Daniel Storzbach

Effects of Gabapentin and Carbamazepine on the EEG and Cognition in Healthy Volunteers

Summary:  Purpose: Antiepileptic drug (AED) therapy can be associated with neurotoxic side effects including cognitive dysfunction. Objective methods for detection of neurotoxicity in individual patients would be useful. We studied the effects of gabapentin (GBP) and carbamazepine (CBZ) on neurophysiologic and cognitive/behavioral measures in healthy volunteers.

Test–retest bias, reliability, and regression equations for neuropsychological measures repeated over a 12–16-week period

The interpretation of neurobehavioral change over time requires knowledge of the test-retest characteristics of the measures. Without this information it is not possible to distinguish a true change (i.e., one reflecting the occurrence or resolution of an intervening process) from that occurring on the basis of chance or systematic bias. We tested a group of 72 healthy young to middle aged adults twice over a 12-to-16-week interval in order to observe the change in scores over time when there was no known intervention. The test battery consisted of seven commonly used cognitive measures and the Profile of Mood States (POMS). Test-retest regression equations were calculated for each measure using initial performance, age, education, and a measure of general intellectual function (Wonderlic Personnel Test) as regressors. Test-retest correlations ranged from .39 (POMS Fatigue) to .89 (Digit Symbol). Cognitive measures generally yielded higher correlations than did the POMS. Univariate regressions based only on initial performance adequately predicted retest performance for the majority of measures. Age and education had a relatively minor influence. Practice effects and regression to the mean were common. These test-retest regression equations can be used to predict retest scores when there has been no known intervention. They can also be used to generate statistical statements regarding the significance of change in an individuals performance over a 12-to-16-week interval.

Efficacy of Cognitive Rehabilitation Therapies for Mild Cognitive Impairment (MCI) in Older Adults: Working Toward a Theoretical Model and Evidence-Based Interventions

To evaluate the efficacy of cognitive rehabilitation therapies (CRTs) for mild cognitive impairment (MCI). Our review revealed a need for evidence-based treatments for MCI and a lack of a theoretical rehabilitation model to guide the development and evaluation of these interventions. We have thus proposed a theoretical rehabilitation model of MCI that yields key intervention targets–cognitive compromise, functional compromise, neuropsychiatric symptoms, and modifiable risk and protective factors known to be associated with MCI and dementia. Our model additionally defines specific cognitive rehabilitation approaches that may directly or indirectly target key outcomes–restorative cognitive training, compensatory cognitive training, lifestyle interventions, and psychotherapeutic techniques. Fourteen randomized controlled trials met inclusion criteria and were reviewed. Studies markedly varied in terms of intervention approaches and selected outcome measures and were frequently hampered by design limitations. The bulk of the evidence suggested that CRTs can change targeted behaviors in individuals with MCI and that CRTs are associated with improvements in objective cognitive performance, but the pattern of effects on specific cognitive domains was inconsistent across studies. Other important outcomes (i.e., daily functioning, quality of life, neuropsychiatric symptom severity) were infrequently assessed across studies. Few studies evaluated long-term outcomes or the impact of CRTs on conversion rates from MCI to dementia or normal cognition. Overall, results from trials are promising but inconclusive. Additional well-designed and adequately powered trials are warranted and required before CRTs for MCI can be considered evidence-based.

Test-Retest Reliability of Psychological and Neurobehavioral Tests Self-Administered by Computer:

A series of 12 psychological and 7 neurobehavioral performance tests were administered twice to a nonclinical normative sample with 1 week between administrations. The tests were presented in a self-administered computerized format. One week test-retest reliabilities were comparable to conventional administration formats. The results suggest that individual test reliability is not affected when tests are administered as part of an extensive multi-measure battery. Computer administered test reliability coefficients also were compared to a Mixed Format (computer-conventional) administration with mixed format reliabilities generally similar to the reliabilities of published conventional tests but also generally lower than same format testing. Compared to psychological test reliability, neurobehavioral test reliability appeared more vulnerable to decreases with mixed format testing. These conclusions should not be generalized to all computer implemented tests as the qualities of the test implementation will affect the outcome.

Assessment of CNS Effects of Antiepileptic Drugs by Using Quantitative EEG Measures

Summary:  Purpose: Antiepileptic drugs (AEDs) can be associated with adverse neurologic effects including cognitive dysfunction. Objective methods for recognizing AED effects on the brain could be valuable for long‐term management. We compared quantitative EEG measures and cognitive tests in a group of patients beginning or ending AED therapy.

Symptom factor analysis, clinical findings, and functional status in a population-based case control study of Gulf War unexplained illness.

Few epidemiological studies have been conducted that have incorporated clinical evaluations of Gulf War veterans with unexplained health symptoms and healthy controls. We conducted a mail survey of 2022 Gulf War veterans residing in the northwest United States and clinical examinations on a subset of 443 responders who seemed to have unexplained health symptoms or were healthy. Few clinical differences were found between cases and controls. The most frequent unexplained symptoms were cognitive/psychological, but significant overlap existed with musculoskeletal and fatigue symptoms. Over half of the veterans with unexplained musculoskeletal pain met the criteria for fibromyalgia, and a significant portion of the veterans with unexplained fatigue met the criteria for chronic fatigue syndrome. Similarities were found in the clinical interpretation of unexplained illness in this population and statistical factor analysis performed by this study group and others.

Effects of oxcarbazepine and phenytoin on the EEG and cognition in healthy volunteers

We studied the EEG and cognitive effects of oxcarbazepine (OXC) and phenytoin (PHT) using a double-blind, randomized, parallel-group design. Thirty-two healthy volunteers received a maximum of 1200 mg of OXC or 360 mg of PHT. EEG and cognitive testing were performed at baseline and after 12 weeks of treatment. For each subject and measure, test-retest Z scores were calculated from regression equations derived from 73 healthy controls. Twenty-six subjects completed the study. Both the OXC and PHT groups had significant slowing of the EEG peak frequency and increased relative theta and delta power. Differences between AEDs (antiepileptic drugs) were not significant. Significant cognitive effects were seen on 5 of 20 measures, primarily measures of motor speed and reaction time. Again, there were no significant differences between AEDs. The only significant difference between AEDs was for the POMS-Vigor scale, favoring OXC. The small sample size may have contributed to the lack of significant differences between AEDs.

Subjective Cognitive Complaints, Affective Distress, and Objective Cognitive Performance in Persian Gulf War Veterans

We examined subjective cognitive complaints, affective distress, and cognitive performance in Persian Gulf veterans who reported illness and cognitive complaints. We predicted a stronger relationship between subjective cognitive complaints and affective distress than between subjective cognitive complaints and objective cognitive performance. This prediction was confirmed in a sample of 100 veterans. The results suggest that cognitive impairment should not be diagnosed in this population without objective confirmation with cognitive testing.

Cognitive effects of pregabalin in healthy volunteers A double-blind, placebo-controlled trial

Background: Antiepileptic drugs (AEDs) can be associated with neurotoxic side effects including cognitive dysfunction, a problem of considerable importance given the usual long-term course of treatment. Pregabalin is a relatively new AED widely used for the treatment of seizures and some types of chronic pain including fibromyalgia. We measured the cognitive effects of 12 weeks of pregabalin in healthy volunteers. Methods: Thirty-two healthy volunteers were randomized in a double-blind parallel study to receive pregabalin or placebo (1:1). Pregabalin was titrated over 8 weeks to 600 mg/d. At baseline, and after 12 weeks of treatment, all subjects underwent cognitive testing. Test-retest changes in all cognitive and subjective measures were Z scored against test-retest regressions previously developed from 90 healthy volunteers. Z scores from the placebo and pregabalin groups were compared using Wilcoxon tests. Results: Thirty subjects completed the study (94%). Three of 6 target cognitive measures (Digit Symbol, Stroop, Controlled Oral Word Association) revealed significant test-retest differences between the pregabalin and placebo groups, all showing negative effects with pregabalin (p < 0.05). These cognitive effects were paralleled by complaints on the Portland Neurotoxicity Scale, a subjective measure of neurotoxicity (p < 0.01). Conclusion: At conventional doses and titration, pregabalin induced mild negative cognitive effects and neurotoxicity complaints in healthy volunteers. These effects are one factor to be considered in the selection and monitoring of chronic AED therapy. Class of Evidence: This study provides Class I evidence that pregabalin 300 mg BID negatively impacts cognition on some tasks in healthy volunteers.

Psychological differences between veterans with and without Gulf War unexplained symptoms

Objective The objective of this study was to assess measures of psychological and neurobehavioral functioning to determine their association with unexplained symptoms in Gulf War veterans. Methods An epidemiological survey focusing on exposures and symptoms was mailed to a random sample of Gulf War veterans from Oregon and southwestern Washington. Volunteers were recruited from survey respondents who agreed to undergo a thorough medical examination and psychological and neurobehavioral assessment. Persistent symptoms with no medical explanation associated with service in the Persian Gulf (eg, fatigue, muscle pain, and memory deficits) that began during or after the war qualified respondents as cases. The 241 veterans with unexplained symptoms were classified as case subjects, and the 113 veterans without symptoms were classified as control subjects. All veterans completed a battery of computerized assessment tests consisting of 12 psychosocial and 6 neurobehavioral tests. Differences between case and control subjects on neurobehavioral and psychological variables were assessed with univariate and multivariate statistical comparisons. Results Case subjects differed substantially and consistently from control subjects on diverse psychological tests in the direction of increased distress and psychiatric symptoms. Case subjects had small but statistically significant deficits relative to control subjects on some neurobehavioral tests of memory, attention, and response speed. A logistic regression model consisting of four psychological variables but no neurobehavioral variables classified case and control subjects with 86% accuracy. Conclusions Our results revealed that Gulf War veterans who report symptoms associated with that conflict differed on multiple psychological measures in the direction of increased distress and performed more poorly on neurobehavioral measures when compared with control subjects who did not report symptoms. This suggests that psychological differences have a prominent role in investigation of possible explanations of Gulf War symptoms.