Cognitive compromise following exercise in monozygotic twins discordant for chronic fatigue syndrome: fact or artifact?

This study examined the effects of exhaustive exercise on cognitive functioning among 21 monozygotic twin pairs discordant for chronic fatigue syndrome (CFS). The co-twin control design adjusts for genetic and family environmental factors not generally accounted for in more traditional research designs of neuropsychological function. Participants pedaled a cycle ergometer to exhaustion; maximum oxygen output capacity (VO2max) as well as perceived exertion were recorded. Neuropsychological tests of brief attention and concentration, speed of visual motor information processing, verbal learning and recognition memory, and word and category fluency were administered with alternate forms to participants pre- and postexercise. The preexercise neuropsychological test performance of CFS twins tended to be slightly below that of the healthy twin controls on all measures. However, twins with CFS did not demonstrate differential decrements in neuropsychological functioning after exercise relative to their healthy co-twins. Because exercise does not appear to diminish cognitive function, rehabilitative treatment approaches incorporating exercise are not contraindicated in CFS.

Satisfaction of forensic psychiatric patients with remote telepsychiatric evaluation.

The level of satisfaction with telepsychiatry evaluations was determined in a sample of 43 forensic psychiatric patient inmates in a large urban jail. A forensic psychiatrist interviewed 20 patients in person, the other 23 remotely via interactive video. Demographic characteristics, physical health status, and psychiatric symptom severity on the Global Severity Index of the Brief Symptom Inventory were comparable in the two groups. Patient satisfaction with the evaluations was moderately high for patients in both groups, with no significant differences between them.

Neuropsychological function in retired workers with previous long-term occupational exposure to solvents.

OBJECTIVES: It is plausible that neurodegenerative processes of aging might have a contributing role in the development of chronic effects of exposure to organic solvents. This study evaluated the risk for neuropsychological deficits among retired workers, relative to their histories of exposure to occupational solvents. METHODS: This cross sectional study evaluated retired male workers, 62-74 years of age, including 89 people with previous long-term occupational exposure to solvents (67 retired painters and 22 retired aerospace manufacturing workers), and 126 retired carpenters with relatively minimal previous exposure to solvents. Subjects completed a standardised neuropsychological evaluation and psychiatric interview, structured interviews for histories of occupational exposure and alcohol consumption, and questionnaires assessing neurological and depressive symptoms. RESULTS: By comparison with the carpenters, the painters on average reported greater cumulative alcohol consumption and had lower scores on the WAIS-R vocabulary subtest, usually presumed to reflect premorbid intellectual functioning. These findings, however, were not sufficient to account for the other study findings. Controlling for age, education, vocabulary score, and alcohol use, the painters had lower mean scores on test measures of motor, memory, and reasoning ability; and a subgroup of aerospace workers with moderate to high cumulative exposure to solvents (n = 8) had lower mean scores on measures of visuomotor speed, and motor, attention, memory, and reasoning ability. Subjects were more likely to have an increased number of relatively abnormal test scores (three or more outlier scores on 17 test measures) among both the painter group (odds ratio (OR), 3.1; 95% confidence interval (95% CI) 1.5 to 6.2) and the subgroup of aerospace workers with higher cumulative exposure (OR 5.6; 95% CI 1.0 to 38). The painters, but not the aerospace workers, reported significantly more neurological and depressive symptoms. CONCLUSIONS: The findings are consistent with residual central nervous system dysfunction from long-term exposure to organic solvents, persisting years after the end of exposure.

Antidepressant efficacy in HIV-seropositive outpatients with major depressive disorder: an open trial of nefazodone.

BACKGROUND: Treatment studies of major depression in patients who are seropositive for the human immunodeficiency virus (HIV) have shown comparable efficacy for both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Nefazodone appears to be more tolerable than TCAs and similar to SSRIs. This study examined the efficacy and tolerability of nefazodone in an open 12-week trial of HIV-seropositive outpatients with major depressive disorder. METHOD: Fifteen HIV-seropositive patients with DSM-IV major depressive disorder and a 21-item Hamilton Rating Scale for Depression (HAM-D) score of > or =18 were treated with open-label nefazodone for 12 weeks. Hamilton Rating Scale for Anxiety, HAM-D, Clinical Global Impressions scale, and Systematic Assessment for Treatment Emergent Events general inquiry (for safety and tolerability) scores were obtained at weeks 2, 4, 6, 8, and 12. RESULTS: Of 15 patients receiving nefazodone, 4 discontinued treatment (1 for adverse effects). Of 11 patients who completed the trial, 8 (73%) were classified as full responders with a 50% reduction in HAM-D scores and final CGI score of 1 or 2, and 10 (91%) were classified as partial responders (only 50% reduction in HAM-D scores). Nefazodone-treated subjects experienced few total adverse effects (mean = 1.5), no sexual side effects, and low rates of adverse-effect-related dropout (1 subject, 7%). CONCLUSION: Depressed HIV-seropositive outpatients respond to nefazodone comparably to other outpatient populations and have few adverse effects, suggesting that nefazodone may have a role in the treatment of depression in HIV-seropositive patients. Potential drug interactions with protease inhibitors indicate that it is essential to evaluate for appropriate dosing to avoid adverse effects and increase overall antidepressant efficacy.

Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients.

OBJECTIVE: This study examined whether a selective serotonin reuptake inhibitor (paroxetine) had comparable efficacy but greater tolerability than a tricyclic antidepressant (imipramine) in depressed patients with HIV infection. METHOD: Seventy-five HIV-positive patients (45% of whom had AIDS) were blindly and randomly assigned to receive paroxetine (N = 25), imipramine (N = 25), or placebo (N = 25) in a 12-week trial. The Hamilton Anxiety Rating Scale, the Hamilton Depression Rating Scale, the Clinical Global Impression scale, and the SAFETEE general inquiry (for safety and tolerability) were administered at weeks 2, 4, 6, 8, and 12. RESULTS: Fifty-six (75%) of the 75 patients completed 6 weeks and 34 (45%) completed 12 weeks of the trial. The mean daily doses of both paroxetine (33.9 mg) and imipramine (162.5 mg) were significantly more effective than placebo; they were comparably effective at weeks 6, 8, and 12 according to the intent-to-treat analysis and at week 8 according to the analysis for the subjects who completed the trial (for them, only imipramine was superior to placebo at week 12). There were significantly more dropouts due to side effects from imipramine (48%) than from both paroxetine (20%) and placebo (24%). CONCLUSIONS: Depressed patients with HIV infection responded to imipramine or paroxetine at a higher rate than to placebo irrespective of severity of immunosuppression. Because paroxetine was much better tolerated than imipramine, its overall effectiveness may be greater. However, because of the small study group and the high attrition rate, these findings cannot be generalized and may need replication in a larger study group.

Depression and Chronic Obstructive Pulmonary Disease: Treatment Trials.

Chronic obstructive pulmonary disease (COPD) affects over 16 million people in the United States and is a major cause of disability and death worldwide. Its prevalence and mortality are increasing disproportionately among the elderly, women, African-Americans, persons of lower socioeconomic status, and the populations of developing countries in which tobacco is aggressively marketed. In contrast to other major chronic diseases such as heart disease and cancer, medical treatments for COPD have not made decisive inroads into its morbidity or death rates over the last 20 years, resulting in continuing efforts to reduce disability in patients with established disease. Depression is a source of increased disability in COPD, and, as in other chronically ill patient populations, is often unrecognized and untreated in the primary and specialty care sectors. Nearly half of all patients experience some depressive symptoms and at least one-fifth have had one or more major depressive episodes, frequently of long duration. Evidence from randomized controlled trials supports the thesis that patients with mild depression improve with multidisciplinary rehabilitation, whereas patients with major depression may require specific pharmacotherapy to achieve significant improvement in mood disorder and day-to-day function. In addition to its impact on disability, depression may contribute indirectly to the etiology and progression of COPD through its relationship to addictive smoking. Mood disorder in adolescence and early adulthood contributes to early smoking and failure to quit, even after the onset of respiratory disease in later life. Patients with a history of major depression are more likely to fail in smoking cessation programs and to develop a major depressive episode when they do stop. This relationship calls for psychiatrically informed intervention models to improve long-term abstinence rates. The functional impairments associated with COPD are themselves potential promoters of depressive morbidity and chronicity, acting through complex causal pathways. Progressive hypoxia due to respiratory insufficiency leads to structural brain changes and neurocognitive deficits that impair day-to-day function and reduce adaptive potential; and oxygen therapy, as now practiced, offers minimal neurocognitive and mood benefits to most patients. Limited data from studies of experimental hypoxia in animals suggest that relatively mild lack of oxygen impairs the function and plasticity of critical neurotransmitter systems implicated in both cognition and mood, although current practice standards withhold oxygen therapy until late in the course of disease when the damaging effects of hypoxia on the brain have become well established. Neuropsychiatric approaches to the prevention, delay, and treatment of brain dysfunction should be a primary objective of research to improve patient outcomes. A comprehensive relational model that links pulmonary disease, hypoxia, neurocognitive impairment, and structural brain disease with depression provides a useful framework for the design of such studies. The near-term research agenda should include three components: (1) practical methods for improving physician and patient recognition of depression and neurocognitive impairment as targets for intervention; (2) additional trials of standard antidepressant treatment approaches for both major and minor depression; and (3) tests of the hypothesis that late-onset depression in patients with COPD is a marker for the presence of neurocognitive deficits and structural brain changes. The long-range research agenda must aim at preventive interventions designed to forestall brain deterioration. Controlled clinical trials of supplemental oxygen in patients with mild hypoxia and minimal cognitive deficits are needed to determine whether early treatment can reverse or moderate decline, reduce the incidence and chronicity of depression, and improve response to antidepressant treatment. Novel neuroprotective therapies such as antioxidant supplementation and modulation of monoaminergic neurotransmission, coupled with overall improvements in long-term respiratory disease management that minimize episodes of increased systemic oxidative stress, should be considered for multisite trials designed to define optimal treatment and prevention.

Cognitive functions and complaints in HIV-1 individuals treated for depression.

Progressive neuropsychological dysfunction and complaints of cognitive difficulty frequently accompany HIV-1 infection. Providing appropriate treatment to HIV-1 patients requires determination of the extent to which the presentation of cognitive complaints reflects HIV-1-associated neuropsychological abnormalities or represents expression of depressive symptomatology. We prospectively treated 75 HIV-1 patients who were not demented but met criteria for major mood disorder with antidepressants for 12 weeks and compared pretreatment and posttreatment measures of depression, cognitive complaints, and neuropsychological performance. Complaints of difficulty with memory and attention were found to be independent of neuropsychological impairment, whereas memory complaints were highly correlated with severity of depression. Cognitive complaints declined significantly across the course of treatment for those patients who responded to antidepressant treatment. All patients, regardless of antidepressant treatment response, exhibited parallel improvement on 12-week follow- up neuropsychological examination. These findings suggest that treatment of depression affects cognitive complaints in HIV-1 individuals and that cognitive complaints of patients in asymptomatic or early symptomatic stages of HIV-1 infection may signal the need for evaluation of depression. In patients with more advanced HIV-1 infection, investigation into the basis of cognitive complaints may require a dual assessment of mood disturbance and neuropsychological status.

Relationships between neuropsychological and oculomotor measures in schizophrenia patients and normal controls.

Establishing the relationship between oculomotor and neuropsychological impairments might facilitate a more coherent description of schizophrenia-associated neurocognitive deficits. Therefore, we assessed several aspects of neuropsychological and oculomotor function in 25 medicated schizophrenia patients and 24 age-matched controls. Neuropsychological tasks included the Wisconsin Cart Sort Test (WCST), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test, and finger tapping speed. Oculomotor functions assessed included smooth pursuit, initiation of smooth pursuit, predictive pursuit, fixation, visually guided saccades, remembered saccades, and antisaccades. Among the schizophrenia patients, predictive pursuit performance correlated significantly with finger tapping (dominant hand), TMT (both parts), and one WCST measure (categories completed). The only other significant correlation among the schizophrenia patients was between antisaccade performance and part A of the TMT. Perseverative errors during the WCST and antisaccade performance were the only measures significantly correlated among the normals. Closely related neurocognitive deficits may be responsible for impairments in TMT, WCST, predictive pursuit, and antisaccade performance in schizophrenia.

Neurologic Manifestationsof HIV Infection Without AIDS:Follow-UP of a Cohortof Homosexual and Bisexual Men.

To identify neurological abnormalities in HIV infection, 159 HIV-seropositive men without AIDS and 76 seronegative controls underwent standardized general and neurological examinations, lumbar puncture (LP), neuropsychological (NP) assessment, and brain magnetic resonance (MR) imaging. History, physical, and laboratory evaluations were repeated every six months. NP tests (all subjects) and MR imaging (seropositives only) was repeated every 6-12 months; LP (seropositives only) was repeated yearly. Mean follow-up was 24.6 months. Neurological abnormalities, most related to hearing, were seen in 60 (38.2%) of 157 seropositives and 23 (30.3%) of 76 controls at baseline (p = NS). During follow-up, 43 (31.6%) of 136 seropositives had persistent hearing abnormalities compared to 9 (14.1%) of 64 seronegatives (p = 0.008). Seven HIV-seropositives developed peripheral neuropathy; this was more common among those with hearing abnormalities (p = 0.03). HIV-seropositives performed less well on NP tests than controls, but overall performance did not decline. Worsening brain atrophy by MR imaging or cerebrospinal fluid abnormalities are more common in HIV-seropositives than seronegatives and may share a common mechanism with peripheral neuropathy. Further study is needed to determine whether these abnormalities portend more serious neurological disease.

Effects of low-dose TRH on cognitive deficits in the ECT postictal state.

A low dose (0.5 mg) of thyrotropin-releasing hormone (TRH), a short-acting tripeptide with known analeptic properties, was administered to eight depressed patients 5 minutes after ECT session 3 or 4 in a double-blind, placebo-controlled crossover design. After TRH infusion the patients displayed selectively better performance on a battery of neuropsychological tests than they did after placebo infusion. Further exploration with pharmacological probes to mitigate ECT postictal cognitive deficits is warranted.

Low-dose thyrotropin-releasing hormone effects in cognitively impaired alcoholics.

The cognitive effects of a low dose of thyrotropin-releasing hormone (TRH) (2.0 mg, IV) were evaluated in 18 chronic alcoholic patients who exhibited memory dysfunction secondary to chronic alcohol abuse. The study used a double-blind crossover design that compared cognitive functions in patients with 2.0 mg of TRH IV as compared with a placebo. TRH was chosen because of its ability to enhance cholinergic transmission. Only minimal effects were seen with TRH. Patients with a shorter duration of alcohol use (mean of 16 years) performed significantly better with TRH as compared with placebo on a test involving verbal learning and memory. Those with a more chronic history of alcohol abuse (mean of 27 years) did not show such a response. All of the subjects showed cardiovascular response to TRH. Factors that may have contributed to the results of our study are discussed. It is our impression that future studies evaluating the cognitive effects of TRH in chronic alcoholics need to include an evaluation of the functional activity of TRH in the brain.

Immunologic, psychological, and neuropsychological factors in multiple chemical sensitivity. A controlled study.

OBJECTIVE: To examine the role of immunologic, psychological, and neuropsychological factors in multiple chemical sensitivity. DESIGN: Case-control comparison. SETTING: Community allergy practice (cases), university-based clinics for musculoskeletal injuries (controls). PARTICIPANTS: Forty-one patients with chemical sensitivity and 34 control patients with chronic musculoskeletal injuries. MAIN OUTCOME MEASURES: Immunologic measures included autoantibody titers, lymphocyte surface markers, and interleukin-1 generation by monocytes. Psychological evaluation included standardized measures of anxiety, depression, and somatization. RESULTS: Immunologic testing did not differentiate patients with chemical sensitivity from controls. The only difference noted (lower interleukin-1 generation among cases) appeared attributable to laboratory methods. Patients with chemical sensitivity reported greater prevalence of current anxiety or depressive disorder (44% versus 15%, P = 0.006). This difference, however, did not appear to precede the onset of chemical sensitivity, and 25% of chemically sensitive patients showed no significant current psychological disturbance. Cases reported significantly more "medically unexplained" physical symptoms before and after the onset of chemical sensitivity. When considering only symptoms that preceded chemical sensitivity, 25% of cases (and no controls) satisfied criteria for somatization disorder. Neuropsychological testing revealed no significant case-control differences. CONCLUSIONS: Immunologic testing failed to confirm findings from earlier uncontrolled studies, militating against proposed immunologic mechanisms. The decreased memory and concentration frequently described in multiple chemical sensitivity were not confirmed by brief neuropsychological testing. Psychological symptoms, although not necessarily etiologic, are a central component of chemical sensitivity.

Cognitive risk factors and neuropsychological performance in HIV infection.

Almost all investigations examining the effects of early HIV infection on neuropsychological functioning in homosexual males have excluded subjects with cognitive risk factors such as recreational drug use and head injury. While insuring that results reflect the influence of the virus on cognition, this selection bias limits the ability to generalize findings. Comprehensive neuropsychological evaluations were compared between two groups of homosexual males with a variety of cognitive risk factors. Subjects were 132 HIV seropositive males (108 CDC class II & III and 24 CDC class IVA & IVC2) and 65 HIV seronegative controls. Recreational drug use in the six months prior to exam was found to interact with HIV infection and was associated with selective areas of cognitive decline and a significantly worse overall neuropsychological performance. Although significantly lower functioning in the domains of Verbal Memory and Attention and Speed of Information processing was noted for subjects with CDC class IVA and IVC2 compared to seropositives with CDC class II & III, overall neuropsychological performance was similar in these two groups. At this early stage of HIV infection, we did not find indication of association between neuropsychological performance and decreased immunological status. A history of head injury and recent recreational drug use emerged as primary cognitive risk factors associated with decreased neuropsychological performance. As 50% of our HIV seropositive subjects reported active recreational drug use, this cognitive risk factor in particular may contribute to the appearance of HIV-related cognitive deficits during early stages of HIV infection.

ECT and TRH: cholinergic involvement in a cognitive deficit state.

In this paper we describe the findings from two preliminary experiments, a human and an animal study, investigating whether thyrotropin-releasing hormone (TRH) can mitigate electroconvulsive therapy (ECT)-induced cognitive deficits. Our results suggest further explorations of TRH and its analogs as possible therapeutic agents for these deficits. We speculate that the major cause of the ECT-induced cognitive deficits is a decrease in cholinergic transmission in the central nervous system. Treatments such as TRH, which enhance cholinergic activity, can reverse the cognitive deficits.

Prospective cerebral MR study of HIV seropositive and seronegative men: correlation of MR findings with neurologic, neuropsychologic, and cerebrospinal fluid analysis.

PURPOSE: As part of a longitudinal study of human immunodeficiency virus type 1 (HIV) infection, we attempted to identify early cerebral MR findings that might correlate to clinical evidence of central nervous system involvement. METHODS: We studied 65 seropositive and 40 seronegative homosexual males using cranial MR, neurologic, immunologic, and neuropsychologic examinations. RESULTS: The incidence of mildly enlarged ventricles, sulci, and punctate areas of abnormal signal in both groups was similar in both groups. Diffuse, poorly defined areas of abnormal white matter signal were difficult to consistently identify in seropositives. Enlarged adenoidal lymphoid tissue was found in 30 (46%) of seropositives and 2 (5%) of seronegatives (P = .0001). The incidence of sinus inflammatory change was similar in the two groups. CONCLUSION: MR of intracranial contents is substantially normal in a non-AIDS HIV(+) population.

Neurologic syndrome in 25 workers from an aluminum smelting plant.

BACKGROUND: This article expands on an earlier series of three patients with a neurologic syndrome, who had all worked in an aluminum smelting plant. METHODS: Twenty-five symptomatic workers from the same plant were referred for a standardized evaluation, including completion of a health questionnaire, neurologic examination, and neuropsychologic evaluation. An exposure index was calculated for each worker based on level and duration of exposure in the potroom, where exposures were the greatest. This index was correlated with symptoms, signs, and neuropsychologic test scores. RESULTS: Twenty-two (88%) of the patients reported frequent loss of balance, and 21 (84%) reported memory loss. Neurologic examination revealed signs of incoordination in 21 (84%) of the patients. Neuropsychologic test results showed preservation in certain spheres of functioning, such as verbal IQ, with substantial impairment in others, particularly memory functioning. On memory tests, 70% to 75% showed mild or greater impairment. The majority (17 of 19 tested, or 89%) showed depression on the Minnesota Multiphasic Personality Inventory. The exposure index was significantly correlated with signs and symptoms of incoordination. CONCLUSIONS: This study and others in humans and animals support the existence of a syndrome characterized by incoordination, poor memory, impairment in abstract reasoning, and depression. Aluminum exposure in the potroom seems the most likely cause.

Central nervous system manifestations in human immunodeficiency virus infection without AIDS.

To characterize neurological and neuropsychological findings associated with human immunodeficiency virus type-I (HIV) infection, 77 seropositive homosexual or bisexual males with no or minor symptoms of HIV were compared prospectively to 44 HIV seronegative men by observers blinded to serological status of the subjects. Neurological symptoms and examination findings were not significantly different between seropositives and seronegatives except for cranial nerve findings, predominantly mild hearing impairment. Mean performance scores for a 15-test neuropsychological battery were within an unimpaired range for both groups, although for five tests, mean scores were significantly poorer in seropositives. After adjustment for vocabulary score, and demographic and psychosocial variables, the mean score of seropositives was significantly worse only for the Benton Visual Retention Test. Magnetic resonance (MR) images of brain were abnormal in 14 (27%) of 52 seropositives and one of 10 seronegatives (value was not significant). HIV was isolated from cerebrospinal fluid (CSF) in 31 (61%) of 51 seropositives. The only clinical or laboratory difference between CSF culture positives and negatives was a higher CSF immunoglobulin synthesis rate in the former subjects (medians of 10.3 versus 0.1 mg/day; p = 0.03). An additional 13 seropositive subjects had immunologic evidence of central nervous system HIV infection, defined by a serum-to-CSF HIV antibody ratio of less than 5.5. Intracranial abnormalities on MR imaging were associated with CSF immunologic responses to HIV. Nervous system involvement occurred in the vast majority of men with early HIV infection, but clinically significant impairment was uncommon.

Chronic central nervous system effects of acute organophosphate pesticide intoxication. The Pesticide Health Effects Study Group.

Acute organophosphate pesticide poisonings cause substantial morbidity and mortality world wide; however, whether organophosphates cause chronic neurological sequelae has not been established. To see whether single episodes of acute unintentional organophosphate intoxication lead to chronic neuropsychological dysfunction, we carried out a retrospective study of agricultural workers in Nicaragua who had been admitted to hospital between July 1, 1986, and July 31, 1988, for occupationally related organophosphate intoxication. This "poisoned" group (36 men) was tested on average about two years after the episode of pesticide poisoning and compared with a matched control group. The poisoned group did much worse than the control group on all neuropsychological subtests, with significantly worse performance on five of six subtests of a World Health Organisation neuropsychological test battery and on 3 of 6 additional tests that assessed verbal and visual attention, visual memory, visuomotor speed, sequencing and problem solving, and motor steadiness and dexterity. Differences in neuropsychological performance could not be explained by other factors. The findings of a persistent decrease in neuropsychological performance among individuals with previous intoxication emphasise the importance of prevention of even single episodes of organophosphate poisoning.