Abstracts

Rationale: Topiramate (TPM) is an anti-seizure medication prescribed for migraine prophylaxis, alcohol dependence treatment and weight loss. Cognitive side effects of TPM include word-finding problems that remain difficult to characterize with traditional neuropsychological assessments. In prior work, we found that TPM measurably decreased fluency of spontaneous speech produced during a picture description task (Marino et al 2012; Pakhomov et al 2013). We also observed in a small sample of participants (n=10) increased number of repetitions on a spontaneous narrative task. The objective of the current study was to further investigate fluency deficits in spontaneous speech over a broader range of TPM doses and confirm effects of TPM on repetitions in spontaneous speech in a larger sample. Methods: Participants were 20 healthy volunteers recruited for a larger, randomized, placebo controlled, double-blind study of cognitive side effects. No drugs were administered during the 1st (pre-) and 5th (post-baseline) visits. During the three remaining visits, participants were randomized in a cross-over design to receive placebo (PBO), lorazepam (LZP, 2 mg), and TPM (dose randomly assigned: 100, 150 or 200 mg). Neuropsychological assessments were performed at 2.5 hours post drug administration and included phonemic (COWA) and semantic verbal fluency (SVF), symbol-digit modalities (SDMT), Trails A and B, and digit span forward (DSF) and backward (DSB). Spontaneous speech was elicited using the Trier task (1 minute to prepare a speech on a topic and 2 minutes to deliver) and was audio-recorded and processed using the System for Automated Language and Speech Analysis (SALSA: Pakhomov et al. 2013). All speech samples were manually transcribed and analyzed to quantify speech fluency measures ?" density of repetitions and disfluencies (hesitations and word fragments) using SALSA. Relative differences were calculated as the within-person difference in each cognitive and speech measurement from their average of the pre-and post-baselines. Linear mixed effects models for the relative differences to test treatments were adjusted for treatment order, visit, TPM dose, gender, age, education and eGFR. Results: As shown in Table 1, significant changes from baseline due to TPM were found on speech measures, SDMT, Trails B, DSF and DSB. TPM effects on speech measures, COWA, SVF, SDMT, DSF and DSB were significantly different from effects of PBO and LZP. Contrary to previous work that found effects of TPM on COWA but not SVF, this study found negative effects of TPM on both tasks. LZP showed significant changes from baseline for word count, SDMT, Trails A, and DSF only; for PBO, word count only. Conclusions: These results are consistent with our prior results that cognitive effects of TPM manifest themselves through paralinguistic characteristics such as increased disfluency and repetitions in spontaneous narratives. In light of the long-standing association between working memory capacity and speech fluency (Daneman, 1990) and the present pattern of results, these data strongly suggest that TPM negatively affects cognition by disrupting verbal working memory processes. Funding: Supported by R01 NS076665 (PI: Marino)