Meaningful change in cognition in multiple sclerosis: method matters.

OBJECTIVE: To determine if different methods of evaluating cognitive change over time yield measurably different outcomes. METHODS: Twelve cognitively impaired patients with clinically definite Multiple sclerosis (10 relapsing-remitting, 2 secondary progressive) underwent neuropsychological testing (baseline, 6, 12 months). Data was analysed using: t-tests evaluating group differences on individual tests, group differences in composite scores, reliable change analyses at the level of the individual, and comparisons regarding number of tests failed at each time point. RESULTS: Group t-tests on individual tests yielded no change. When tests were grouped according to theoretical constructs, analyses revealed change in processing speed. Reliable change estimates revealed that 16% of the sample deteriorated. When change was measured with respect to the number of domains affected at each time point, 58% of the sample deteriorated on at least one subtest. CONCLUSIONS: Methodology has a significant impact on interpretation of longitudinal data. In the same group of subjects, traditional group analyses documented no change in individual test scores or change on a single composite score. Analyses of individual results documented change from 16 to 58% of the sample. Advantages and disadvantages of each method were discussed. Findings have implications for interpretation of longitudinal studies.

Short-form prediction of WAIS-R scores in a sample of individuals diagnosed with multiple sclerosis.

A short form of the Wechsler Adult Intelligence Scale--Revised (WAIS-R) developed by Ward (WAIS-R/7 SF; 1990) was used to generate Verbal, Performance, and Full Scale IQ scores (VIQ, PIQ, and FSIQ, respectively) in 66 individuals diagnosed with multiple sclerosis (MS). Short-form scores were highly correlated with WAIS-R scores. However, the short-form VIQ and PIQ, but not FSIQ, scores differed significantly from corresponding WAIS-R scores. WAIS-R/7 SF VIQ, PIQ, and FSIQ scores fell within 5, 9, and 6 absolute error points, respectively, of corresponding WAIS-R IQ scores in 95% of cases. Classification of IQ scores into ranges (e.g., average, high average, etc.) based on the scheme outlined by Wechsler (1981) was consistent between WAIS-R/7 SF and WAIS-R scores in 81.8% (for VIQ), 74.8% (for PIQ), and 89.4% (for FSIQ) of cases. These findings are discussed within the context of using the WAIS-R/7 SF in the assessment of MS patients.

Proactive influence of a surgical stressor on locomotor activity, exploration and anxiety-related behaviour following acute footshock in the mouse.

The putative proactive influence of graded surgical stressors including intraventricular cannulation, sham surgery and no surgery on footshock-associated variations of locomotor activity, rearing and anxiogenic behaviour in the light-dark paradigm was evaluated among CD-1 mice. Neither sham surgery nor cannulation of the lateral ventricle altered baseline measures of locomotor activity or rearing relative to the performance of nonoperated control animals. Cannulation exacerbated the depressant influence of acute footshock on locomotor activity, while sham surgery mitigated the disruptive effect of the stressor on locomotor activity during the initial 15-min period of the test session. Footshock suppressed the vertical activity scores of mice regardless of surgical history. Only intraventricular cannulation reduced the baseline time in light scores of mice in the light-dark paradigm with repeated testing relative to animals in the sham surgery and no-surgery conditions. Baseline transition scores were not differentially affected by surgical history. Typically, transition scores were reduced on day 2 relative to day 1, but additional performance decrements were precluded on day 3. Footshock interacted with the surgical stressor of intraventricular cannulation in exaggerating reduced time in light relative to the performance of mice in the remaining surgical conditions. Transition frequency was not differentially influenced by the nature of the surgical stressor and subsequent exposure to footshock. The implications of these data for stressor-induced pathology are discussed.

Vulnerability to stressor-induced disturbances in self-stimulation from the dorsal and ventral A10 area: differential effects of intraventricular D-Ala2-Met5-enkephalinamide, D-Ala2, N-Me-Phe4, Gly-Ol5-enkephalin, and D-Pen2, D-Pen5-enkephalin administration.

D-Ala2-Met5-enkephalinamide (DALA) (1.0 microg/microl) was administered intraventricularly to mice responding for electrical stimulation from the dorsal or ventral aspects of the VTA immediately prior to footshock (Experiment 1). Predictably, footshock reduced self-stimulation from the dorsal but not the ventral VTA immediately, 24, and 168 h following the stressor. Intraventricular DALA administration effected a partial attenuation of stressor-induced self-stimulation reductions from the dorsal VTA immediately and 24 h poststressor. Deficits appeared among DALA-Shocked mice responding for brain stimulation from the ventral VTA during comparable test intervals. The long-term depressant influence of footshock on self-stimulation from the dorsal VTA was abolished among DALA-treated mice and DALA-associated reductions in self-stimulation from the ventral A10 region among stressed mice were not evident 1 week later. Administration of D-Ala2, N-Me-Phe4, Gly-Ol5-enkephalin (DAGO) (0.01 microg/microl) or D-Pen2, D-Pen5-enkephalin (DPDPE) (1.0 microg/microl) intraventricularly prior to footshock effected an immediate and a delayed antagonism, respectively, of the stressor on self-stimulation from the dorsal VTA, which persisted for 1 week. Prophylactic administration of 0.001 microg/microl DAGO or 0.01 microg/microl DPDPE prior to the stressor failed to influence self-stimulation from the ventral VTA (Experiment 2). Administration of 0.01 microg/microl DAGO or 1.0 microg/microl DPDPE among mice responding for brain stimulation from the dorsal VTA following footshock produced a weak therapeutic effect immediately poststressor, but effected protracted amelioration of footshock-induced reductions of self-stimulation from the dorsal VTA (Experiment 3). Taken together, mu, delta, and mu-delta activation influenced self-stimulation differentially from the dorsal and ventral VTA according to the temporal order of opioid peptide challenge relative to stressor imposition. These data are discussed with respect to stressors, motivational alterations, and the putative modulating influence of endogenous enkephalin activity in subareas of the VTA.

Differential effects of immunologic challenge on self-stimulation from the nucleus accumbens and the substantia nigra.

Paralleling the effects of uncontrollable stressors, systemic administration of sheep red blood cells (SRBC) provokes brain neurotransmitter alterations, including DA variations within mesocorticolimbic regions, coinciding with or slightly preceding the peak immune response. Inasmuch as stressors disrupt responding for brain stimulation from the nucleus accumbens, possibly reflecting the anhedonic consequences of stressors, the present investigation assessed whether antigenic challenge would also influence responding for brain stimulation. Sheep red blood cell administration was found to reduce responding for brain stimulation from the nucleus accumbens, without affecting performance from the substantia nigra. The alterations of self-stimulation from the nucleus accumbens occurred at times that approximated the peak immune response. These data suggest that antigenic challenge may induce anhedonic-like effects that may be secondary to central neurochemical alterations engendered by the treatment. The possibility is also entertained that antigenic challenge may be interpreted as a stressor and contribute to alterations of affect.

Variations of motor activity following intraventricular (D-Pen2, D-Pen5)-enkephalin administration: interaction with acute uncontrollable foot-shock in mice.

The effects of intraventricular administration of (D-Pen2, D-Pen5)-enkephalin (DPDPE) (0.005, 1.0, and 2.5 micrograms/microlitter in a 1-microlitter vol.) on horizontal activity, rearing, and exploratory head dipping were assessed among CD-1 mice exposed to acute uncontrollable foot-shock 15 min following stressor termination. Foot-shock reduced horizontal activity, rearing, and exploratory head dipping during the immediate 15-min poststressor interval. Mice challenged with 0.005 micrograms DPDPE were behaviorally indistinguishable from vehicle-treated subjects. The 1.0-microgram dose of DPDPE increased horizontal activity in stressed and nonstressed subjects. Intraventricular infusion of 2.5 micrograms DPDPE potentiated horizontal activity in previously stressed mice but had no effect in nonstressed animals. The suppression of rearing and exploratory head dipping following uncontrollable foot-shock was not ameliorated by the delta-receptor agonist, and DPDPE was without effect on rearing and exploratory head dipping in nonstressed animals. Potential neurochemical mechanisms associated with the expression of these stressor associated behaviors are discussed.

Behavioral, neurochemical, anatomical and electrophysiological correlates of panic disorder: multiple transmitter interaction and neuropeptide colocalization.

Neurochemical accounts of panic disorder focus on peripheral indices of central transmitter activity, hormonal correlates and therapeutic efficacy. Anxiogenic agents augment norepinephrine activity, some anxiolytics increase serotonin neurotransmission while benzodiazepines and antidepressants influence catecholamine, indoleamine and gamma-aminobutyric acid turnover in infrahuman subjects. Reliable correlates of central transmitter activity in panic disorder are not in evidence. While animal models of anxiety may not mirror the symptom profile of panic, neurobiological accounts of panic disorder fail to consider extensive central colocalization of neurotransmitter and putative neurotransmitters. In effect, transmitter release in major ascending and descending transmitter systems is modulated by variable neuropeptide interfacing. The behavioral concomitants of psychological disturbance likely follow from variable neurochemical release induced by stimuli as well as conditioning and sensitization. The functional role of receptor sites associated with multiple neurochemical systems may vary and the sensitivity and/or density of receptor sites may be modified. Accordingly, the behavioral and neurochemical concomitants of acute and chronic pathology may be fundamentally different from one another. The present review argues that the symptoms of panic disorder and the etiology of the illness must be evaluated against a background of genetic, organismic and experiential factors. Such variables presumably underlie the diverse behavioral symptoms associated with panic disorder and variations in the therapeutic efficacy of pharmacological treatment.