Bone biochemistry in children with fractures presenting with non-accidental injury.

BACKGROUND: In cases of fractures in children with suspicion of non-accidental injury (NAI), biochemical markers of calcium homeostasis should be performed. OBJECTIVES: To describe the pattern of biochemistry in children with fractures NAI is suspected. PARTICIPANTS AND SETTING: Children ≤2 years of age who had undergone a skeletal survey as part of a child protection investigation where 1/+ fracture was identified over a ten-year period (2012-2021) at the Royal Hospital for Children, Glasgow. METHODS: A retrospective review of case notes was conducted. Established criteria to classify NAI were used to distinguish confirmed NAI from non-NAI. Biochemical markers of calcium homeostasis were classified as normal or abnormal using local reference ranges. Vitamin D deficiency was classified as Vitamin D < 25 nmol/L and insufficiency as 25-50 nmol/L. RESULTS: One hundred and twenty-seven children were identified, of whom 107 (84 %) had bone biochemistry performed. Twenty-nine children (24 %) had injuries that were classified as confirmed NAI. In cases where NAI was confirmed either at case conference or by criminal conviction 14/29 (48 %) had one or more abnormal bone biochemical markers. None of the children displayed clinical or radiological evidence of rickets. Alkaline phosphatase (ALP) was higher in children with confirmed NAI (median 296 vs. 261, p = 0.01) but there were no other statistically significant differences in biochemical levels between those with confirmed NAI compared to those without. Those with confirmed NAI were from areas with lower SIMD score (2.0 vs. 3.0 p = 0.01) but no other differences were found between the groups. CONCLUSION: No clear predictors of NAI are demonstrated on biochemistry alone in young children with fractures.

Relationship of Morphometrics and Symptom Severity in Female Type I Chiari Malformation Patients with Biological Resilience.

In the present study we report the relationship among MRI-based skull and cervical spine morphometric measures as well as symptom severity (disability-as measured by Oswestry Head and Neck Pain Scale and social isolation-as measured by the UCLA Loneliness scale) on biomarkers of allostatic load using estrogen, interleukin-6, C-reactive protein, and cortisol in a sample of 46 CMI patients. Correlational analyses showed that McRae line length was negatively associated with interleukin-6 and C-reactive protein levels, and Analysis of Variance (ANOVA) showed joint effects of morphometric measures (McRae line length, anterior CSF space) and symptom severity (disability and loneliness) on estrogen and intereukin-6 levels. These results are consistent with allostatic load. That is, when the combination of CSF crowding and self-report symptom (disability and loneliness) severity exceed the capacity of biological resilience factors, then biomarkers such as neuroprotective estrogen levels drop, rather than rise, with increasing symptom severity.

Posterior Tibial Slope in Anterior Cruciate Ligament Surgery: A Systematic Review.

Background: While the literature suggests a correlation between posterior tibial slope and sagittal stability of the knee, there is a lack of consensus relating to how to measure the slope, what a normal slope value would be, and which critical values should guide extra surgical treatment. We performed a systematic literature review looking at the posterior tibial slope and cruciate ligament surgery. Our aims were to define a gold standard measurement technique of posterior tibial slope, as well as determining its normal range and the important values for consideration of adjuncts during cruciate ligament surgery. Methods: Electronic searches of MEDLINE (PubMed), CINAHL, Cochrane, Embase, ScienceDirect, and NICE in June 2020 were completed. Inclusion criteria were original studies in peer-reviewed English language journals. A quality assessment of included studies was completed using the Methodological Index for Non-Randomized Studies (MINORS) Criteria. Results: Two-hundred and twenty-one papers were identified; following exclusions 34 papers were included for data collection. The mean MINORS score was 13.8 for non-comparative studies and 20.4 for comparative studies, both indicating fair to good quality studies. A large variation in the posterior tibial slope measurement technique was identified, resulting in a wide range of values reported. A significant variation in slope value also existed between different races, ages and genders. Conclusion: Cautiously, the authors suggest a normal range of 6-12º, using the proximal tibial axis at 5 and 15 cms below the joint. We suggest 12º as a cut-off value for slope-reducing osteotomy as an adjunct to revision ligament reconstruction.

Shear's role in non-union. Measuring mean angle of long bone multi-fragmentary non-unions.

INTRODUCTION: Both mechanical and biological theories have been proposed in the development of non-union. The mechanical theory suggests that a high strain environment in a fracture will predispose it to non-union. While in simple fractures and wedge fractures there are only one and two primary fracture planes respectively, in multi-fragmentary fractures there are many and a non-union may form along any of the original fracture lines, however the plane which experiences the highest strain is at 45O - the shear plane. We hypothesise that in multi-fragmentary fractures the initial fracture line that most often fails to unite will tend towards the plane with the highest strain. OBJECTIVES: 1) Define the mean non-union angle in a cohort of multi-fragmentary tibial and femoral fractures. 2) In wedge-like fractures within the cohort, define and compare the mean angle of initial fracture planes which go on to form a non-union to those that unite 3) In comminuted fractures within the cohort, define the mean non-union angle DESIGN: Retrospective cohort study SETTING: Level-1 trauma centre METHODOLOGY: Fractures were categorised into wedge-like and comminuted. A published technique was utilised to measure fracture and non-union angles. In wedge-like fractures, united and non-united initial planes were compared. In comminuted fractures only the mean non-union angle was defined. Demographic patient data was also collected. RESULTS: 183 non-unions were screened, 68 patients were included. The mean non-union angle was 56°(SD 18) across all fractures. In wedge-like fractures the mean non-union angle was 59°(SD 18). In comminuted fractures the mean non-union angle was 50°(SD 19). Non-united initial fracture planes in wedge-like fractures showed a peaked distribution about a mean of 58° while united fracture planes were distributed at the extremities of the range. CONCLUSIONS: In patients with multi-fragmentary fractures resulting in non-union, the mean tibial non-union angle was 52° while the mean femoral non-union angle was 65°. In wedge-like fractures, non-unions occurred more commonly than appropriate union in fractures between 41°-80°. The non-union angle is closer to 45° in comminuted fractures than in wedge-like fractures. These results support the mechanical theory that strain from the shear plane is an important factor in the formation of non-unions. LEVEL OF EVIDENCE: Prognostic level 3.

A Wolf in Hiding: Epilepsy and Post-ictal Psychosis As Unrecognized Presenting Features of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems. Many patients present with neurological and psychiatric signs and symptoms at some point in the course of the disease. Here, we present a patient with neuropsychiatric SLE (NPSLE) who presented with long-standing and difficult-to-control epileptic seizures and post-ictal psychotic symptoms prior to the diagnosis of SLE. A 39-year-old patient with a ten-year history of uncontrolled epileptic seizures despite multiple medications and recent diagnosis of chronic kidney disease presented to the emergency department following multiple witnessed seizures. Her seizures were controlled following initial interventions and the patient was admitted to the hospital to control metabolic acidosis and hyperkalemia. Later, the patient developed psychosis with auditory hallucinations, combative behavior, and agitation which were controlled with restraints and sedatives. Initial serological and urinary studies revealed disturbances of multiple systems and triggered broad workup resulting in positive serological SLE markers. The patient was then started on immunosuppressive medications with prompt control of post-ictal psychosis. The patient was discharged with immunosuppressive regimen and control of her seizures. This case highlights that signs and symptoms of NPSLE may appear before the onset of SLE diagnosis. Additionally, our patient had long-standing epilepsy with post-ictal psychosis, which has not been reported in the literature before. We believe this case highlights the challenges in the diagnosis of NPSLE, the rapid control of seizures and/or psychosis with SLE treatment, and the necessity to broaden the differential diagnosis in atypical presentation of seizures and/or psychosis.

Influence of Pain on Cognitive Dysfunction and Emotion Dysregulation in Chiari Malformation Type I.

It has been well demonstrated that the cerebellum is associated with cognitive and affective processing as well as the traditionally conceptualized motor function. In the present chapter, we explore the behavioral and neurobiological implications of a common congenital cerebellar condition, Chiari malformation Type I, on cognitive and affective processing. We also emphasize the associations between Chiari-related chronic pain, cognitive dysfunction, and emotion dysregulation. Based on our review of the literature, we argue that chronic pain can account for a substantial amount of the cognitive dysfunction and emotion dysregulation in Chiari malformation Type I. Yet, there also exists aspects of Chiari-related cognitive dysfunction and emotion dysregulation that appear to be at least partially independent of chronic pain and more directly associated with abnormalities in cerebrospinal fluid flow dynamics and cerebro-cerebellar communication pathways.

Chasing the Cup: A Comprehensive Review of Spinal Cord Injuries in Hockey.

Ice hockey is a high-speed sport with a high rate of associated injury, including spinal cord injury (SCI). The incidence of hockey-related SCI has increased significantly in more recent years. A comprehensive literature search was conducted with the PubMed, Medline, Google Scholar, and Web of Science databases using the phrases "hockey AND spinal cord injuries" to identify relevant studies pertaining to hockey-related SCIs, equipment use, anatomy, and biomechanics of SCI, injury recognition, and return-to-play guidelines. Fifty-three abstracts and full texts were reviewed and included, ranging from 1983 to 2021. The proportion of catastrophic SCIs is high when compared to other sports. SCIs in hockey occur most commonly from a collision with the boards due to intentional contact resulting in axial compression, as well as flexion-related teardrop fractures that lead to spinal canal compromise and neurologic injury. Public awareness programs, improvements in equipment, and rule changes can all serve to minimize the risk of SCI. Hockey has a relatively high rate of associated SCIs occurring most commonly due to flexion-distraction injuries from intentional contact. Further investigation into equipment and hockey arena characteristics as well as future research into injury recognition and removal from and return to play is necessary.

The role of elastin on the mechanical properties of the anterior leaflet in porcine tricuspid valves.

Elastin is present in the extracellular matrix (ECM) of connective tissues, and its mechanical properties are well documented. In Marfan syndrome, however, the inability to properly code for the protein fibrillin-1 prematurely leads to the degradation and loss of elastin fiber integrity in the ECM. In this study, the role of elastin in the ECM of the anterior leaflet of the tricuspid valve was investigated by examining the biomechanical behavior of porcine leaflets before and after the application of the enzyme elastase. Five loading protocols were applied to the leaflet specimens in two groups (elastase-treated and control samples). The mechanical response following elastase application yielded a significantly stiffer material in both the radial and circumferential directions. At a physiological level of stress (85 kPa), the elastase group had an average strain of 26.21% and 6.32% in the radial and circumferential directions, respectively, at baseline prior to elastase application. Following elastase treatment, the average strain was 5.28% and 0.97% in the radial and circumferential directions, respectively. No statistically significant change was found in the control group following sham treatment with phosphate-buffered saline (PBS). Two-photon microscopy images confirmed that after the removal of elastin, the collagen fibers displayed a loss of undulation. With a significant reduction in radial compliance, the ability to withstand physiological loads may be compromised. As such, an extracellular matrix that is structurally deficient in elastin may hinder normal tricuspid valve function.

Adult Age Differences in Self-Reported Pain and Anterior CSF Space in Chiari Malformation.

Chiari malformation type I (CMI) is a neural disorder with sensory, cognitive, and motor defects, as well as headaches. Radiologically, the cerebellar tonsils extend below the foramen magnum. To date, the relationships among adult age, brain morphometry, surgical status, and symptom severity in CMI are unknown. The objective of this study was to better understand the relationships among these variables using causal modeling techniques. Adult CMI patients (80% female) who either had (n = 150) or had not (n = 151) undergone posterior fossa decompression surgery were assessed using morphometric measures derived from magnetic resonance images (MRI). MRI-based morphometry showed that the area of the CSF pocket anterior to the cervico-medullary junction (anterior CSF space) correlated with age at the time of MRI (r = - .21). Also, self-reported pain increased with age (r = .11) and decreased with anterior CSF space (r = - .18). Age differences in self-reported pain were mediated by anterior CSF space in the cervical spine area-and this effect was particularly salient for non-decompressed CMI patients. As CMI patients age, the anterior CSF space decreases, and this is associated with increased pain-especially for non-decompressed CMI patients. It is recommended that further consideration of age-related decreases in anterior CSF space in CMI patients be given in future research.

Radiation in orthopaedics (RIO) study: a national survey of UK orthopaedic surgeons.

OBJECTIVES: Orthopaedic surgeons have a responsibility to minimise risks of ionising radiation to patients, themselves and staff. This study aims to establish the understanding of radiation practice, legislation and risk by orthopaedic surgeons. METHODS: A nationwide online survey of UK-based orthopaedic surgeons was conducted. Participants answered 18 multiple-choice questions assessing level of radiation safety training, basic principles/knowledge of ionising radiation, relevant legislation and operating practice. RESULTS: A total of 406 surgeons completed the survey. 92% reported using intraoperative ionising radiation at least once per week. 38% received no formal training on radiation safety. Knowledge of basic principles of radiation and legislation was limited. There was variable knowledge when labelling an image intensifier machine and choosing its safest orientation. Poor uptake of radiation protection equipment was noted. Only 19% agreed they had adequate training in ionising radiation safety and 27% reported receiving adequate training in equipment emitting ionising radiation in the operating theatre. CONCLUSION: Many orthopaedic surgeons in the UK do not believe they are adequately trained in radiation safety. There is a deficiency amongst practicing surgeons in basic knowledge, relevant legislation and practicalities of the use of ionising radiation in the operating room. This could potentially put patients and health-care professionals at additional risk. We recommend that a standardised national training programme on the basic principles and safety of ionising radiation is implemented for all practicing orthopaedic surgeons. ADVANCES IN KNOWLEDGE: This paper is the first UK national survey amongst orthopaedic surgeons and is one of the largest reported internationally.

Functional connectivity abnormalities in Type I Chiari: associations with cognition and pain.

There is initial evidence of microstructural abnormalities in the fibre-tract pathways of the cerebellum and cerebrum of individuals diagnosed with Type I Chiari malformation. However, it is unclear whether abnormal white matter architecture and macro-level morphological deviations that have been observed in Chiari translate to differences in functional connectivity. Furthermore, common symptoms of Chiari include pain and cognitive deficits, but the relationship between these symptoms and functional connectivity has not been explored in this population. Eighteen Type I Chiari patients and 18 age-, sex- and education-matched controls underwent resting-state functional MRI to measure functional connectivity. Participants also completed a neuropsychological battery and completed self-report measures of chronic pain. Group differences in functional connectivity were identified. Subsequently, pathways of significant difference were re-analyzed after controlling for the effects of attention performance and self-reported chronic pain. Chiari patients exhibited functional hypoconnectivity between areas of the cerebellum and cerebrum. Controlling for attention eliminated all deficits with the exception of that from the posterior cerebellar pathway. Similarly, controlling for pain also eliminated deficits except for those from the posterior cerebellar pathway and vermis VII. Patterns of Chiari hyperconnectivity were also found between regions of the cerebellum and cerebrum in Chiari patients. Hyperconnectivity in all regions was eliminated after controlling for attention except between left lobule VIII and the left postcentral gyrus and between vermis IX and the precuneus. Similarly, hyperconnectivity was eliminated after controlling for pain except between the default mode network and globus pallidus, left lobule VIII and the left postcentral gyrus, and Vermis IX and the precuneus. Evidence of both hyper- and hypoconnectivity were identified in Chiari, which is posited to support the hypothesis that the effect of increased pain in Chiari draws on neural resources, requiring an upregulation in inhibitory control mechanisms and resulting in cognitive dysfunction. Areas of hypoconnectivity in Chiari patients also suggest disruption in functional pathways, and potential mechanisms are discussed.

Is the AO spine thoracolumbar injury classification system reliable and practical? a systematic review.

Controversy surrounding the classification of thoracolumbar injuries has given rise to various classification systems over the years, including the most recent AOSpine Thoracolumbar Injury Classification System (ATLICS). This systematic review aims to provide an up-to-date evaluation of the literature, including assessment of a further three studies not analysed in previous reviews. In doing so, this is the first systematic review to include the reliability among non-spine subspecialty professionals and to document the wide variety between reliability across studies, particularly with regard to sub-type classification. Relevant studies were found via a systematic search of PubMed, EBESCO, Cochrane and Web of Science. Data extraction and quality assessment were conducted in line with Cochrane Collaboration guidelines. Twelve articles assessing the reliability of ATLICS were included in this review. The overall inter-observer reliability varied from fair to substantial, but the three additional studies in this review, compared to previous reviews, presented on average only fair reliability. The greatest variation of results was seen in A1 and B3 subtypes. Least reliably classified on average was A4 subtype. This systematic review concludes that ATLICS is reliable for the majority of injuries, but the variability within subtypes suggests the need for further research in assessing the needs of users in order to increase familiarity with ATLICS or perhaps the necessity to include more subtype-specific criteria into the system. Further research is also recommended on the reliability of modifiers, neurological classification and the application of ATLICS in a paediatric context.

Reproducibility and reliability analysis of the Luk Distal Radius and Ulna Classification for European patients with adolescent idiopathic scoliosis.

PURPOSE: Current clinical and radiological methods of predicting a patient's growth potential are limited in terms of practicality, accuracy and known to differ in different races. This information influences optimal timing of bracing and surgical intervention in adolescent idiopathic scoliosis (AIS). The Luk classification was developed to mitigate limitations of existing tools. Few reliability studies are available and are limited to certain geographical regions with varying results. This study was performed to analyze reproducibility and reliability of the Luk Distal Radius and Ulna Classification in European patients. METHODS: This is a radiological study of 50 randomly selected left hand and wrist radiographs of patients with AIS referred to a tertiary referral centre. They were assessed for bone maturity using the Luk Distal Radius and Ulna Classification. Assessment was performed twice by four examiners at an interval of one month. Statistical analysis was performed using the intraclass correlation (ICC) method to determine the reliabilities within and between the examiners. RESULTS: In total, 50 radiographs (M:F = 13:37) with a mean age of 13.7 years (10 to 18) were assessed for reliability. The inter-rater ICC value was 0.918 for radius assessment and 0.939 for ulna assessment. The intra-rater ICC values for radius assessment ranged between 0.897 and 0.769 and between 0.948 and 0.786 for ulna assessment. There was near perfect correlation for both assessments. CONCLUSION: This study provides independent evidence that the Luk Distal Radius and Ulna Classification is a reliable tool for assessment of skeletal maturity for European patients. Minimal clinical experience is required to reliably utilize it. LEVEL OF EVIDENCE: IV.

The use of ionising radiation in orthopaedic surgery: principles, regulations and managing risk to surgeons and patients.

The use of ionising radiation for plain film radiography and computerised tomography is fundamental in both diagnostics and treatment for orthopaedics. However, radiation is not without risk as high exposure can increase the risk of cancer. Little time is spent educating doctors about the relative risks of radiation, both to patients and themselves. In addition, there are common misunderstandings about the best ways to mitigate such risk. We aim to provide an overview of the fundamental principles of the use of ionising radiation and its risks within the context of orthopaedic surgery. While providing a narrative review of the current literature, we discuss the basic physics, standards of good practice and relevant UK and European regulations. We discuss the risks to patients and surgeons and suggest ways that these can be mitigated in the operating theatre. A thorough understanding of the risks, and appropriate procedural rules, with respect to the use of ionising radiation is essential for those in orthopaedic practice.

Impact of Surgical Status, Loneliness, and Disability on Interleukin 6, C-Reactive Protein, Cortisol, and Estrogen in Females with Symptomatic Type I Chiari Malformation.

Chiari malformation type I (CMI) provides an opportunity for examining possible moderators of allostatic load. CMI patients who had (n = 43) and had not (n = 19) undergone decompression surgery completed questionnaires regarding pain, disability, and loneliness, and provided serum samples for IL-6, CRP, estrogen, and free estradiol assays, and saliva samples to assess diurnal cortisol curves. ANOVAs examining surgical status (decompressed versus non-decompressed), loneliness (high vs. low), and disability (high vs. low) as independent variables and biomarker variables as dependent factors found that loneliness was associated with higher levels of cortisol, F(1, 37) = 4.91, p = .04, η2P = .11, and lower levels of estrogen, F(1, 36) = 7.29, p = .01, η2P = .17, but only in decompressed patients. Results highlight the possible impact of loneliness on biological stress responses and the need to intervene to reduce loneliness in patients with symptomatic CMI.

A comparison of anterior knee pain, kneeling pain and functional outcomes in suprapatellar versus infrapatellar tibial nailing.

INTRODUCTION: Anterior knee pain and kneeling pain are some of the most common complications following intramedullary nailing of tibial shaft fractures. With the increased uptake of suprapatellar nailing at our institution, we undertook a service evaluation to assess anterior knee pain and kneeling pain in patients who underwent the suprapatellar tibial nailing technique compared with the infrapatellar approach. METHODOLOGY: Data from all consecutive intramedullary tibial nailing operations between January 2014 and July 2017 were analysed from a prospectively collected database. All acute diaphyseal fracture nailing procedures were included. All patients were reviewed between six-month and four-year post-operation. Each patient was asked to complete a standardised questionnaire with three main outcome measures: pain on kneeling, presence of anterior knee pain and the severity of pain. RESULTS: After exclusions, a total of 148 patients were identified. A total of 102 responses were received, 41 in the infrapatellar group (73.2%) and 61 in the suprapatellar group (66.3%). A longer time from surgery to telephone follow-up response was noted in the infrapatellar group: 32.4 months (interquartile range, 16.1) vs. 19.3 months (interquartile range, 17.4), p < 0.001. A trend towards lower reported anterior knee pain was noted in the suprapatellar group (67.9% VS 53.7%). Most patients reported mild or no pain on kneeling, with no significant difference between the two groups. There was also no significant difference in severity of knee pain between the two groups and no significant effect on the Kujala score. CONCLUSION: With the comparable pain outcomes between the two groups, our analysis supports the continued use of the suprapatellar tibial nailing technique for tibial shaft fractures at our institution.

Defining the Mean Angle of Diaphyseal Long Bone Nonunions-Does Shear Prevail?

OBJECTIVES: To define the mean angle of a series of diaphyseal nonunions based on radiographic analysis. DESIGN: A retrospective cohort study. SETTING: Two level-1 trauma centers. PATIENTS: One hundred twenty patients presenting with nonunion. INTERVENTION: A mean nonunion angle was calculated from a series of AP and lateral X-rays using a standardized technique. The nonunion angle was then estimated in a single plane by considering the greater of the 2 measured angles. Additional data collected included patient age, sex, nonunion site, initial fracture angle, and original fracture pattern. MAIN OUTCOME MEASUREMENT: Single plane nonunion angle. RESULTS: The mean angles of all nonunion in coronal plane was 42 degrees (SD 17 degrees) and 42 degrees in sagittal plane (SD 18 degrees) and 48 degrees (SD 15 degrees) in single plane. The single plane nonunion angle in fractures which were originally multiplanar was steeper to those occurring in originally single plane fractures (P 0.002) although both were close to 45 degrees. There was no significant difference in the nonunion angles on subgroup analysis of cohort location, sex, or anatomic location. CONCLUSIONS: This study demonstrates the mean angle of diaphyseal nonunions from long bones of the lower limb approaches 45 degrees. This is noted in all types of fractures and is irrespective of anatomic location or sex. This confirms the hypothesis that shear is likely to play a role in the development of a nonunion. This study provides further evidence that nonunions occur primarily because of mechanical instability. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

An Electrophysiological Study of Aging and Perceptual Letter-Matching.

Background: Previous studies on perceptual letter-matching have found that younger and older adults showed "fast-same" effects for response time and "false-different" effects for errors but the effects were more pronounced for older adults. According to the Noisy Operator Theory, internal noise in visual processing distorts "same" trials into appearing different whereas distortion for "different" trials does not affect performance. Older adults have a "noisier" representation of items within perceptual processing which can impact perceptual matching. However, EEG measures may provide a more direct measure of letter-matching decisions. Methods: We measured the P300 event-related potential (ERP) amplitude, an index of familiarity in stimulus categorization, and behavioral measures (response time and accuracy) to assess letter-matching performance. Results: Individuals responded faster to "same" trials than to "different" trials but were less accurate. Older adults showed similar P300 amplitudes across trial type whereas younger adults produced a larger amplitude for "same" than "different" trials, suggesting that older adults showed less familiarity for "same" trials than did younger adults - a prediction of the Noisy Operator Theory. Conclusions: These ERP results are consistent with the Noisy Operator Theory - suggesting that an age-related increase in internal noise affected letter-matching performance.

Cannabidiol normalizes resting-state functional connectivity in treatment-resistant epilepsy.

OBJECTIVE: Resting-state (rs) network dysfunction is a contributing factor to treatment resistance in epilepsy. In treatment-resistant epilepsy (TRE), pharmacological and nonpharmacological therapies have been shown to improve such dysfunction. In this study, our goal was to prospectively evaluate the effect of highly purified plant-derived cannabidiol (CBD; Epidiolex®) on rs functional magnetic resonance imaging (fMRI) functional connectivity (rs-FC). We hypothesized that CBD would change and potentially normalize the rs-FC in TRE. METHODS: Twenty-two of 27 participants with TRE completed all study procedures including longitudinal pre-/on-CBD rs-fMRI (8M/14F, mean age = 36.2 ±â€¯15.9 years, TRE duration = 18.3 ±â€¯12.6 years); there were no differences in age (p = 0.99) or sex (p = 0.15) between groups. Assessments collected included seizure frequency (SF), Chalfont Seizure Severity Scale (CSSS), Columbia Suicide Severity Rating Scale (C-SSRS), Adverse Events Profile (AEP), and Profile of Mood States (POMS). Twenty-three healthy controls (HCs) received rs-fMRI and POMS once. RESULTS: Participants with TRE showed average decrease of 71.7% in SF (p < 0.0001) and improved CSSS, AEP, and POMS confusion, depression, and fatigue subscores (all p < 0.05) on-CBD with POMS scores becoming similar to those of HCs. Paired t-tests showed significant pre-/on-CBD changes in rs-FC in cerebellum, frontal areas, temporal areas, hippocampus, and amygdala with some of them correlating with improvement in behavioral measures. Significant differences in rs-FC between pre-CBD and HCs were found in cerebellum, frontal, and occipital regions. After controlling for changes in SF with CBD, these differences were no longer present when comparing on-CBD to HCs. SIGNIFICANCE: This study indicates that highly purified CBD modulates and potentially normalizes rs-FC in the epileptic brain. This effect may underlie its efficacy. This study provides Class III evidence for CBD's normalizing effect on rs-FC in TRE.