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Prolonged survival of mice with established intracerebral glioma receiving combined treatment with peroxisome proliferator-activated receptor–γ thiazolidinedione agonists and interleukin-2–secreting syngeneic/allogeneic fibroblasts

Alessandra Spagnolo, Roberta P. Glick, Henry Lin, Edward P. Cohen, Douglas L. Feinstein, and Terry Lichtor

Object

In this study the authors explored the benefits of treating C57Bl/6 mice with an established intracerebral glioma by combining immunotherapy with interleukin (IL)-2–secreting syngeneic/allogeneic fibroblasts administered into the tumor bed along with the chemotherapeutic agent pioglitazone, a thiazolidinedione (TZD). The TZDs are agonists of the peroxisome proliferator-activated receptor–γ. They have been found to exert antiproliferative effects on several transformed cell lines. Data from prior studies by these authors have revealed the immunotherapeutic properties of the IL-2–secreting fibroblasts in treating intracerebral gliomas in mice.

Methods

The sensitivity of GL261 glioma cells and primary astrocytes to pioglitazone was determined in vitro by incubating the cells with increasing amounts of the drug. Viability was assessed by measuring lactate dehydrogenase release, and effects on metabolism were determined by measuring superoxide production and levels of superoxide dismutase. The GL261 cells were injected intracerebrally into C57Bl/6 mice, followed by treatment with pioglitazone either orally or intracerebrally into the tumor bed. The effect of the combined therapy was determined by injecting C57Bl/6 mice with an established intracerebral GL261 glioma with IL-2–secreting allogeneic fibroblasts and pioglitazone directly into the tumor bed through a unique cannula system.

Pioglitazone was found to induce cell death in GL261 glioma cells grown in vitro while causing only modest damage to astrocytes. The application of pioglitazone also resulted in a significantly greater induction of cellular superoxide in glioma cells than in astrocytes, which can activate apoptotic pathways. Pioglitazone administered intracerebrally (p < 0.05) but not orally was found to prolong survival in mice harboring an intracerebral glioma. Synergistic effects of combination therapy on prolonging survival were found in mice receiving both pioglitazone and IL-2–secreting fibroblasts (p < 0.005, compared with untreated animals). Pioglitazone induces metabolic and oxidative stresses that are tolerated by astrocytes but not glioma cells, which could account for selective vulnerability and increased sensitivity to IL-2, suggesting potential for the use of this Food and Drug Administration–approved drug in the treatment of brain tumors.

Conclusions

The data indicate the beneficial effects of combination therapy using pioglitazone and immunotherapy in mice harboring intracerebral glioma.

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Does recovery after sport-related concussion vary by time point in a season? A multi-sport investigation

Anthony E. Bishay, Kristen L. Williams, Jacob Jo, Samuel Fitch, Douglas P. Terry, and Scott L. Zuckerman

OBJECTIVE

Seasonality, or the specific point in time within a season in which the injury occurs, may have an impact on the recovery following sport-related concussions (SRCs). In a cohort of high school athletes across multiple sports, the authors sought to investigate the impact of seasonality on 1) concussion frequency, 2) acute symptom presentation (initial Post-Concussion Symptom Scale [PCSS] score), and 3) recovery outcomes, including the time to return to learn (RTL), symptom resolution (SR), and return to play (RTP).

METHODS

A retrospective, single-institution, cohort study was conducted with adolescent athletes aged 14–19 years who sustained an SRC between November 2017 and April 2022 and presented to a multidisciplinary specialty concussion clinic. The time from first practice to the end of the regular season was evenly trichotomized into early, middle, and late season. Teams that participated in the playoffs were included in a subanalysis. One-way ANOVA and independent t-tests were used to compare PCSS scores, RTL, SR, and RTP across seasonality. Univariable and multivariable regressions were used to determine predictors for recovery, defined as total days from initial visit to each outcome.

RESULTS

Of the 1504 eligible athletes, 620 high school athletes met inclusion criteria; 491 (79.2%) sustained a concussion during the regular season with 73 (14.9%), 136 (27.7%), and 282 (57.4%) concussions occurring in the early, middle, and late seasons, respectively. No differences were seen for initial PCSS score, RTL, SR, or RTP across early-, middle-, and late-season concussions. The initial PCSS score was significantly higher for playoff compared with regular-season concussions (playoffs: 33.4 ± 27.5; regular season: 23.3 ± 22.8; t = −1.979, p = 0.048). A subanalysis of playoff concussions (n = 24) compared with regular-season concussions showed that concussion in the playoffs was associated with a higher initial PCSS score in univariable (β = 0.093, p = 0.048) and multivariable (β = 0.112, p = 0.014) analyses.

CONCLUSIONS

The majority of concussions occurred during the late-season period. No difference in acute symptoms or recovery outcomes was seen when comparing the three regular season time points. Playoff concussions were associated with significantly increased symptom scores compared with nonplayoff concussions.

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Do academic accommodations help students recover following sport-related concussion? A retrospective study of 96 youth athletes

Grant H. Rigney, Jacob Jo, Carter Burns, Kristen L. Williams, Douglas P. Terry, and Scott L. Zuckerman

OBJECTIVE

Many schools utilize academic accommodations to help athletes return-to-learn after sport-related concussion, yet little is known about the impact of accommodations on recovery. In a cohort of adolescent athletes with sport-related concussion, the authors sought to 1) describe academic accommodations, 2) determine predictors of receiving accommodations, and 3) determine how accommodations influenced recovery, as defined by days to return-to-learn, symptom resolution, and return-to-play.

METHODS

A retrospective survey study was undertaken that included all athletes between the ages of 12 and 24 years who were seen at a regional sport-related concussion center from April 1, 2020, to April 1, 2022. Demographic characteristics, past medical history, injury characteristics, school-related factors, and recovery were collected via a telephone-based survey and from medical charts. The independent variable was the use of academic accommodations by students. The outcome variables included days to return-to-learn, symptom resolution, and return-to-play. Univariable and multivariable logistic regression analyses were performed.

RESULTS

Of 300 athletes contacted, 96 consented to participate in this study (mean age ± SD 16.6 ± 2.6 years, 60.4% male). The mean return-to-learn was 9.0 ± 13.2 days. In total, 63.5% of athletes received some kind of school accommodation. The most common accommodations included extra time on tests (46/96 [47.9%] athletes) and extra time for assignments (43/96 [44.8%]), whereas preferential seating in class (0/96 [0.0%]) and reduced workloads (4/96 [4.2%]) were the least commonly used accommodations. Multivariable logistic regression revealed that White race (OR 0.17, 95% CI 0.02–0.71, p = 0.03) and higher initial Post-Concussion Symptom Scale (PCSS) score (OR 1.04, 95% CI 1.01–1.07, p = 0.02) were predictive of receiving accommodations. Univariable models showed that receiving accommodations was not predictive of return-to-learn (β = 4.67, 95% CI −0.92 to 10.25, p = 0.10), symptom resolution (β = 24.71, 95% CI −17.41 to 66.83, p = 0.26), or return-to-play (β = 13.35, 95% CI −14.56 to 41.27, p = 0.35). Regarding other predictors of each outcome, several factors emerged irrespective of accommodations. Multivariable analysis revealed that longer time to return-to-learn was associated with a history of psychiatric illness (β = 8.00, 95% CI 1.71–14.29, p = 0.02) and initial PCSS score (β = 0.14, 95% CI 0.06–0.23, p < 0.01). Finally, predictors of days to return-to-play included school personnel who were knowledgeable of concussion (β = −5.07, 95% CI −9.93 to −0.21, p = 0.04) and higher initial PCSS score (β = 0.67, 95% CI 0.04–1.29, p = 0.03).

CONCLUSIONS

The most common accommodation was extra time on tests/assignments, whereas reduced workload was the least common. White race and greater initial PCSS score were associated with receiving accommodations. Receiving accommodations did not significantly impact days to return-to-learn, symptom resolution, or return-to-play.

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Use of acute cognitive symptom cluster to predict return-to-learn duration following a sport-related concussion

Alan R. Tang, Philip J. Davis, Kristen L. Williams, Alan Z. Grusky, Katherine S. Hajdu, Brian Q. Hou, Aaron M. Yengo-Kahn, Scott L. Zuckerman, and Douglas P. Terry

OBJECTIVE

Adolescents sustaining sport-related concussion often experience difficulties with the return-to-learn (RTL) process. Whereas the initial symptom burden has predicted prolonged RTL, no studies have established a relationship between acute cognitive symptoms and RTL duration. The authors sought to evaluate the relationship between initial cognitive symptoms and RTL duration.

METHODS

A retrospective single-institution cohort study of adolescent athletes aged 12–23 years who were evaluated within 5 days of a diagnosed sport-related concussion between November 2017 and October 2020 was conducted. Athletes missing cognitive symptom ratings and RTL data were excluded. The primary exposure variable was the Cognitive Symptom Ratio (CSR), defined as total cognitive symptom cluster score divided by total Post-Concussion Symptom Scale (PCSS) score from the initial clinic visit. Primary and secondary outcomes were time to RTL and total length of care, respectively. Multivariable Cox proportional hazards modeling was used to assess the effect of CSR on RTL duration.

RESULTS

Of 653 athletes evaluated within 5 days of injury, 346 patients were included in the final cohort. Athletes reported a median initial PCSS score of 21 (interquartile range [IQR] 6–37) and a median cognitive symptom score of 4 (IQR 0–9). Most patients endorsed some degree of difficulty concentrating (n = 212, 61.3%). The median CSR was 0.18 (IQR 0.00–0.27). On multivariable regression analysis, a higher CSR was associated with prolonged RTL duration (HR 0.30, 95% CI 0.13–0.69, p = 0.004). When initial PCSS score was added to the model, the previously significant association between CSR and RTL was no longer significant (HR 0.67, 95% CI 0.29–1.59, p = 0.367). When dichotomized based on frequency distribution, a higher proportion of patients with low CSR achieved RTL by 7 days postinjury (82.2% vs 69.9%, p = 0.007), a difference not seen at 14 days (92.2% vs 87.3%, p = 0.133).

CONCLUSIONS

An acute ratio of cognitive symptoms may predict patients at increased risk for prolonged RTL and those with normal PCSS scores who may experience difficulties once resuming school activities.

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Does earlier vestibular therapy after sport-related concussion lead to faster recovery?

Michael Zargari, Kristen Williams, Jacob Jo, Trevor J. Anesi, Olivia L. Prosak, Amad Amedy, Anthony E. Bishay, Scott L. Zuckerman, and Douglas P. Terry

OBJECTIVE

Many patients experience vestibular dysfunction following a sport-related concussion (SRC). Vestibular rehabilitation therapy has recently become more well established. In a cohort of athletes with SRC, the authors sought to 1) assess the relationship between symptoms at the initial clinic visit and time to referral for vestibular therapy, and 2) evaluate whether earlier referral to vestibular therapy was associated with faster recovery, as defined as days to return to learn (RTL), symptom resolution (SR), and return to play (RTP).

METHODS

A retrospective cohort study was conducted using a regional multidisciplinary concussion center’s database. Patients aged 12–23 years diagnosed with SRC who received vestibular rehabilitation therapy between October 2017 and October 2021 were included. Demographics and Post-Concussion Symptom Scale (PCSS) scores were extracted. The independent variable of interest was time to vestibular therapy referral. The three outcome variables were RTL, SR, and RTP. Spearman’s rho correlation (rho) was used to evaluate the relationship between total PCSS score and individual symptoms (balance problems, blurred vision, and dizziness) and time to referral for vestibular therapy. Multivariable linear regression was performed to determine the impact of time to vestibular therapy on the three outcomes of RTL, SR, and RTP. Covariates included initial symptom burden, age, and prior concussions.

RESULTS

Forty-two concussed athletes were referred for vestibular therapy (mean age 16.8 ± 2.7 years; 54.8% female). The mean time from concussion to the initial clinic visit was 22.4 ± 20.2 days, and the mean time from the initial clinic visit to vestibular therapy referral was 4.9 ± 11.3 days. Initial total PCSS scores (rho[37] = 0.05, p = 0.78) and individual symptoms, including balance problems (rho[33] = −0.004, p = 0.98), blurred vision (rho[34] = −0.17, p = 0.33), and dizziness (rho[33] = 0.07, p = 0.67), were not correlated with time to referral for vestibular therapy. Multivariable linear regression analysis found that earlier vestibular therapy referral was predictive of shorter days to SR (p = 0.002) and RTP (p = 0.02) but not RTL (p = 0.59).

CONCLUSIONS

In athletes with SRC referred for vestibular therapy, earlier vestibular therapy referral was significantly associated with faster time to RTP and SR. Future investigations should focus on identifying common postconcussive signs and symptoms that serve as indications for referral to vestibular therapy.

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Predicting early versus late recovery from sport-related concussion using decision tree analysis

Jackson H. Allen, Alan R. Tang, Katherine S. Hajdu, Brian Q. Hou, Alan Z. Grusky, Heidi Chen, Christopher M. Bonfield, Scott L. Zuckerman, Douglas P. Terry, and Aaron M. Yengo-Kahn

OBJECTIVE

Accurately predicting early (≤ 14 days) versus typical (15–27 days) or delayed (≥ 28 days) recovery from sport-related concussion (SRC) may allow for improved resource utilization and precision in planning and carrying out rehabilitation. In this study, the authors sought to develop an algorithm that enables accurate differentiation of recovery periods and duration after SRC. The authors hypothesized that data regarding initial symptom burden as quantified by a Post-Concussion Symptom Scale (PCSS) score, time to presentation, and number of prior concussions would be the most useful for analyzing predictive factors for concussion recovery duration.

METHODS

A retrospective case-control study was conducted to assess the primary outcome of days to clinical recovery following SRC in pediatric patients. Data from patients 12–18 years old presenting within 28 days of injury to an SRC clinic between November 11, 2017, and October 10, 2020, were analyzed. Patients with positive evidence of injury on head imaging or incomplete records were excluded. The primary outcome was duration of clinical recovery, grouped as early (≤ 14 days), typical (15–27 days), or delayed (≥ 28 days). Recovery was defined as follows: 1) symptom resolution or return to baseline, or 2) initiation of graduated return to play. CHAID (chi-square automatic interaction detection) analysis was used to optimize a decision tree based on 16 input factors, including age, sex, initial PCSS score, time to clinic presentation, number of prior concussions, and presence of defined symptom clusters. The cohort was randomized into training (70%) and test (30%) samples for algorithm validation.

RESULTS

A total of 493 patients met the inclusion criteria (mean age 15.7 ± 1.5 years, 68.2% male, 70.0% White). The median time to presentation was 5 days (IQR 2–10 days). Most patients (52.3%) recovered within 14 days of injury, 21.5% recovered within 15–27 days, and 26.2% had a recovery period of 28 days or longer. The variables most predictive of recovery were initial PCSS score (cutoffs ≤ 6, 7–28, or ≥ 29), time to presentation (≤ 7 vs > 7 days), or prior concussions (0 vs ≥ 1). The model accurately discriminated between early versus typical or delayed recovery duration groupings (area under the curve 0.80, Youden index 0.44), and correctly classified > 90% of patients who recovered early.

CONCLUSIONS

This novel three-factor predictive tool enabled accurate discrimination of early versus typical or delayed SRC recovery to better allocate resources, counsel patients, and make timely referrals.

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Return-to-learn after sport-related concussion: does school level matter?

Jacob Jo, Kristen L. Williams, Tyler M. Hill, Garrett M. Perry, Olivia L. Prosak, Amad Amedy, Trevor J. Anesi, Douglas P. Terry, and Scott L. Zuckerman

OBJECTIVE

Return-to-learn (RTL) after sport-related concussion (SRC) is an important yet understudied topic. The authors sought to do the following: 1) describe patterns of RTL among athletes by school level (i.e., middle school, high school, college); and 2) evaluate the predictive value of school level on RTL duration.

METHODS

A retrospective, single-institution cohort study of adolescent and young adult athletes 12–23 years old who sustained an SRC between November 2017 and April 2022 and who presented to a multidisciplinary specialty concussion clinic was conducted. The independent variable was school level, trichotomized into middle school, high school, and college. Time to RTL was the primary outcome and was defined as days from SRC to return to any academic activities. ANOVA was used to compare RTL duration across school levels. A multivariable linear regression was performed to evaluate for predictive value of school level on RTL duration. Covariates included the following: sex, race/ethnicity, learning disorder, psychiatric conditions, migraines, family history of psychiatric conditions/migraines, initial Post-Concussion Symptom Scale score, and number of prior concussions.

RESULTS

Of 1007 total athletes, 116 (11.5%) were in middle school, 835 (83.0%) were in high school, and 56 (5.6%) were in college. The mean RTL times (in days) were as follows: 8.0 ± 13.1 (middle school), 8.5 ± 13.7 (high school), and 15.6 ± 22.3 (college). One-way ANOVA showed a statistically significant difference between groups (F[2, 1007] = 6.93, p = 0.001). A Tukey post hoc test revealed a longer RTL duration in collegiate athletes when compared to middle school (p = 0.003) and high school (p < 0.001) athletes. Collegiate athletes had longer RTL duration compared to other school levels (β = 0.14, p < 0.001). There was no difference between middle school and high school athletes (p = 0.935). The subanalysis revealed a longer RTL duration in high school freshmen/sophomores (9.5 ± 14.9 days) when compared to juniors/seniors (7.6 ± 12.6 days; t = 2.05, p = 0.041), and being an older (junior/senior) high school athlete was predictive of shorter RTL duration (β = −0.11, p = 0.011).

CONCLUSIONS

When examining patients who presented to a multidisciplinary sport concussion center, RTL duration was longer in collegiate athletes when compared to middle and high school athletes. Younger high school athletes had longer time to RTL compared to their older counterparts. This study provides insight into how varying scholastic environments may contribute to RTL.

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Acute psychological symptom profiles in high school football players following sport-related concussion

Maryam Y. Jawid, Kristen L. Williams, Jacob Jo, Tyler M. Hill, Olivia L. Prosak, Amad Amedy, Trevor J. Anesi, Douglas P. Terry, and Scott L. Zuckerman

OBJECTIVE

In a cohort of high school football athletes, the authors sought to 1) describe the proportion of those with acute psychological symptoms postconcussion, 2) determine predictors of more acute psychological symptoms postconcussion, and 3) determine if acute psychological symptoms impact recovery.

METHODS

A retrospective cohort study of high school football athletes (14–18 years of age) who sustained a sport-related concussion between November 2017 and April 2022 and presented to a multidisciplinary concussion center was performed. Based on their Post-Concussion Symptom Scale (PCSS) scores at the initial clinic visit, their total psychological symptom cluster score was calculated by summing their scores for the four affective symptoms (irritability, sadness, nervousness, and feeling more emotional). The psychological symptom ratio was defined as the ratio of the psychological symptom cluster score to the total initial PCSS score. Primary outcomes included time to return to learn (RTL), symptom resolution, and return to play (RTP). Uni- and multivariable regression analyses were performed controlling for demographic factors, learning disabilities, attention-deficit/hyperactivity disorder, and personal and/or family history of psychological diagnoses and migraine.

RESULTS

A total of 195 male football players (mean age 16.2 ± 1.2 years) were included in the study. About one-third of the sample (n = 70, 35.9%) reported at least one psychological symptom. Of these 70 athletes, their psychological symptom scores were 1 (10.3%), 2 (7.7%), and ≥ 3 (17.9%). Irritability was the most endorsed psychological symptom (25.1%), followed by nervousness (15.9%), feeling more emotional (12.8%), and sadness (11.8%). The multivariable regression model showed that a positive psychological history (B = 2.66, 95% CI 0.74–4.58, p = 0.007) and family psychological history (B = 2.43, 95% CI 0.98–3.88, p = 0.001) were significant predictors of a higher psychological symptom cluster score. Multivariable linear regression analysis showed that a higher psychological symptom cluster score was associated with a longer time to RTP (B = 1.22, 95% CI 0.17–2.264, p = 0.023) but not with time to symptom resolution or RTL. The psychological symptom ratio was not a significant predictor.

CONCLUSIONS

In a cohort of male football players, 36% reported at least one psychological symptom, with irritability being most commonly reported. Athletes with a personal and/or family history of psychological disorders experienced more acute psychological symptoms following a sport-related concussion. A higher psychological symptom cluster score was associated with delayed time to RTP but not time to RTL or symptom resolution.

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Sport-related concussion in 8- to 12-year-olds: an understudied population

Michael Zargari, Jacob Jo, Kristen Williams, Aaron M. Yengo-Kahn, E. Haley Vance, Christopher M. Bonfield, Douglas P. Terry, and Scott L. Zuckerman

OBJECTIVE

Most studies regarding sport-related concussion (SRC) focus on high school and collegiate athletes; however, little has been published on children younger than 12 years of age. In a cohort of children aged 8–12 years with SRC, the authors sought to describe demographics, initial presentation, and recovery in this understudied population.

METHODS

A retrospective cohort study of children aged 8–12 years who sustained an SRC between November 2017 and April 2022 and were treated at a regional sports concussion center was conducted. Demographic information, injury characteristics, traditional Sport Concussion Assessment Tool 5 (SCAT5) and Child/Parent SCAT5 scores, and outcomes, defined as days to return to learn (RTL), symptom resolution, and return to play (RTP), were reported. Outcomes in boys and girls were compared using effect size analyses given sample size constraints.

RESULTS

Forty-seven athletes were included. The mean age was 11.0 ± 0.8 years, and the majority were male (34, 72.3%). A sizable proportion of patients visited an emergency department (19, 40.4%), and many received head imaging (16, 34.0%), mostly via CT (n = 13). The most common sport for boys was football (15, 44.1%), and the most common sports for girls were soccer (4, 30.8%) and cheerleading (4, 30.8%). These athletes reported a variety of symptoms on presentation. It took a mean of 8.8 ± 10.8 days to RTL, 27.3 ± 38.3 days to reach symptom resolution, and 35.4 ± 41.9 days to RTP. When comparing boys versus girls, there appeared to be moderate differences in symptom severity scores (Cohen’s d = 0.44 for SCAT5, 0.13 for Child SCAT5, and 0.38 for Parent SCAT5) and minimal differences in recovery (Cohen’s d = 0.11 for RTL, n = 35; 0.22 for symptom resolution, n = 22; and 0.12 for RTP, n = 21).

CONCLUSIONS

In this cohort of concussed athletes aged 8–12 years, a little less than half of the athletes initially presented to the emergency department, and approximately one-third received acute head imaging. Across all athletes, the mean RTL was slightly more than a week and the mean symptom resolution and RTP were both approximately 1 month; however, much of the cohort is missing recovery outcome measures. This study demonstrated a strong positive correlation between Child SCAT5 and Parent SCAT5 symptom reporting. Future efforts are needed to evaluate differences in clinical presentation and outcomes following SRC between children and older populations.

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Abnormal functional connectivity of the posterior hypothalamus and other arousal regions in surgical temporal lobe epilepsy

Jasmine W. Jiang, Saramati Narasimhan, Graham W. Johnson, Hernán F. J. González, Derek J. Doss, Jared S. Shless, Danika L. Paulo, Douglas P. Terry, Catie Chang, Victoria L. Morgan, and Dario J. Englot

OBJECTIVE

This study sought to characterize resting-state functional MRI (fMRI) connectivity patterns of the posterior hypothalamus (pHTH) and the nucleus basalis of Meynert (NBM) in surgical patients with mesial temporal lobe epilepsy (mTLE), and to investigate potential correlations between functional connectivity of these arousal regions and neurocognitive performance.

METHODS

The study evaluated resting-state fMRI in 60 patients with preoperative mTLE and in 95 healthy controls. The authors first conducted voxel-wise connectivity analyses seeded from the pHTH, combined anterior and tuberal hypothalamus (atHTH; i.e., the rest of the hypothalamus), and the NBM ipsilateral (ipsiNBM) and contralateral (contraNBM) to the epileptogenic zone. Based on these results, the authors included the pHTH, ipsiNBM, and frontoparietal neocortex in a network-based statistic (NBS) analysis to elucidate a network that best distinguishes patients from controls. The connections involving the pHTH and ipsiNBM from this network were included in age-corrected pairwise region of interest (ROI) analysis, along with connections between arousal structures, including the pHTH, ipsiNBM, and brainstem arousal regions. Finally, patient functional connectivity was correlated with clinical neurocognitive testing scores for IQ as well as attention and concentration tests.

RESULTS

The voxel-wise analysis demonstrated that the pHTH, when compared with the atHTH, showed more widespread functional connectivity decreases in surgical mTLE patients when compared with controls. It was also observed that the ipsiNBM, but not the contraNBM, showed decreased functional connectivity in mTLE. The NBS analysis uncovered a perturbed network of frontoparietal regions, the pHTH, and ipsiNBM that distinguishes patients from controls. Age-corrected ROI analysis revealed functional connectivity decreases between the pHTH and bilateral superior frontal gyri, medial orbitofrontal cortices, rostral anterior cingulate cortices, and inferior parietal cortices in mTLE when compared with controls. For the ipsiNBM, there was reduced connectivity with bilateral medial orbitofrontal and rostral anterior cingulate cortices. Age-corrected ROI analysis also demonstrated upstream connectivity decreases from controls between the pHTH and the brainstem arousal regions, cuneiform/subcuneiform (CSC) nuclei, and ventral tegmental area, as well as the ipsiNBM and CSC nuclei. Reduced functional connectivity was also detected between the pHTH and ipsiNBM. Lastly, neurocognitive test scores for attention and concentration were found to be positively correlated with the functional connectivity between the pHTH and ipsiNBM, suggesting worse performance associated with connectivity perturbations.

CONCLUSIONS

This study demonstrated perturbed resting-state functional connectivity of arousal regions in surgical mTLE and is one of the first investigations to demonstrate decreased functional connectivity of the pHTH with frontoparietal regions and other arousal regions. Connectivity disturbances in arousal regions may contribute to neurocognitive deficits in surgical mTLE patients.