An association between resting state EEG parameters and the severity of topiramate-related cognitive impairment.

INTRODUCTION: Many commonly prescribed drugs cause cognitive deficits. We investigated whether parameters of the resting-state electroencephalogram (rsEEG) are related to the severity of cognitive impairments associated with administration of the antiseizure drug topiramate (TPM) and the benzodiazepine lorazepam (LZP). METHODS: We conducted a double-blind, randomized, placebo-controlled crossover study. After a baseline visit, subjects completed three sessions at which they received either a single dose of TPM, LZP, or placebo. Four-hours after drug administration and at baseline, subjects completed a working memory (WM) task after their rsEEG was recorded. After quantifying drug-related behavioral (WM accuracy (ACC)/reaction time (RT)) and electrophysiological (alpha, theta, beta (1,2), gamma power) change for each subject, we constructed drug-specific mixed effects models of change for each WM and EEG measure. Regression models were constructed to characterize the relationship between baseline rsEEG measures and drug-related performance changes. RESULTS: Linear mixed effects models showed theta power increases in response to TPM administration. The results of the regression models revealed a number of robust relationships between baseline rsEEG parameters and TPM-related, but not LZP-related, WM impairment. CONCLUSIONS: We showed for the first time that parameters of the rsEEG are associated with the severity of TPM-related WM deficits; this suggests that rsEEG measures may have novel clinical applications in the future.

Severity of Topiramate-Related Working Memory Impairment Is Modulated by Plasma Concentration and Working Memory Capacity.

Drug side effects that impair cognition can lead to diminished quality of life and discontinuation of therapy. Topiramate is an antiepileptic drug that elicits cognitive deficits more frequently than other antiepileptic drugs, impairing multiple cognitive domains including language, attention, and memory. Although up to 40% of individuals taking topiramate may experience cognitive deficits, we are currently unable to predict which individuals will be most severely affected before administration. The objective of this study was to show the contributions of plasma concentration and working memory capacity in determining the severity of an individual's topiramate-related cognitive impairment. Subjects were enrolled in a double-blind, placebo-controlled crossover study during which they received a single dose of either 100, 150, or 200 mg topiramate. Working memory function was assessed using a modified Sternberg working memory task with 3 memory loads administered 4 hours after dosing. After adjustment for differences in working memory capacity, each 1 µg/mL of topiramate plasma concentration was associated with a 3.6% decrease in accuracy for all memory loads. Placebo effects occurred as a function of working memory capacity, with individuals with high working memory capacity experiencing less severe placebo-related impairment compared with those with low working memory capacity. Our results demonstrate that severity of topiramate-related cognitive deficits occurs as a function of both drug exposure and baseline cognitive function. By identifying patient- and exposure-related characteristics that modulate the severity of cognitive side effects, topiramate dosing strategies may be individually tailored in the future to prevent unwanted cognitive impairment.

Working Memory Capacity Is Negatively Associated with Memory Load Modulation of Alpha Oscillations in Retention of Verbal Working Memory.

Working memory capacity (WMC) measures the amount of information that can be maintained online in the face of distraction. Past work has shown that the efficiency with which the frontostriatal circuit filters out task-irrelevant distracting information is positively correlated with WMC. Recent work has demonstrated a role of posterior alpha oscillations (8-13 Hz) in providing a sensory gating mechanism. We investigated the relationship between memory load modulation of alpha power and WMC in two verbal working memory experiments. In both experiments, we found that posterior alpha power increased with memory load during memory, in agreement with previous reports. Across individuals, the degree of alpha power modulation by memory load was negatively associated with WMC, namely, the higher the WMC, the less alpha power was modulated by memory load. After the administration of topiramate, a drug known to affect alpha oscillations and have a negative impact on working memory function, the negative correlation between memory load modulation of alpha power and WMC was no longer statistically significant but still somewhat detectable. These results suggest that (1) individuals with low WMC demonstrate stronger alpha power modulation by memory load, reflecting possibly an increased reliance on sensory gating to suppress task-irrelevant information in these individuals, in contrast to their high WMC counterparts who rely more on frontal areas to perform this function and (2) this negative association between memory load modulation of alpha oscillations and WMC is vulnerable to drug-related cognitive disruption.

Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy.

OBJECTIVE: To evaluate the pharmacokinetics of a purified oral cannabidiol (CBD) capsule administered with and without food in adults with refractory epilepsy. METHODS: Adult patients who were prescribed CBD for seizures, had localization-related intractable epilepsy with ≥4 seizures per month, and qualified for Minnesota cannabis were enrolled. A single dose of 99% pure CBD capsules was taken under both fasting (no breakfast) and fed (high fat 840-860 calorie) conditions. Blood sampling for CBD plasma concentrations was performed under each condition between 0 and 72 hours post-dose and measured by a validated liquid chormatography-mass spectometry assay. CBD pharmacokinetic profiles including maximum concentration (Cmax ), area-under-the-curve from zero to infinity (AUC0-∞ ), and time-to-maximum concentration (Tmax ) were calculated. The confidence intervals (CIs) for log-transformed Cmax and AUC0-∞ ratios between fed and fasting states were calculated. Seizure and adverse events information was collected. RESULTS: Eight patients completed the study. On average Cmax was 14 times and AUC0-∞ 4 times higher in the fed state. The 90% CI for the ratio of fed versus fast conditions for Cmax and AUC0-∞ were 7.47-31.86 and 3.42-7.82, respectively. No sequence or period effect for Cmax and AUC0-∞ was observed. No adverse events were reported. SIGNIFICANCE: Administering CBD as a capsule rather than a liquid allows for more precise determination of pharmacokinetics parameters and is more representative of CBD swallowed products. The fat content of a meal can lead to significant increases in Cmax and AUC0-∞ and can account for variability in bioavailability and overall drug exposure within patients with oral products.

Individual Differences in Working Memory Capacity Predict Topiramate-Related Cognitive Deficits.

PURPOSE/BACKGROUND: Topiramate (TPM) and lorazepam (LZP) are two examples of frequently prescribed medications that are associated with a high incidence of cognitive impairment; however, the factors that underlie interindividual differences in side effect profiles have not been fully characterized. Our objective was to determine whether working memory capacity (WMC), the amount of information that can be stored and manipulated in memory over short time intervals, is one such factor. METHODS/PROCEDURES: Twenty-nine healthy volunteers completed a double-blind, randomized, placebo-controlled crossover study during which they received placebo (PBO), TPM, and LZP in random order. Four hours after drug administration, a blood draw was taken to establish drug concentrations, and subjects performed a verbal working memory task while the accuracy and reaction time of their responses were recorded. Working memory capacity was calculated based on accuracy rates during the PBO session, and the role of WMC in moderating the severity of drug-related cognitive impairment was assessed by examining drug-related performance changes from PBO as a function of WMC. FINDINGS/RESULTS: Both TPM and LZP had a negative impact on task performance, although only TPM-related deficits were modulated by WMC; high WMC was associated with more severe impairments and heightened sensitivity to increasing TPM concentrations. IMPLICATIONS/CONCLUSIONS: We have identified a potential clinical risk factor, high WMC, which is associated with drug-related adverse cognitive events. These data provide objective evidence in support of clinical observations that high-functioning patients are more likely to experience severe cognitive impairments.

Thai lexical tone perception in native speakers of Thai, English and Mandarin Chinese: an event-related potentials training study.

BACKGROUND: Tone languages such as Thai and Mandarin Chinese use differences in fundamental frequency (F0, pitch) to distinguish lexical meaning. Previous behavioral studies have shown that native speakers of a non-tone language have difficulty discriminating among tone contrasts and are sensitive to different F0 dimensions than speakers of a tone language. The aim of the present ERP study was to investigate the effect of language background and training on the non-attentive processing of lexical tones. EEG was recorded from 12 adult native speakers of Mandarin Chinese, 12 native speakers of American English, and 11 Thai speakers while they were watching a movie and were presented with multiple tokens of low-falling, mid-level and high-rising Thai lexical tones. High-rising or low-falling tokens were presented as deviants among mid-level standard tokens, and vice versa. EEG data and data from a behavioral discrimination task were collected before and after a two-day perceptual categorization training task. RESULTS: Behavioral discrimination improved after training in both the Chinese and the English groups. Low-falling tone deviants versus standards elicited a mismatch negativity (MMN) in all language groups. Before, but not after training, the English speakers showed a larger MMN compared to the Chinese, even though English speakers performed worst in the behavioral tasks. The MMN was followed by a late negativity, which became smaller with improved discrimination. The High-rising deviants versus standards elicited a late negativity, which was left-lateralized only in the English and Chinese groups. CONCLUSION: Results showed that native speakers of English, Chinese and Thai recruited largely similar mechanisms when non-attentively processing Thai lexical tones. However, native Thai speakers differed from the Chinese and English speakers with respect to the processing of late F0 contour differences (high-rising versus mid-level tones). In addition, native speakers of a non-tone language (English) were initially more sensitive to F0 onset differences (low-falling versus mid-level contrast), which was suppressed as a result of training. This result converges with results from previous behavioral studies and supports the view that attentive as well as non-attentive processing of F0 contrasts is affected by language background, but is malleable even in adult learners.

Effects of native language and training on lexical tone perception: an event-related potential study.

Tone languages such as Thai use pitch differences to distinguish lexical meaning. Previous behavioral studies have reported that naïve listeners can discriminate among lexical tones, but that native language background affects performance. The present study uses ERPs to determine whether native speakers of a tone language (Mandarin Chinese) and of a non-tone language (English) differ in their pre-attentive discrimination among Thai lexical tones, and whether training has a different effect in these two language groups. EEGs were obtained from 10 native Mandarin Chinese speakers, 10 English and 10 Thai speakers in an oddball paradigm: The Thai syllable [k(h)a:] pronounced with a high rising or low falling tone, was presented as an infrequent deviant amidst a standard mid level tone [k(h)a:] syllable, while participants watched a silent movie. Next, the Chinese and English participants completed a 2-day perceptual identification training on the mid level and low falling tones, and returned for a post training EEG. The low falling tone deviant elicited a Mismatch Negativity (MMN) in all participant groups before and after training; the high rising deviant elicited no, or a smaller, MMN, which became larger after training only in the English group. The high rising deviant also elicited a later negativity (350-650 ms) versus the mid level standard, which decreased after training in the Chinese group. These results suggest that non-Thai speakers can pre-attentively discriminate among Thai tones, but are sensitive to different physical properties of the tones, depending on their native language. English speakers are more sensitive to early pitch differences, whereas native speakers of Mandarin Chinese are more sensitive to the (later) pitch contour.

Processing bare quantifiers in discourse.

During reading or listening, language comprehenders construct a mental representation of the objects and events mentioned. This model is augmented and modified incrementally as the discourse unfolds. In this paper we focus on the interpretation of bare quantifiers, that is, expressions such as 'two', to investigate the processes underlying the construction and modification of the discourse model. Bare quantifiers are temporarily ambiguous when sentences are processed incrementally. For instance, in 'Three ships were in the port. Two...', 'two' can either refer to a subset of the set just mentioned (e.g.,'two of the three ships'), a different set of the entities mentioned (e.g., 'two other ships'), or a set of different entities (e.g., 'two people'). Data from previous studies, and a current completion study, suggest that the subset interpretation is preferred over the establishment of a different set. The current study aimed to investigate ERP correlates of quantifier interpretation and their timing. Quantifiers that unambiguously signaled the establishment of a new referent elicited a late positive component (900-1500 ms), which we interpret as a Late Positive Complex, related to the difficulty involved in context updating. An additional 500-700 ms positivity was elicited only in a subset of readers, suggesting that there are individual differences in quantifier interpretation and the timing thereof.