted for Publication: May 30, 2019.
Corresponding Author: Jonathan K. Lee, MD, Imaging Institute, Cleveland Clinic, 9500 Euclid Ave, Ste L10, Cleveland, OH 44195 (email@example.com).
Published Online: September 9, 2019. doi:10.1001/jamaneurol.2019.2861
Author Contributions: Dr Lee had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lee, Wu, Banks, Bernick, Modic, Jones.
Acquisition, analysis, or interpretation of data: Lee, Wu, Bullen, Banks, Bernick, Ruggieri, Bennett, Jones.
Drafting of the manuscript: Lee, Wu, Bullen, Banks, Ruggieri, Jones.
Critical revision of the manuscript for important intellectual content: Lee, Wu, Banks, Bernick, Modic, Bennett, Jones.
Statistical analysis: Bullen, Bennett.
Obtained funding: Bernick.
Administrative, technical, or material support: Lee, Wu, Bernick, Ruggieri, Bennett, Jones.
Supervision: Banks, Modic, Jones.
Conflict of Interest Disclosures: Dr Lee reported receiving grants from Lincy Foundation, Ultimate Fighting Championship, Spike TV/Bellator MMA, Top Rank Promotions, Golden Boy Promotions, August Rapone Family Foundation, and Haymon Boxing during the conduct of the study. Dr Bernick reported receiving grants from Ultimate Fighting Championship and Bellator/Spike TV during the conduct of the study and personal fees from Allergan outside the submitted work. No other disclosures were reported.
Funding/Support: This work was funded by the Lincy Foundation, Ultimate Fighting Championship, Spike TV/Bellator MMA, Top Rank Promotions, Golden Boy Promotions, August Rapone Family Foundation, and Haymon Boxing.
Role of the Funder/Sponsor: The funding sources did support collection of the data; however, they were not involved in the design or conduct of the study; the management, analysis, or interpretation of the data; the preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.
Meeting Presentation: This study was presented at the 56th Annual Meeting of the American Society of Neuroradiology; June 5, 2018; Vancouver, British Columbia, Canada.
Additional Contributions: Megan Griffiths, ELS, Imaging Institute, Cleveland Clinic, edited the manuscript. She was not compensated for her contribution.