Association between resistance to cerebrospinal fluid flow and cardiac-induced brain tissue motion for Chiari malformation type I.

PURPOSE: Chiari malformation type I (CMI) patients have been independently shown to have both increased resistance to cerebrospinal fluid (CSF) flow in the cervical spinal canal and greater cardiac-induced neural tissue motion compared to healthy controls. The goal of this paper is to determine if a relationship exists between CSF flow resistance and brain tissue motion in CMI subjects. METHODS: Computational fluid dynamics (CFD) techniques were employed to compute integrated longitudinal impedance (ILI) as a measure of unsteady resistance to CSF flow in the cervical spinal canal in thirty-two CMI subjects and eighteen healthy controls. Neural tissue motion during the cardiac cycle was assessed using displacement encoding with stimulated echoes (DENSE) magnetic resonance imaging (MRI) technique. RESULTS: The results demonstrate a positive correlation between resistance to CSF flow and the maximum displacement of the cerebellum for CMI subjects (r = 0.75, p = 6.77 × 10-10) but not for healthy controls. No correlation was found between CSF flow resistance and maximum displacement in the brainstem for CMI or healthy subjects. The magnitude of resistance to CSF flow and maximum cardiac-induced brain tissue motion were not statistically different for CMI subjects with and without the presence of five CMI symptoms: imbalance, vertigo, swallowing difficulties, nausea or vomiting, and hoarseness. CONCLUSION: This study establishes a relationship between CSF flow resistance in the cervical spinal canal and cardiac-induced brain tissue motion in the cerebellum for CMI subjects. Further research is necessary to understand the importance of resistance and brain tissue motion in the symptomatology of CMI.

The Relationship Between Imbalance Symptom and Cardiac Pulsation Induced Mechanical Strain in the Brainstem and Cerebellum for Chiari Malformation Type I.

Chiari malformation Type I (CMI) is known to have an altered biomechanical environment for the brainstem and cerebellum; however, it is unclear whether these altered biomechanics play a role in the development of CMI symptoms. We hypothesized that CMI subjects have a higher cardiac-induced strain in specific neurological tracts pertaining to balance, and postural control. We measured displacement over the cardiac cycle using displacement encoding with stimulated echoes magnetic resonance imaging in the cerebellum, brainstem, and spinal cord in 37 CMI subjects and 25 controls. Based on these measurements, we computed strain, translation, and rotation in tracts related to balance. The global strain on all tracts was small (<1%) for CMI subject and controls. Strain was found to be nearly doubled in three tracts for CMI subjects compared to controls (p < 0.03). The maximum translation and rotation were ∼150 µm and ∼1 deg, respectively and 1.5-2 times greater in CMI compared to controls in four tracts (p < 0.005). There was no significant difference between strain, translation, and rotation on the analyzed tracts in CMI subjects with imbalance compared to those without imbalance. A moderate correlation was found between cerebellar tonsillar position and strain on three tracts. The lack of statistically significant difference between strain in CMI subjects with and without imbalance could imply that the magnitude of the observed cardiac-induced strain was too small to cause substantial damage to the tissue (<1%). Activities such as coughing, or Valsalva may produce a greater strain.

Imaging and health metrics in incidental cerebellar tonsillar ectopia: findings from the Adolescent Brain Cognitive Development Study (ABCD).

PURPOSE: Incidental cerebellar tonsillar ectopia (ICTE) that meets the radiographic criterion for Chiari malformation type I (CMI) is an increasingly common finding in the clinical setting, but its significance is unclear. The present study examined posterior cranial fossa (PCF) morphometrics and a broad range of health instruments of pediatric ICTE cases and matched controls extracted from the Adolescent Brain Cognitive Development (ABCD) dataset. METHODS: One-hundred-six subjects with ICTE and 106 matched controls without ICTE were identified from 11,411 anatomical MRI of healthy screened pediatric subjects from the ABCD project. Subjects were matched by sex, age, body mass index, race, and ethnicity. Twenty-two brain morphometrics and 22 health instruments were compared between the two groups to identify unrecognized CMI symptoms and assess the general health impact of ICTE. RESULTS: Twelve and 15 measures were significantly different between the ICTE and control groups for females and males, respectively. Notably, for females, the anterior CSF space was significantly smaller (p = 0.00005) for the ICTE group than controls. For males, the clivus bone length was significantly shorter (p = 0.0002) for the ICTE group compared to controls. No significant differences were found among the 22 health instruments between the two groups. CONCLUSION: This study demonstrated that pediatric ICTE subjects have similar PCF morphometrics to adult CMI. ICTE alone did not appear to cause any unrecognized CMI symptoms and had no impact on the subjects' current mental, physical, or behavioral health. Still, given their cranial and brain morphology, these cases may be at risk for adult-onset symptomatic CMI.

Association Between Resistance to Cerebrospinal Fluid Flow Near the Foramen Magnum and Cough-Associated Headache in Adult Chiari Malformation Type I.

Cough-associated headaches (CAHs) are thought to be distinctive for Chiari malformation type I (CMI) patients and have been shown to be related to the motion of cerebrospinal fluid (CSF) near the foramen magnum (FM). We used computational fluid dynamics (CFD) to compute patient-specific resistance to CSF motion in the spinal canal for CMI patients to determine its accuracy in predicting CAH. Fifty-one symptomatic CMI patients with cerebellar tonsillar position (CTP) ≥ 5 mm were included in this study. The patients were divided into two groups based on their symptoms (CAH and non-CAH) by review of the neurosurgical records. CFD was utilized to simulate CSF motion, and the integrated longitudinal impedance (ILI) was calculated for all patients. A receiver operating characteristic (ROC) curve was evaluated for its accuracy in predicting CAH. The ILI for CMI patients with CAH (776 dyn/cm5, 288-1444 dyn/cm5; median, interquartile range) was significantly larger compared to non-CAH (285 dyn/cm5, 187-450 dyn/cm5; p = 0.001). The ILI was more accurate in predicting CAH in CMI patients than the CTP when the comparison was made using the area under the ROC curve (AUC) (0.77 and 0.70, for ILI and CTP, respectively). ILI ≥ 750 dyn/cm5 had a sensitivity of 50% and a specificity of 95% in predicting CAH. ILI is a parameter that is used to assess CSF blockage in the spinal canal and can predict patients with and without CAH with greater accuracy than CTP.

Clivus length distinguishes between asymptomatic healthy controls and symptomatic adult women with Chiari malformation type I.

PURPOSE: While the presence of cerebellar tonsillar descent in radiological images has been used as evidence of Chiari malformation type I (CMI), tonsillar ectopia alone is insufficient to identify individuals with symptomatic CMI. This study sought to identify differences in brain morphology between symptomatic CMI and healthy controls in adult females. METHODS: Two hundred and ten adult females with symptomatic CMI and 90 age- and body mass index-matched asymptomatic female controls were compared using seven brain morphometric measures visible on magnetic resonance images. The CMI and control groups were divided into four subgroups based on the tonsillar position (TP) relative to the foramen magnum: group 1 was made up of healthy controls with normal TP (TP < 0 mm); group 2 was comprised of control individuals with low-lying TP (1-5 mm); group 3 was comprised of symptomatic CMI patients with low-lying TP (1-5 mm); group 4 contained symptomatic CMI patients with severe tonsillar descent (6-13 mm). RESULTS: All morphometrics for symptomatic CMI with severe tonsillar descent were significantly different than those for both control groups. The CMI group with low-lying TP was significantly different for four measures when compared to controls with normal TP. However, only clivus length was statistically different between the CMI and healthy control groups with low-lying TP. CONCLUSION: This study demonstrates that clivus length distinguishes adult female healthy individuals with low-lying tonsils from those with symptomatic CMI. Further investigation is required to understand the importance of a shorter clivus length on CMI symptomatology and pathophysiology.

Transient Decrease in Cerebrospinal Fluid Motion is Related to Cough-Associated Headache in Chiari I Malformation (Original Research Article).

INTRODUCTION: Short-lasting cough-associated Headache (CAH) in patients with Chiari I Malformation (CMI) is believed to be due to transient worsening of CSF flow obstruction at the foramen magnum. We assessed changes in CSF flow in response to coughing in CMI patients with CAH and compared to those without CAH and healthy participants (HP) using real-time MRI. MATERIALS AND METHODS: Seventeen CMI patients (12 with CAH, 5 without CAH) and 6 HP were prospectively assessed using real-time pencil-beam imaging (PBI) MR sequence. A 64-mm length PBI cylinder was placed at the cranio-cervical junction. CSF stroke volume (SVCSF) was assessed during resting, post-coughing and relaxation phases via a 90-second scan. SVCSF was measured at six levels at 5-mm intervals between 10 and 35 mm below the foramen magnum. During each phase, SVCSF was compared between CMI with and without CAH and HP and corrected for multiple comparisons. RESULTS: At multiple consecutive levels, post-coughing SVCSF was significantly lower in CMI with CAH compared to both CMI without CAH and HP (p <0.05). No differences in post-coughing SVCSF were seen between CMI without CAH and HP. At rest or relaxation phase, no differences in SVCSF were seen between patients with and without CAH but minimal differences were seen between CMI with CAH and HP. CONCLUSIONS: A decrease in CSF flow after coughing in CMI patients with CAH supports the notion that CAH is caused by transient worsening of CSF flow obstruction at the foramen magnum.

Measuring Heart Rate Accurately in Patients With Parkinson Disease During Intense Exercise: Usability Study of Fitbit Charge 4.

BACKGROUND: Parkinson disease (PD) is the second most common neurodegenerative disease, affecting approximately 1% of the world's population. Increasing evidence suggests that aerobic physical exercise can be beneficial in mitigating both motor and nonmotor symptoms of the disease. In a recent pilot study of the role of exercise on PD, we sought to confirm exercise intensity by monitoring heart rate (HR). For this purpose, we asked participants to wear a chest strap HR monitor (Polar Electro Oy) and the Fitbit Charge 4 (Fitbit Inc) wrist-worn HR monitor as a potential proxy due to its convenience. Polar H10 has been shown to provide highly accurate R-R interval measurements. Therefore, we treated it as the gold standard in this study. It has been shown that Fitbit Charge 4 has comparable accuracy to Polar H10 in healthy participants. It has yet to be determined if the Fitbit is as accurate as Polar H10 in patients with PD during rest and exercise. OBJECTIVE: This study aimed to compare Fitbit Charge 4 to Polar H10 for monitoring HR in patients with PD at rest and during an intensive exercise program. METHODS: A total of 596 exercise sessions from 11 (6 male and 5 female) participants were collected simultaneously with both devices. Patients with early-stage PD (Hoehn and Yahr ≤2) were enrolled in a 6-month exercise program designed for patients with PD. They participated in 3 one-hour exercise sessions per week. They wore both Fitbit and Polar H10 during each session. Sessions included rest, warm-up, intense exercise, and cool-down periods. We calculated the bias in the HR of the Fitbit Charge 4 at rest (5 min) and during intense exercise (20 min) by comparing the mean HR during each of the periods to the respective means measured by Polar H10 (HRFitbit - HRPolar). We also measured the sensitivity and specificity of Fitbit Charge 4 to detect average HRs that exceed the threshold for intensive exercise, defined as 70% of an individual's theoretical maximum HR. Different types of correlations between the 2 devices were investigated. RESULTS: The mean bias was 1.68 beats per minute (bpm) at rest and 6.29 bpm during high-intensity exercise, with an overestimation by Fitbit Charge 4 in both conditions. The mean bias of the Fitbit across both rest and intensive exercise periods was 3.98 bpm. The device's sensitivity in identifying high-intensity exercise sessions was 97.14%. The correlation between the 2 devices was nonlinear, suggesting Fitbit's tendency to saturate at high values of HR. CONCLUSIONS: The performance of Fitbit Charge 4 is comparable to Polar H10 for assessing exercise intensity in a cohort of patients with PD (mean bias 3.98 bpm). The device could be considered a reasonable surrogate for more cumbersome chest-worn devices in future studies of clinical cohorts.

Prospective, Longitudinal Study of Clinical Outcome and Morphometric Posterior Fossa Changes after Craniocervical Decompression for Symptomatic Chiari I Malformation.

BACKGROUND AND PURPOSE: The time course of changes in posterior fossa morphology, quality of life, and neurologic function of patients with Chiari I malformation after craniocervical decompression requires further elaboration. To better understand the pace of these changes, we longitudinally studied patients with Chiari I malformation, with or without syringomyelia, before and after the operation for up to 5 years. MATERIALS AND METHODS: Thirty-eight symptomatic adult patients (35 women, 3 men) diagnosed with Chiari I malformation only (n = 15) or Chiari I malformation and syringomyelia (n = 23) and without previous Chiari I malformation surgery were enrolled in a clinical study. Patients underwent outpatient study visits and MR imaging at 7 time points (ie, initial [before the operation], 3 months, 1 year, 2 years, 3 years, 4 years, and 5 years) during 5 years. The surgical procedure for all patients was suboccipital craniectomy, C1 laminectomy, and autologous duraplasty. RESULTS: Morphometric measurements demonstrated an enlargement of the CSF areas posterior to the cerebellar tonsils after the operation, which remained largely stable through the following years. There was a decrease in pain and improved quality of life after the operation, which remained steady during the following years. Reduction in pain and improved quality of life correlated with CSF area morphometrics. CONCLUSIONS: Most changes in MR imaging morphometrics and quality of life measures occurred within the first year after the operation. A 1-year follow-up period after Chiari I malformation surgery is usually sufficient for evaluating surgical efficacy and postoperative MR imaging changes.

Audiovestibular Findings in a Cohort of Patients with Chiari Malformation Type I and Dizziness.

Chiari Malformation Type I (CM1) is a neurological condition in which the cerebellar tonsils extend past the foramen magnum. While many studies have reported dizziness symptoms in patients with CM1, the prevalence of peripheral labyrinthine lesions is largely unknown. This study aimed to comprehensively describe the audiovestibular phenotype in a cohort of patients with CM1 expressly referred for dizziness. Twenty-four patients with CM1 and a complaint of dizziness/vertigo were evaluated. Hearing and auditory brainstem tract function were essentially normal. While vestibular abnormalities were most prevalent during rotational testing (33%), abnormal functional balance was the most common finding (40%). Patients with CM1 had a greater likelihood of exhibiting an abnormal sensory organization test (SOT) postural stability score for fixed platform conditions, and for the somatosensory analysis score. While no significant associations were identified between tonsillar ectopia extent and any vestibular/balance outcome measure, a significant negative association was identified between neck pain and the somatosensory sensory analysis score. Abnormal functional balance in the somatosensory domain was remarkable, with poorer scores associated with neck pain. An isolated peripheral vestibulopathy was present in only 8% of patients. Despite the low prevalence of vestibulopathy, vestibular/balance assessment is warranted to identify patients who may benefit from referral to specialized medical disciplines.

SLIC-Occ: functional segmentation of occupancy images improves precision of EC50 images.

BACKGROUND: Drug occupancy studies with positron emission tomography imaging are used routinely in early phase drug development trials. Recently, our group introduced the Lassen Plot Filter, an extended version of the standard Lassen plot to estimate voxel-level occupancy images. Occupancy images can be used to create an EC50 image by applying an Emax model at each voxel. Our goal was to apply functional clustering of occupancy images via a clustering algorithm and produce a more precise EC50 image while maintaining accuracy. METHOD: A digital brain phantom was used to create 10 occupancy images (corresponding to 10 different plasma concentrations of drug) that correspond to a ground truth EC50 image containing two bilateral local "hot spots" of high EC50 (region-1: 25; region-2: 50; background: 6-10 ng/mL). Maximum occupancy was specified as 0.85. An established noise model was applied to the simulated occupancy images and the images were smoothed. Simple Linear Iterative Clustering, an existing k-means clustering algorithm, was modified to segment a series of occupancy images into K clusters (which we call "SLIC-Occ"). EC50 images were estimated by nonlinear estimation at each cluster (post SLIC-Occ) and voxel (no clustering). Coefficient of variation images were estimated at each cluster and voxel, respectively. The same process was also applied to human occupancy data produced for a previously published study. RESULTS: Variability in EC50 estimates was reduced by more than 80% in the phantom data after application of SLIC-Occ to occupancy images with only minimal loss of accuracy. A similar, but more modest improvement was achieved in variability when SLIC-Occ was applied to human occupancy images. CONCLUSIONS: Our results suggest that functional segmentation of occupancy images via SLIC-Occ could produce more precise EC50 images and improve our ability to identify local "hot spots" of high effective affinity of a drug for its target(s).

Diagnostic utility of parasagittal measurements of tonsillar herniation in Chiari I malformation.

BACKGROUND AND PURPOSE: Although the cerebellar tonsils are parasagittal structures, the extent of tonsillar herniation (ETH) in Chiari I malformation (CMI) is currently measured in the midsagittal plane. We measured the ETH of each cerebellar tonsil in the parasagittal plane and assessed their diagnostic utility by comparing them to the midsagittal ETH measurements in predicting cough-associated headache (CAH), an indicator of clinically significant disease in CMI. METHODS: Eighty-five CMI patients with 3D-MPRAGE images were included. Neurosurgeons determined the presence of CAH. Sagittal images were used to measure ETH in the midsagittal (MS_ETH) and parasagittal planes (by locating tonsillar tips on each side on reformatted coronal images). Given the parasagittal ETH (PS_ETH) asymmetry in the majority of cases, they were considered Smaller_PS_ETH or Larger_PS_ETH. The accuracy of ETH measurements was assessed by the receiver operating characteristic (ROC) curve. RESULTS: Of 85 patients, 46 reported CAH. ROC analysis showed an area under the curve (AUC) of 0.78 for Smaller_PS_ETH significantly better than 0.65 for MS-ETH in predicting CAH (p = 0.001). An AUC of 0.68 for Larger_PS_ETH was not significantly different from MS_ETH. The sensitivity and specificity of predicting CAH were 87% and 28% for MS_ETH >6 mm versus 90% and 46% for Smaller_PS_ETH >6 mm, and 52% and 67% for MS_ETH >9 mm versus 48% and 87% for Smaller_PS_ETH >9 mm. At ETH >15 mm, no differences were seen between the measurements. CONCLUSIONS: Diagnostic utility of ETH measurements in detecting clinically significant CMI can be improved by parasagittal measurements of the cerebellar tonsillar herniation.

A new hypothesis for the pathophysiology of symptomatic adult Chiari malformation Type I.

Chiari malformation Type I (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum. The pathophysiology of CMI is not well elucidated; however, the prevailing theory focuses on the underdevelopment of the posterior cranial fossa which results in tonsillar herniation. Symptoms are believed to be due to the herniation causing resistance to the natural flow of cerebrospinal fluid (CSF) and exerting a mass effect on nearby neural tissue. However, asymptomatic cases vastly outnumber symptomatic ones and it is not known why some people become symptomatic. Recently, it has been proposed that CMI symptoms are primarily due to instability of either the atlanto-axial (AA) or the atlanto-occipital (AO) joint and the cerebellar tonsils herniate to prevent mechanical pinching. However, only a small percentage of patients exhibit clinical instability and these theories do not account for asymptomatic herniations. We propose that the pathophysiology of adult CMI involves a combination of craniocervical abnormalities which leads to tonsillar herniation and reduced compliance of the cervical spinal canal. Specifically, abnormal AO and/or AA joint morphology leads to chronic cervical instability, often subclinical, in a large portion of CMI patients. This in turn causes overwork of the suboccipital muscles as they try to compensate for the instability. Over time, the repeated, involuntary activation of these muscles leads to mechanical overload of the myodural bridge complex, altering the mechanical properties of the dura it merges with. As a result, the dura becomes stiffer, reducing the overall compliance of the cervical region. This lower compliance, combined with CSF resistance at the same level, leads to intracranial pressure peaks during the cardiac cycle (pulse pressure) that are amplified during activities such as coughing, sneezing, and physical exertion. This increase in pulse pressure reduces the compliance of the cervical subarachnoid space which increases the CSF wave speed in the spinal canal, and further increases pulse pressure in a feedback loop. Finally, the abnormal pressure environment induces greater neural tissue motion and strain, causing microstructural damage to the cerebellum, brainstem, and cervical spinal cord, and leading to symptoms. This hypothesis explains how the combination of craniocervical bony abnormalities, anatomic CSF restriction, and reduced compliance leads to symptoms in adult CMI.

Quantification of Cerebellar Crowding in Type I Chiari Malformation.

This study was focused on a semi-automated morphometric analysis of the cerebellum in the mid-sagittal plane as an alternative to tonsillar descent alone in the evaluation of Chiari malformation type 1 (CMI) patients. Morphometric analyses of posterior fossa structures were performed on mid-sagittal MRI images of 375 individuals (females, > 18 years, 235 CMI and 140 healthy controls). Twenty-six parameters including linear, angular and area measurements together with non-dimensional ratios were calculated. Eighteen parameters were found to be significantly different between CMI and control subjects. Smaller posterior cranial fossa (PCF) area in CMI subjects was attributed to a smaller PCF area anterior to the brainstem. The cerebellar area was found to be larger in CMI subjects as compared to controls (15.1%), even without inclusion of the tonsillar area below the foramen magnum (FM) (8.4%). The larger cerebellar area in CMI subjects was due to cranial-caudal elongation of the cerebellum, predominately below the fastigium. The cerebrospinal fluid spaces below the FM were smaller in CMI subjects as compared to controls. Overall, greater cerebellar crowding was identified in CMI subjects relative to healthy controls. These observations may improve our understanding of the pathophysiology of CMI in adult female patients.