FULL-LENGTH ORIGINAL RESEARCH

The corpus callosum and recovery of working after surgery *1Karen Blackmon, *1Heath R. Pardoe, *William B. Barr, †‡Babak A. Ardekani, *§Werner K. Doyle, *Orrin Devinsky, *Ruben Kuzniecky, and *¶Thomas Thesen

Epilepsia, **(*):1–8, 2015 doi: 10.1111/epi.12931

SUMMARY Objective: For patients with medically intractable focal epilepsy, the benefit of must be weighed against the risk of cognitive decline. Clinical factors such as age and presurgical cognitive level partially predict cognitive outcome; yet, little is known about the role of cross-hemispheric white matter pathways in support- ing postsurgical recovery of cognitive function. The purpose of this study is to deter- mine whether the presurgical corpus callosum (CC) midsagittal area is associated with pre- to postsurgical change following epilepsy surgery. Methods: In this observational study, we retrospectively identified 24 adult patients from an epilepsy resection series who completed preoperative high-resolution T1- weighted magnetic resonance imaging (MRI) scans, as well as pre- and postsurgical neuropsychological testing. The total area and seven subregional areas of the CC were measured on the midsagittal MRI slice using an automated method. Standardized indi- ces of auditory-verbal working memory and delayed memory were used to probe cognitive change from pre- to postsurgery. CC total and subregional areas were regressed on memory-change scores, after controlling for overall brain volume, age, presurgical memory scores, and duration of epilepsy. Dr. Karen Blackmon Results: Patients had significantly reduced CC area relative to healthy controls. We is assistant professor found a positive relationship between CC area and change in working memory, but in the Neurology not delayed memory; specifically, the larger the CC, the greater the postsurgical Department at New improvement in working memory (b = 0.523; p = 0.009). Effects were strongest in York University. posterior CC subregions. There was no relationship between CC area and presurgical memory scores. Significance: Findings indicate that larger CC area, measured presurgically, is related to improvement in working memory abilities following epilepsy surgery. This suggests that transcallosal pathways may play an important, yet little understood, role in post- surgical recovery of cognitive functions. KEY WORDS: Epilepsy, MRI, Corpus callosum, Short-term memory, Executive func- tion, Neuronal plasticity.

Accepted December 31, 2014. *Department of Neurology, Comprehensive Epilepsy Center, New York For patients with medically intractable focal epilepsy, the University School of Medicine, New York, New York, U.S.A.; †Department of Psychiatry, New York University School of Medicine, New York, New best option for achieving seizure control is often surgical York, U.S.A.; ‡The Nathan S. Kline Institute for Psychiatric Rese- resection.1 However, the benefit of epilepsy surgery must arch, Orangeburg, New York, U.S.A.; Departments of §, be weighed against the risk of cognitive decline, which is and ¶Radiology, New York University School of Medicine, New York, New York, U.S.A. commonly observed in the domains of language and long- 1These authors contributed equally to the manuscript. term memory.2,3 Conversely, postsurgical gains in execu- Address correspondence to Karen Blackmon, Department of Neurology, tive domains such as attention and working memory can be NYU Epilepsy Center, New York University, 223 East 34th Street, New 4 York, NY 10016, U.S.A. E-mail: [email protected] observed. Clinical (e.g., epilepsy duration, presurgical cog- Wiley Periodicals, Inc. nitive level) and demographic (e.g., age) factors predict 5 © 2015 International League Against Epilepsy postsurgical cognitive outcomes. Yet, little is known about

1 2 K. Blackmon et al. the degree to which cross-hemispheric white matter path- medically refractory seizures; (2) completed a research ways promote recovery of cognitive functions following MRI scan prior to surgery; (3) had clinical neuropsychologi- epilepsy surgery. cal testing prior to surgery; (4) completed research neuro- Functional reorganization following epilepsy surgery is a psychological testing following surgery; (5) were between phenomenon that has been widely reported.4,6,7 The spatial the ages of 17 and 65 (to fall within the standardization sam- pattern of functional reorganization can be broadly classi- ple range for the working memory index); (6) had at least a fied as within the same hemisphere (ipsilesional) or to low average intellectual quotient score (IQ > 70); (7) had homologous regions in the contralateral hemisphere no history of significant head trauma or diffuse encephalop- (contralesional). Reorganization of lateralized functions athy; and (8) no history of drug or alcohol dependence. such as language and verbal memory is associated with in- Healthy control participants were recruited through com- trahemispheric reorganization following left hemisphere munity advertisement and gave consent to participate in this resections,6,7 and accompanied by structural changes in study. Control participants were excluded from analyses if ipsilesional white matter tracts.7 However, functional reor- they reported any prior history of neurologic disorders, ganization of bilaterally represented cognitive domains such psychiatric disorders, head injury, or substance abuse. as working memory8 may rely more on contralesional reor- ganization, facilitated by cross-hemispheric white matter Clinical variables tracts. This possibility has yet to be investigated. Clinical data abstracted for all patients includes age at Corpus callosum (CC) atrophy is common in the context time of presurgical research scan, duration of epilepsy, of chronic epilepsy.9 Here, we test whether presurgical CC handedness, side of surgery, resection lobe, years postsur- area is associated with changes in memory functions after gery, and whether participants had seizure recurrence post- epilepsy surgery. To quantify CC area, we apply a computa- surgery (yes/no). tional method that segments the CC from the midsagittal section of a whole brain T1-weighted magnetic resonance Memory indices imaging (MRI) scan and calculates total and subregional The Wechsler Adult Intelligence Scale (WAIS-III or CC area.10,11 CC area in patients with chronic treatment- WAIS-IV)—Working Memory Index (WMI),12,13 and resistant epilepsy (TRE) is compared to age-matched California Verbal Learning Test-II14 (CVLT-II) or Rey healthy controls to determine whether presurgical CC atro- Auditory Verbal Learning Test15 (RAVLT) were acquired phy is present. Then, the linear relationship between presur- as part of a standard clinical neuropsychological work-up gical CC area and change in auditory-verbal working for epilepsy surgery and at least 6 months postsurgically memory and delayed memory from pre- to postsurgery is for research. assessed. Our hypothesis is that the CC area will be associ- The WMI comprises a digit span task, letter-number ated with change in memory functions, independent of sequencing (WAIS-III), and/or mental arithmetic (WAIS- established predictors such as age, presurgical cognitive IV) task, which require mentally rehearsing and manipulat- level, and epilepsy duration. Finally, we analyze seven ing auditory-verbal information; therefore, the particular distinct subregions of the CC to explore the spatial pattern working memory index that we used is specific to auditory- of effects. verbal, rather than visuospatial, working memory abilities. Depending on the version of the WAIS administered (Third Methods or Fourth Edition), test-retest reliability metrics for the WMI range from 0.85 to 0.92.12,13 WMI scores from the Standard protocol and patient consents WAIS-III and WAIS-IV are strongly correlated (r = 0.87), All patients consented to the use of their clinical records thus supporting their combined analysis.13 To operational- for the purpose of research, as well as for MRI scanning ize change in WMI scores from pre- to postsurgery, a and neuropsychological testing. Study procedures were change score was calculated and used as a dependent vari- approved by the New York University Institutional Review able in subsequent analyses: (WMI-change score = postsur- Board. gical WMI À presurgical WMI). Lower numbers indicate worse postsurgical performance. Participants Either the CVLT-II or RAVLT was administered to For this observational, longitudinal study, we retrospec- patients pre- and postsurgically to probe verbal memory. In tively identified consecutive participants with TRE from an both tests, examinees are read a list of 15 (RAVLT) or 16 epilepsy surgical series at the New York University Com- (CVLT-II) words and asked to recall them across a series of prehensive Epilepsy Center, spanning from 2007 to 2013. five learning trials. Retention and free recall are tested after Neuropsychological measures were obtained longitudinally a brief (5-min) and long (20-min) delay, followed by a yes/ pre- and postsurgery and MRI was obtained cross-section- no recognition test. To utilize data from both tests, we used ally prior to surgery. The following criteria were used to the standardized, age-corrected delayed recall z-scores as a select patients: (1) had a focal neocortical resection to treat measure of verbal delayed recall (DR). To operationalize

Epilepsia, **(*):1–8, 2015 doi: 10.1111/epi.12931 3 Callosal Atrophy and Memory in Epilepsy change in DR scores from pre- to postsurgery, a change marized in Table 1. Details regarding Wada test results and score was calculated and used as a dependent variable in surgery for each patient are provided in Table S1. subsequent analyses: (DR-change score = postsurgical DR z-score À presurgical DR z-score). Lower numbers indicate Group differences on the working memory index (WMI) worse postsurgical performance. Presurgical WMI scores were significantly lower in patients than controls (t46 = À4.1; p = 0.0002; See MRI and image analysis Table 2). This difference remained significant after control- T1-weighted three-dimensional (3D) magnetization ling for years of education (F1,45 = 9.01; p = 0.004), which prepared rapid gradient echo (MPRAGE) MRI studies were were lower in TRE patients than controls (see Table 1). The acquired from each participant prior to epilepsy surgery on a left TRE group had reduced WMI scores relative to controls 3-Tesla Siemens Allegra research-dedicated scanner (voxel (t32 = À2.27; p = 0.03), as did the right TRE group 3 size = 1 9 191.33 mm , echo time = 3.25 msec, repetition (t36 = À3.94; p = 0.0004), and the temporal lobe only time = 2,530 msec, TI = 1,100 msec, flip angle = 7 group (t39 = À3.96; p = 0.0003); the extratemporal lobe degrees). The total CC cross-sectional area and seven CC group had marginally reduced WMI scores relative to con- subregional areas (according to the Witelson subdivision trols (t29 = À1.964; p = 0.059). There was no difference in scheme16) were delineated on the midsagittal slice and mea- presurgical WMI scores between patients with right or left sured automatically using “yuki” (www.nitrc.org/projects/ TRE (t22 = 1.3; p = 0.18) or between patients with tempo- 10,11 art), an automatic CC segmentation algorithm (Fig. 1). ral and extratemporal TRE (t22 = À0.95; p = 0.35); there- Brain volume was measured using “Brain Extraction Tool,” fore, these groups are combined in all further analyses. distributed as part of the FSL software package (http:// Pairwise t-tests showed that WMI scores in TRE patients 17 fsl.fmrib.ox.ac.uk/fsl/fslwiki/BET). did not differ from pre- to postsurgery (t23 = À0.27; p = 0.79); however, WMI-change scores ranged from À29 Statistics to 34, indicating a large degree of individual variability in The Shapiro-Wilk test was used to test for normality in all pre- to postsurgical WMI-change. To determine whether the variables. Analysis of covariance (ANCOVA) was used to degree of change in WMI scores could be categorized as test for a group differences between patients and controls on reliable “decline” or “improvement,” the magnitude was the CC area and each subregion area, after controlling for compared to published 90% reliable change indices for the overall brain volume. A hierarchical regression model was WAIS working memory index.18 We utilized reliable used to test for a linear relationship between each unit change indices (RCIs) established in an epilepsy cohort with increase in CC total area or subregion area and pre- to post- a similar proportion of temporal to extratemporal cases.17 A surgical change in WMI and DR, after controlling for decrease in performance by at least 17 points (À17) was overall brain volume, age at surgery, presurgical WMI required to be classified as “WMI-decline” and an increase (or presurgical DR), and epilepsy duration. of at least 13 points (+13) was required to be classified as “WMI-improvement” (90% confidence interval), over and Results above that observed in a similar cohort that did undergo epilepsy surgery. This criterion allows for a sensitive Sample characteristics estimate of postoperative cognitive change that can be Twenty-four patients (13 male) met study criteria. attributed to surgical intervention rather than ongoing Healthy control participants were matched to patients by seizures and medication use. Based on this criterion, 8% age (Æ5 years). Patient and control characteristics are sum- (N = 2) showed postsurgical improvement in WMI, 84%

ABC

Figure 1. Corpus callosum segmentation and area measurement. The automated approach identifies the midsagittal plane (A). The corpus callosum is segmented (B) and the area enclosed by the red line is measured. The corpus callosum is further subdivided using the Witelson subdivi- sion scheme (C) to generate seven corpus callosum subregions: rostrum (red, W1); genu (orange, W2); anterior body (yellow, W3); mid-body (green, W4); posterior body (blue, W5); isthmus (slate, W6); splenium (turquoise, W7). Epilepsia ILAE

Epilepsia, **(*):1–8, 2015 doi: 10.1111/epi.12931 4 K. Blackmon et al.

Table 1. Demographic and clinical characteristics of the sample TRE patients (N = 24) Healthy controls (N = 24) Sex 13 male/11 female 15 male/9 female Handedness 3 left/2 ambidextrous/18 right 1 left/23 right Min–Max Mean (SD) Min–Max Mean (SD) Age 17–51 30.42 (9.7) 18–52 29.92 (9.8) a Years of education 10–19 14.71 (2.6) 13–20 16.6 (2.1) Epilepsy duration 2–50 18.58 (13.11) Resection side 10 left/14 right Resection lobe 17 TL, 5 FL, 1 PL, 1 TL + FL Temporal/extratemporal 17 temporal/7 extratemporal Postoperative seizure outcome 18 seizure-free/6 recurrent seizures

TRE, treatment-resistant epilepsy; TL, temporal lobe; FL, frontal lobe; PL, parietal lobe. a TRE group mean years of education is significantly lower than control mean at p < 0.05.

Table 2. Pre- and postsurgical working memory index and delayed memory scores TRE patients (N = 24) Controls (N = 24) Range Mean (SD) Range Mean (SD) Mean difference 95% CI Presurgical WMI 69–124 94.9 (12.5)* 80–150 111.9 (16.2)* À16.9 À25.4 to À8.5 Postsurgical WMI 69–125 95.7 (15.6) N/A WMI change À29 to 34 0.8 (13.7) N/A Presurgical DR À3.5 to 1.5 À0.7 (1.3)* À4 to 1.5 0.3 (1.3)* À1.0 À1.8 to À0.3 Postsurgical DR À3.5 to 1.0 À1.0 (1.4) N/A DR change À2.5 to 3.0 À0.3 (1.1) N/A

TRE, treatment-resistant epilepsy; WMI, working memory index; DM, delayed memory; CI, confidence interval. * Significant at p < 0.05.

showed no change (N = 20), and 8% (N = 2) showed and extratemporal TRE (t22 = 0.116; p = 0.91); therefore, decline. these groups are combined in all further analyses. There was no significant difference in WMI-change Pairwise t-tests showed that DR scores in TRE patients between patients with a temporal versus an extratemporal did not decline, on average, from pre- to postsurgery lobe resection (t22 = À0.25; p = 0.8). In addition, there was (t23 = 1.15; p = 0.26), which may be due to reduced scores no difference in WMI-change between patients who had a presurgically. DR-change scores ranged from a decline of recurrence in seizures versus those who became seizure free 2.5 standard deviations (SD) to improvement of 3 SD, indi- postsurgery (t22 = À0.5; p = 0.64). cating a wide range of pre- to postsurgical DR-change. Patients who had temporal lobe surgery did not show signif- Group differences on verbal delayed recall (DR) icantly greater decline in DR scores than those that had an Presurgical DR scores from the CVLT-II and RAVLT did extratemporal lobe resection (t22 = À0.529; p = 0.602), not differ in the TRE group (t21 = À0.157; p = 0.877), and neither did left relative to right hemisphere surgical which supports their combination in subsequent analyses. patients (t22 = À1.411; p = 0.172). Finally, there was no Presurgical DR z-scores were lower in patients than controls difference in DR-change between patients who had a recur- (t46 = À2.703; p = 0.01; see Table 2). This difference rence in seizures versus those who became seizure free post- remained significant after controlling for years of education surgery (t22 = À1.23; p = 0.23). (F1,45 = 4.16; p = 0.047). Within specific patient sub- groups, the left TRE group had reduced DR scores relative Is there evidence of CC atrophy in patients with focal to controls (t32 = À2.45; p = 0.02), as did the right TRE TRE relative to controls? group (t36 = À2.032; p = 0.05), and the temporal lobe only CC cross-sectional area was normally distributed (Shap- group (t39 = À2.398; p = 0.02); the extratemporal lobe iro-Wilk statistic = 0.977; p = 0.462). Patients with TRE group had marginally reduced DR scores relative to controls had smaller CC area (mean 615.92 mm2, SD 76.45 mm2), 2 2 (t29 = À1.9; p = 0.06). There was no difference in presurgi- relative to controls (mean 676.97 mm , SD 83.89 mm ): cal DR scores between patients with right or left TRE t46 = À2.635; p = 0.01. Group differences remained (t22 = À0.538; p = 0.74) or between patients with temporal after controlling for overall brain volume (F2,48 = 6.21;

Epilepsia, **(*):1–8, 2015 doi: 10.1111/epi.12931 5 Callosal Atrophy and Memory in Epilepsy p = 0.016). The Witelson subregions of the CC are depicted Is corpus callosum cross-sectional area associated with in Figure 1, color-labeled as W1–W7, from anterior to pos- DR change in patients with TRE? terior. Group differences between TRE patients and controls There was no significant relationship between presurgical were apparent in mid to posterior subregions, after control- DR z-scores and CC area in the TRE group (r = 0.005; ling for overall brain volume. Specifically, group differ- p = 0.981). This remained the case after controlling for ences were significant in W3 (F2,48 = 4.16; p = 0.04), W4 brain volume, age at time of scanning, and duration of (F2,48 = 9.69; p = 0.003), W6 (F2,48 = 10.69; p = 0.002), epilepsy (b = À0.21; p = 0.924). In addition, there was no and W7 (F2,48 = 4.35; p = 0.04) but not in W1 relationship between presurgical CC area and DR-change (F2,48 = 0.03; p = 0.86), W2 (F2,48 = 0.84; p = 0.36), or scores (r = À0.024; p = 0.912). This null finding W5 (F2,48 = 1.74; p = 0.19; see Fig. 2B). There were no remained after controlling for brain volume, age at time of significant differences between the temporal and extratem- scanning, duration of epilepsy, and presurgical DR scores poral TRE group in the CC total area or subregional areas. (b = À0.04; p = 0.86). Given the absence of a relationship between overall CC area and DR, we did not further investi- Is corpus callosum cross-sectional area associated with gate CC subregions. WMI change in patients with TRE? There was no significant relationship between presurgical Discussion WMI scores and CC area in the TRE group (r = 0.28; p = 0.89). This remained the case after controlling for brain Our results demonstrate that a larger presurgical CC is volume, age at time of scanning, and duration of epilepsy associated with improvement in auditory-verbal working (b = 0.038; p = 0.872). However, presurgical CC area was memory, but not delayed memory, following epilepsy sur- strongly associated with a change in WMI scores from pre- gery. Quantitative measurement revealed smaller presurgi- to postsurgery (see Fig. 3A; r = 0.557; p = 0.005). This cal CC area in patients with treatment-resistant epilepsy relationship remained significant after controlling for brain (TRE), relative to controls, after controlling for overall volume, age at time of scanning, duration of epilepsy, and brain volume. Variation in CC area was associated with pre- presurgical WMI scores (b = 0.523; p = 0.009). These to postsurgical change in working memory, after controlling more established predictors accounted for 19% of the vari- for established predictors of cognitive outcome, such as age ance in WMI change, whereas CC area contributed an addi- and level of cognitive functioning.3,5 This was not the case tional 25.9% of the variance. Anterior CC subregions for longer-term retention of verbal information; there was W1–W3 did not contribute incremental variance to WMI- no relationship between CC area and pre- to postsurgical change after controlling for established predictors; however, change in delayed verbal memory. Thus, CC area has the the more posterior subregions W4–W7 were each indepen- potential to offer additional prognostic information for sur- dently associated with WMI-change: (see Fig. 3B [W4: gical decision-making, independent of established demo- b = 0.478; p = 0.023]; [W5: b = 0.522; p = 0.013]; [W6: graphic and clinical predictors, but only for specific b = 0.589; p = 0.002], and [W7: b = 0.595; p = 0.005]). cognitive domains. Results suggest that the risk of working

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Figure 2. (A) Corpus callosum mid-sagittal area is reduced in patients with treatment-resistant epilepsy compared with healthy controls. (B) Bar plot depicting average differences between patients and controls when the corpus callosum is subdivided using the Witelson scheme; W1 represents the anterior end of the corpus callosum (rostrum/genu) and W7 is the posterior end (splenium). The figure shows that differ- ences are primarily evident in the mid-to-posterior sections of the corpus callosum in this group of patients with epilepsy. The bar plot shows the magnitude of differences, with stars designating statistical significance at a threshold of p < 0.05. Epilepsia ILAE

Epilepsia, **(*):1–8, 2015 doi: 10.1111/epi.12931 6 K. Blackmon et al.

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Figure 3. (A) Scatter plot depicting a linear correlation between WMI-change and corpus callosum total mid-sagittal area, with higher corpus callo- sum area scores associated with greater improvement in verbal working memory after surgery. (B) Bar graph depicting the effect size (R2-change expressed as percent) of the relationship between WMI-change and each Witelson subregion. The largest effect sizes were observed in the posterior regions of the corpus callosum. Epilepsia ILAE memory decline in populations considered to be at risk (i.e., Posterior CC subregions showed the strongest rela- older age, higher intellectual functioning) may be mitigated tionship with pre- to postsurgical change in working by strong cross-hemispheric connectivity or conversely, that memory. Postmortem and in vivo diffusion tensor imag- the possibility of improvement in working memory may be ing tract-tracing studies demonstrate that bi-hemispheric attenuated in the context of CC atrophy. occipital, parietal, and temporal lobe pathways traverse Our finding of lower CC area in TRE patients supports the more posterior isthmus of the CC and pathways prior findings of CC atrophy in the context of chronic, medi- connecting frontal cortical regions traverse anterior CC cally refractory seizures,9,19–21 and extends these findings regions.16,26,27 Bilateral frontoparietal network involve- by defining the spatial pattern of atrophy. We show that the ment in working memory is commonly appreciated28; mid to posterior subregions of the CC are smaller in TRE however, mesial and lateral temporal regions also play patients relative to controls, which is consistent with what a role,29,30 with evidence of bilateral temporal involve- has been found in a temporal lobe epilepsy only sample.22 ment in healthy controls4 and temporal lobe epilepsy Although this might reflect the large number of patients patients.31 In a longitudinal investigation of changes in with temporal lobe epilepsy in our sample, we found no functional MRI–blood oxygen level dependent (fMRI- differences between temporal and extratemporal patients in BOLD) activity during a visuospatial working memory CC area or the area of CC subregions. This suggests that task administered pre– and post–anterior temporal lobec- posterior CC atrophy might also be a factor to consider in tomy, postsurgical improvement was associated with extratemporal lobe epilepsy; however, a larger sample is increased (task-positive) parietal lobe activity, as well needed to detect subtle effects of seizure onset localization as with increased ipsilateral and contralateral deactiva- on CC atrophy. tion (task-negative) of hippocampal activity.4 This sug- A positive relationship between posterior callosal size gests that both temporal and parietal network and overall intelligence in adults with epilepsy has been rep- reorganization are critical to postsurgical recovery of licated across several studies.23–25 However, the same rela- working memory functions; however, it remains unclear tionship has not been found between CC area and language whether transcallosal pathways might have facilitated or memory functions,24 which is consistent with what we the contralateral network reorganization that was dem- observed in our presurgical data. This suggests that prior to onstrated. surgery, the efficiency of working memory and long-term One possible role for the CC in supporting postsurgical memory functions does not appear to be related to CC size. recovery of working memory function is through coordina- In contrast, we found that a change in working memory abil- tion of bilateral temporal, frontal, and parietal cortical activ- ities from pre- to postsurgery is strongly associated with CC ity during working memory tasks; however, the absence of a size, indicating that transcallosal pathways play an impor- relationship between presurgical CC area and working tant, yet little understood, role in postsurgical recovery of memory in our data does not support this. Another possibil- working memory functions. ity is that posterior transcallosal pathways play a unique role

Epilepsia, **(*):1–8, 2015 doi: 10.1111/epi.12931 7 Callosal Atrophy and Memory in Epilepsy in facilitating contralateral reorganization of auditory-ver- presurgical level of memory functioning is also bal working memory functions. Postsurgical resilience or reported.41,42 This variability suggests the need to identify recovery of cognitive functions can be explained by func- predictive factors. Although our findings did not support tional redundancies (i.e., multiple cortical representation of CC area as a potential explanatory factor for DR-change, the same function) in bi-hemispheric homologous regions other “brain reserve” factors such as the structural and func- that are largely co-innervated or inhibited by transcallosal tional integrity of the ipsilateral hemisphere should con- pathways,32,33 but can be released (disinhibited) in the con- tinue to be explored. In sum, although our TRE group was text of chronic seizures, pathology, or surgical resection.34 heterogenous in terms of surgical location, the consistency In rats, reorganization of sensorimotor function following of the relationship between CC area and WMI-change is experimental occlusion of the middle cerebral artery is facil- promising for generalization to the TRE population. This is itated by intact transcallosal pathways and attenuated by CC especially critical because increasingly more extratemporal atrophy.35 In humans, similar findings of contralateral atten- patients are being referred for epilepsy surgery.43 tion36 and motor37 reorganization following stroke suggest acute unmasking of redundant sites in the contralateral Conclusion hemisphere via transcallosal pathways. Thus, evidence from animal and human data support the CC as an important The current study provides evidence that a larger corpus structure for facilitating contralateral reorganization of callosum, measured presurgically, is associated with stabil- function following epilepsy surgery. ity or improvement in auditory-verbal working memory fol- The absence of a relationship between CC area and lowing epilepsy surgery. The relationship between CC area change in delayed verbal memory suggests that transcallosal and WMI-change was independent of overall brain volume, pathways may not be critical to recovery of long-term mem- suggesting that the CC may play a specific role in support- ory functions, such as memory consolidation, retention, or ing postsurgical recovery of cognitive functions. Thus, the retrieval. Longitudinal fMRI investigation of memory func- structural integrity of the CC may be an important factor to tions pre– and post–anterior temporal lobe surgery supports consider in surgical planning. a greater role for ipsilateral, rather than contralateral, mesial A considerable advantage of our method is that the MRI temporal regions in memory reorganization.6 Lateralization scan used in this analysis is easily obtainable on any current of cognitive functions could be a factor in explaining the clinical MRI scanner. Future studies should apply a similar degree to which postsurgical reorganization relies on transc- methodology for measuring CC area to a set of clinically allosal pathways. For example, strongly lateralized func- acquired T1-weighted scans to test application in a clinical tions such as language may rely more on ipsilateral setting. A standardized acquisition protocol would be opti- reorganization following anterior temporal lobectomy, as mal to ensure that variability due to different acquisition has been demonstrated,7 whereas bilaterally represented parameters is eliminated. Acquisition of a postsurgical MRI functions such as working memory may rely more on scan proximal to the time of postoperative cognitive testing transcallosal pathways to support contralateral reorganiza- would be ideal to evaluate the degree to which changes in tion. Future longitudinal investigations of structural and morphometric features explain changes in cognitive perfor- functional changes pre- and postsurgery are needed to mance. Finally, future studies should determine whether CC directly investigate whether CC size might be related to con- area offers prognostic value by comparing the predicted to tralateral changes in fMRI-BOLD activity during working observed WMI scores in an independent sample. In sum, memory, but not delayed memory, tasks. results from this study support an important role for the CC in recovery of working memory following epilepsy surgery; Limitations however, additional research is needed to determine the Limitations of the current study include heterogeneity mechanisms underlying this effect and its prognostic rele- of seizure focus and surgical resection in the patient vance in surgical planning. group. Although there were no significant differences between the temporal and extratemporal groups on presur- Acknowledgments gical CC area, WMI, or DR scores, supporting their com- bination in final analyses, the small size of patient This work was supported by Finding a Cure for Epilepsy and Seizures (FACES) and the Epilepsy Foundation (Target Research Initiative for subgroups may have reduced our ability to identify subtle Cognitive and Psychiatric Aspects of Epilepsy) and Amazon Web Services localization-related differences. This may also explain Education in Research Grants. why we did not observe greater verbal memory decline in the left hemisphere or temporal lobe only group. How- Disclosure ever, findings of verbal memory decline following epi- lepsy surgery vary. Although decline in delayed memory None of the authors have any conflicts of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethi- is commonly reported after left anterior temporal lobe – cal publication and affirm that this report is consistent with those guide- resection,38 40 memory stability or a gradual return to lines.

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