FULL-LENGTH ORIGINAL RESEARCH The corpus callosum and recovery of working memory after epilepsy 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 epilepsy surgery 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 §Neurosurgery, 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