Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers.

OBJECTIVE: To evaluate the cognitive effects of topiramate (TPM) and gabapentin (GBP). METHODS: Forty healthy volunteers were randomized to a 12-week course of TPM, GBP, or placebo. Doses were gradually escalated over 10 weeks to a maximum of 400 mg/day of TPM or 3,600 mg/day of GBP or to the highest tolerated dose. Subjects were interviewed and examined biweekly. Cognitive testing was performed prior to initiating the drug and again 12 weeks later, at least 2 weeks after achieving plateau dosing. For each subject and cognitive measure, test-retest Z scores were calculated based on regression equations derived from 73 healthy volunteers. Group comparisons utilized the Wilcoxon test. RESULTS: There were significant TPM vs GBP and TPM vs placebo differences in test-retest Z scores for four of six target cognitive measures (Digit Symbol, Story Recall, Selective Reminding, Controlled Oral Word Association), always indicating worse retest performance for subjects receiving TPM. Overall, 12 of 24 cognitive measures were similarly affected. TPM effects were large, and several target measures averaged >2 SD of negative change. One measure was significantly affected by GBP. CONCLUSIONS: Topiramate (TPM) impaired cognitive test performance, whereas gabapentin had minimal effects. The effects of TPM were of sufficient magnitude potentially to affect daily and occupational function.

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.

Posttraumatic stress symptomatology is associated with unexplained illness attributed to Persian Gulf War military service.

OBJECTIVE: Controversy exists concerning unexplained illness in Persian Gulf War veterans, especially regarding the contribution of psychological trauma. We sought to determine if war zone trauma or posttraumatic stress symptomatology (PTSS) are associated with illnesses reported by Gulf War veterans that were documented by medical examination but not attributable to a medical diagnosis. METHODS: A total of 1119 (55% response rate) of 2022 randomly sampled veterans of the United States Persian Gulf War were screened and 237 cases and 113 controls were identified by medical examination for a case-control study comparing Persian Gulf War military veterans with or without medically documented, but unexplained, symptoms. Multivariate logistic regression and cross-validation analyses examined self-report measures of demographics, subjective physical symptoms and functioning, psychiatric symptoms, stressors, war zone trauma, and PTSS, to identify correlates of case-control status. RESULTS: Posttraumatic stress symptomatology and somatic complaints were independently associated with case status, as were (although less consistently) war zone trauma and depression. Age, education, and self-reported health, stress-related somatization, pain, energy/fatigue, illness-related functional impairment, recent stressors, and anxiety were univariate (but not multivariate) correlates of case status. CONCLUSIONS: PTSS related to war zone trauma warrants additional prospective research study and attention in clinical screening and assessment as a potential contributor to the often debilitating physical health problems experienced by Persian Gulf War veterans.

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 individual's performance over a 12-to-16-week interval.

Neurobehavioral deficits in Persian Gulf veterans: additional evidence from a population-based study.

Reports of low-concentration nerve gas exposures during the Gulf War (GW) have spurred concern about possible health consequences and symptoms reported by many returning veterans. The Portland Environmental Hazards Research Center is studying veterans from the northwest United States who report persistent, unexplained "Gulf War" symptoms (cases) and those who do not report those symptoms (controls). An epidemiological survey focused on exposures and symptoms was mailed to a random sample of GW veterans from Oregon and southwestern Washington. Volunteers recruited from survey respondents agreed to undergo a thorough medical examination and psychological and neurobehavioral assessment. Persistent symptoms with no medical explanation associated with Persian Gulf service (e.g., fatigue, muscle pain, memory deficits) beginning during or after the war qualified respondents as cases. The 239 cases with unexplained symptoms and the 112 controls without symptoms were administered a computerized assessment battery of 12 psychosocial and 6 neurobehavioral tests. Replicating and extending previous interim findings, a subgroup of veterans emerged from the initial analysis in the form of extreme outliers which produced a visually and quantitatively obvious bimodal distribution. This led, as it had previously, to analyses of the outliers as a separate group (labeled "slow ODTP"), which confirmed the initial findings of neurobehavioral differences between the outliers and the other cases and controls and provided more convincing evidence that the majority of cases who report neurobehavioral symptoms have no objective evidence of neurobehavioral deficits. However, the larger group of symptomatic veterans do have highly significant and compelling evidence of psychological distress based on scores from 11 separate psychological tests. Whereas the cases differed from the controls by poorer neurobehavioral test performance, extraction of the slow ODTP participants (almost all cases) eliminated neurobehavioral performance differences between the remaining cases and the controls and provided support for the hypothesis that the slow ODTP cases might have been from the unhealthy end of the GW population prior to the war. However, there was no evidence of poor motivation, pre-GW educational differences, or greater association with abnormal psychological function in this group than in other cases or controls.

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.

Self-reported exposures and their association with unexplained illness in a population-based case-control study of Gulf War veterans.

Many factors have been considered as possible causes of the unexplained illness reported by veterans of the Gulf War (GW). In this study, we report an analysis of risk factors and unexplained illness in a population-based sample of GW veterans who underwent clinical evaluation. Multiple risk factors were compared in 241 veterans who met criteria for unexplained illness and 113 healthy controls. Results suggest that GW unexplained illness is most highly associated with combat conditions, heat stress, and having sought medical attention during the GW. When controlling for multiple simultaneous exposures during the GW, interactions around pyridostigmine bromide, insecticides and repellents, and stress were not significant. These results indicate that most unexplained illness in GW veterans cannot be explained by neurotoxic effects of exposures to chemicals that inhibit cholinesterase activity.

Neurobehavioral deficits associated with chronic fatigue syndrome in veterans with Gulf War unexplained illnesses.

Gulf War unexplained illnesses (GWUI) are a heterogeneous collection of symptoms of unknown origin known to be more common among veterans of the Gulf War than among nonveterans. In the present study we focused on one of these unexplained illnesses. We tested the hypothesis that in a sample of Persian Gulf War veterans chronic fatigue syndrome (CFS) was associated with cognitive deficits on computerized cognitive testing after controlling for the effects of premorbid cognitive differences. We obtained Armed Forces Qualification Test (AFQT) data acquired around the date of induction into the military on 94 veterans of the Gulf War, 32 with CFS and 62 healthy controls. Controls performed better than participants diagnosed with CFS on the AFQT. Cognitive deficits were associated with CFS on 3 of 8 variables after the effect of premorbid AFQT scores was removed with ANCOVA.

Neurobehavioral testing in humans.

The evaluation of the effects of chemical exposures on humans is a worldwide concern, and most chemicals have not been evaluated for neurotoxic effect. Human neurobehavioral research or clinical evaluations of populations exposed to chemicals must be carefully planned and structured. This unit describes the steps required to create such a study, select the appropriate measures, and evaluate the results.

Psychological differences between veterans with and without Gulf War unexplained symptoms. Portland Environmental Hazards Research Center.

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.

Improved prediction of nonepileptic seizures with combined MMPI and EEG measures.

PURPOSE: Nonepileptic seizures (NESs) are frequently mistaken for epileptic seizures (ESs). Improved detection of patients with NESs could lead to more appropriate treatment and medical cost savings. Previous studies have shown the MMPI/MMPI-2 to be a useful predictor of NES. We hypothesized that combining the MMPI-2 with a physiologic predictor of epilepsy (routine EEG; rEEG) would result in enhanced prediction of NES. METHODS: Consecutive patients undergoing CCTV-EEG monitoring underwent rEEG evaluation and completed an MMPI-2. Patients were subsequently classified as having epilepsy (n = 91) or NESs (n = 76) by using standardized criteria. Logistic regression was used to predict seizure type classification. RESULTS: Overall classification accuracy was 74% for rEEG, 71% for MMPI-2 Hs scale, and 77% for MMPI-2 Hy scale. The model that best predicted diagnosis included rEEG, MMPI-2, and number of years since the first spell, resulting in an overall classification accuracy of 86%. CONCLUSIONS: The high accuracy achieved by the model suggests that it may be useful for screening candidates for diagnostic telemetry.

Comparison of MMPI-2 profiles of Gulf War veterans with epileptic and nonepileptic seizure patients.

As part of a larger study of illnesses related to service in the Gulf War, MMPI-2 profiles of epileptic seizure (ES) patients; nonepileptic seizure (NES) patients; Gulf War veterans with unexplained cognitive, psychological, musculoskeletal, fatigue, or dermatologic symptoms; and asymptomatic Gulf War veterans (Controls) were analyzed. There were 70 people in each group. Seizure diagnosis was based upon intensive EEG monitoring. Gulf War cases were mildly abnormal on MMPI-2 Scales Hs and D and significantly higher than controls on 8 of 10 MMPI-2 clinical scales, but they were significantly lower than NES patients on several scales including Hs and Hy.

Gulf War unexplained illnesses: persistence and unexplained nature of self-reported symptoms.

Most published reports of health symptoms among Gulf War (GW) veterans have been based on self-reported questionnaire data. The presence of these symptoms at the time of a clinical evaluation and the unexplained nature of the symptoms have not been described. We report the findings of a sample of symptomatic veterans that were examined as part of a population-based case-control study of GW unexplained illnesses. Participants in the case-control study were selected from responders to a cross-sectional survey of a random sample of GW veterans residing in the northwestern United States. The initial survey questionnaire solicited information on the presence of fatigue and psychological/cognitive, gastrointestinal, musculoskeletal, and dermatological problems. The persistence of the symptoms and possible explanatory diagnoses were explored at the time of the clinical evaluation. Findings from the first 225 participants who completed clinical examinations indicate significant differences between self-reported symptoms on the survey questionnaire and those confirmed at the time of clinical exam. The agreement between symptoms reported both on the survey and at the time of examination varies across the symptom groups. While self-reported unexplained fatigue was confirmed at the time of clinical encounter in 79% of participants, self-reported gastrointestinal symptoms were confirmed at the clinical encounter in only 20% of participants. Differences between symptoms reported on the survey questionnaire and those confirmed at the time of clinical encounter were attributable to finding a clinical diagnosis for the symptom, resolution of symptom(s) between time of questionnaire and clinical exam, and inadvertent endorsement of the symptom on the questionnaire. These findings suggest that due to the possibility of outcome misclassification, inappropriate conclusions may be drawn about the association between exposures and unexplained illnesses in GW veterans from data derived solely from self-administered questionnaires.

Cognitive functioning in schizophrenia: implications for psychiatric rehabilitation.

Research in psychopathology and the cognitive neurosciences suggests new applications in psychiatric rehabilitation. Analysis of performance deficits on laboratory tasks can contribute to treatment planning, individual and family counseling, and staff consultation, much like it does in cases of brain injury and other types of central nervous system neuropathology. Recognition of the nature of cognitive impairments in schizophrenia can inform design of psychosocial techniques such as social and living skills training. Cognitive impairments are increasingly seen as potential targets for pharmacological and psychosocial treatment and rehabilitation. In this article, three key issues for application of cognitive technology in psychiatric rehabilitation of schizophrenia and related disorders are formulated as straightforward, clinically relevant questions: (1) What is the prognostic significance of cognitive impairment in acute psychosis? (2) Can cognitive functioning improve in the chronic, residual course? (3) How does cognitive improvement benefit other aspects of recovery and rehabilitation? These questions are addressed through review of previous findings and new multivariate analyses of cognitive functioning in the acute, post-acute, and chronic residual phases of schizophrenia.

Neurobehavioral deficits in Persian Gulf veterans: evidence from a population-based study. Portland Environmental Hazards Research Center.

Reports of low-concentration nerve gas exposures during the Persian Gulf War have spurred concern about possible health consequences and refocused interest on the symptoms reported by many returning military veterans. The Portland Environmental Hazards Research Center is studying veterans from the Northwest USA who report persistent, unexplained "Persian Gulf" symptoms (cases) or who do not report those symptoms (controls). Of the first 101 veterans studied, cases differed substantially from controls on a broad range of psychological tests indicative of increased distress. A subgroup of cases was identified with objective deficits on neurobehavioral tests of memory, attention, and response speed.

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.

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.

The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease.

OBJECTIVE: To determine the effect of treatment with Ginkgo biloba extract on objective measures of cognitive function in patients with Alzheimer disease (AD) based on formal review of the current literature. METHODS: An attempt was made to identify all English and non-English-language articles in which G. biloba extract was given to subjects with dementia or cognitive impairment. Inclusion criteria for the meta-analysis were (1) sufficiently characterized patients such that it was clearly stated there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, or National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this by our review; (2) clearly stated study exclusion criteria, ie, those studies that did not have stated exclusions for depression, other neurologic disease, and central nervous system-active medications were excluded; (3) use of standardized ginkgo extract in any stated dose; (4) randomized, placebo-controlled and double-blind study design; (5) at least 1 outcome measure was an objective assessment of cognitive function; and (6) sufficient statistical information to allow for meta-analysis. RESULTS: Of more than 50 articles identified, the overwhelming majority did not meet inclusion criteria, primarily because of lack of clear diagnoses of dementia and AD. Only 4 studies met all inclusion criteria. In total there were 212 subjects in each of the placebo and ginkgo treatment groups. Overall there was a significant effect size of 0.40 (P<.0001). This modest effect size translated into a 3% difference in the Alzheimer Disease Assessment Scale-cognitive subtest. CONCLUSIONS: Based on a quantitative analysis of the literature there is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G. biloba extract on objective measures of cognitive function in AD. The drug has not had significant adverse effects in formal clinical trials but there are 2 case reports of bleeding complications. In AD, there are limited and inconsistent data that preclude determining if there are effects on noncognitive behavioral and functional measures as well as on clinician's global rating scales. Further research in the area will need to determine if there are functional improvements and to determine the best dosage. Additional research will be needed to define which ingredients in the ginkgo extract are producing its effect in individuals with AD.

U.S. Gulf War Veterans: service periods in theater, differential exposures, and persistent unexplained illness. Portland Environmental Hazards Research Centre.

Approximately 80,000 of the 697,000 American men and women who were stationed in SW Asia during the Gulf War (GW) report unexplained illness consisting of symptoms of persistent fatigue, cognitive difficulties, such as mild memory loss, diffuse muscle and joint pain, gastrointestinal symptoms, skin lesions, and respiratory problems, among others. Associations between major symptom groups and periods of deployment in the theater of operations have been sought in a population-based, clinical case-control study of GW veterans resident in the north-western region of the United States. No statistically significant differences were evident in the proportion of cases with unexplained fatigue, cognitive/psychological or musculoskeletal symptoms among veterans present in SW Asia in 3 specific time periods: (a) 8/1/1990-12/31/1990 (which includes Desert Shield), (b) the period surrounding Desert Storm (1/1/1991-3/31/1991), and (c) the (post-combat) period immediately following hostilities (4/1/1991-7/31/1991). There was a trend for all 3 case symptoms to be more common among GW veterans who served in the post-combat period. As numbers in these deployment groups were small, and power to detect differences low, the apparent absence of significant differences in the frequency of major symptom groups among these veterans requires confirmation in a larger study. Deployment for discrete periods in SW Asia is a method to separate distinct constellations of environmental factors; these are useful for analyses of associations among symptoms and exposures given the near-total absence of objective data on chemical and other possible exposures in the theater of operations.

Computer-administration of questionnaires: a health screening system (HSS) developed for veterans.

The introduction of microcomputers in psychological research has spawned a burgeoning number of tests of psychological or behavioral function, but few computerized systems for administering questionnaires have been developed. A Health Screening System (HSS) is described that combines the benefits of the paper-and-pencil format (e.g., convenient navigation within test questions) and the added benefits of computer-implementation (e.g., efficiency, automated scoring). The HSS features; a) appealing test appearance (e.g., text in large-size fonts, color backgrounds); b) clear wording of tests and instructions (identical wording as original tests except when clarity is served by changes); c) limiting need for Examiner-Subject interaction (e.g., continuously available on-line training, navigation within test questions, answer review capability, durable 9-button response unit); d) options (e.g., question skipping, spoken instructions, test questions, and answers on command); e) modification capabilities (e.g., color, text, test layout editing, control of test order, automated breaks, addition of tests to system); and f) extras (e.g., kernel of main instruction on each test screen, digitized video, audio message from Examiner in training, copyright notification on each screen, raw and summary data outputs in spreadsheet formal). Ten HSS tests were administered to 22 US military veterans, who took slightly longer to complete them than did 10 veterans who were administered the same tests in their original paper-and-pencil format. User reaction to the computerized HSS was positive.