Genetic susceptibility to multiple sclerosis: interactions between conserved extended haplotypes of the MHC and other susceptibility regions.

BACKGROUND: To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC "risk-haplotypes" nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation. METHODS: The SNP-data from the WTCCC was phased at the MHC and three non-MHC susceptibility-regions. CEHs at the MHC were classified into five haplotype-groups: (HLA-DRB1*15:01 ~ DQB1*06:02 ~ a1)-containing (H +); extended-risk (ER); all-protective (AP); neutral (0); and the single-CEH (c1). MS-associations for different "risk-combinations" at the MHC and other non-MHC "risk-loci" and the appropriateness of additive and multiplicative risk-accumulation models were assessed. RESULTS: Different combinations of "risk-haplotypes" produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, (H +)-haplotypes had greater impact when combined with (0)-haplotypes than with (H +)-haplotypes, whereas, (H +)-haplotypes had greater impact when combined with a (c1)-haplotypes than with (0)-haplotypes. Similarly, risk-genotypes (0,H +), (c1,H +), (H + ,H +) and (0,c1) were additive with risks from non-MHC risk-loci, whereas risk-genotypes (ER,H +) and (AP,c1) were unaffected. CONCLUSIONS: Genetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual's particular combination of "risk-haplotypes" and how these loci interact.

Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial.

BACKGROUND: Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16 y, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. METHODS: The 372 trial patients were randomly assigned to placebo (n=123), IFNB-1b 50 microg (n=125) or IFNB-1b 250 microg (n=124) subcutaneously every other day for at least 2 y. Some remained randomised for up to 5 y but, subsequently, patients received treatment according to physicians' discretion. Patients were re-contacted and asked to participate. Efficacy related measures included MRI parameters, relapse rate, the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite Measure and conversion to secondary progressive MS. RESULTS: Of the 88.2% (328/372) of patients who were identified, 69.9% (260/372) had available case report forms. No differences in outcome between original randomisation groups could be discerned using standard disability and MRI measures. However, mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group (18.3% (20/109) for placebo versus 8.3% (9/108) for IFNB-1b 50 microg and 5.4% (6/111) for IFNB-1b 250 microg). CONCLUSIONS: The original treatment assignment could not be shown to influence standard assessments of long-term efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 microg or 250 microg. The dataset provides important resources to explore early predictors of long-term outcome.

Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures.

Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via (1)HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm(3); P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention.

Neurite Orientation Dispersion and Density Imaging for Assessing Acute Inflammation and Lesion Evolution in MS.

BACKGROUND AND PURPOSE: MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations. MATERIALS AND METHODS: Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM. RESULTS: The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions. CONCLUSIONS: NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

Treatment of early multiple sclerosis: the value of treatment initiation after a first clinical episode.

Multiple sclerosis is a chronic, demyelinating disorder of the central nervous system. It is characterised by progressive neurological disability, which is likely to occur as a result of permanent axonal damage. Such damage may be reflected by brain atrophy, which can be identified early in the course of the disease. Patients who present with an initial episode of inflammatory demyelination, commonly referred to as a clinically isolated syndrome, are at high risk of developing clinically definite multiple sclerosis, especially if their magnetic resonance imaging studies suggest the presence of multi-focal disease. Treatment with disease-modifying therapies at the initial episode of demyelination may postpone this development. In this review we present an overview of evidence supporting early treatment initiation. We focus on three large placebo-controlled trials of interferon beta therapy: Controlled High-Risk Avonex Multiple Sclerosis Prevention Study, Early Treatment of Multiple Sclerosis and Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment. Results from these early treatment studies are presented, and the impact of using interferon beta treatment in the early stages of disease is discussed with the aim of considering optimal therapeutic strategies to improve long-term patient outcome.

Neutralizing antibodies to interferon beta-1b are not associated with disease worsening in multiple sclerosis.

The clinical impact of neutralizing antibodies (NAbs) on interferon beta (IFNbeta) efficacy was studied in three large patient cohorts comprising 6698 multiple sclerosis (MS) patients receiving IFNbeta-1b across North America, Europe, and Australia. In North America and Europe, NAb testing was generally undertaken because of a poor clinical response; in Australia, it was mandatory for every patient. Of the 6697 patients tested, 28.9% had at least one NAb titre > or = 20 neutralizing units (NU)/ml, 14.4% had NAb titres > or = 100 NU/ml and 7.7% had NAb titres > or = 400 NU/ml. The NAb-positive rate of 37.0% in Australia was significantly greater than those in North America (21.3%) and Europe (27.6%), and this was observed at every NAb titre level. Our results suggest that NAbs are not responsible for poor clinical responses and that NAb status is of little clinical value. These findings will need to be confirmed in a large independent study.

The epidemiology of multiple sclerosis: insights to a causal cascade.

MS-pathogenesis involves both genetic-susceptibility and environmental determinants. Three (or more) sequential environmental-factors are implicated. The first acts near birth, the second acts during childhood/adolescence, and the third acts subsequently. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem particularly well-suited to the first two environmental-events but other factors (e.g., obesity and smoking behavior) seem also to be involved in the causal scheme. MS-pathogenesis can be modeled by incorporating both the environmental and genetic-factors into a causal scheme, which can then help to explain some of the changes in MS-epidemiology (e.g., increasing disease-prevalence, changing sex-ratio, and regional-variations in monozygotic-twin-concordance-rates), which have been taking place recently. This model suggests that genetic-susceptibility is overwhelmingly the most important determinant of MS and that, at least, 92.5% of individuals (and likely much more) are, essentially, incapable of developing MS, regardless of their specific environmental-exposures. Nevertheless, the genetics is complex and the contribution of any specific gene to MS-susceptibility seems to be quite modest. Thus, even for the DRB1*1501 allele (the strongest known MS-susceptibility marker), most carriers are not in the genetically-susceptible group. Moreover, 45-50% of individuals with MS lack this allele entirely and some of the haplotypes that carry this allele don't also confer any disease-risk. Finally, because the prevalence of genetic-susceptibility seems to be so similar throughout North America and Europe, and despite the crucial importance of a person's genetic make-up to disease pathogenesis, it is the environmental-factors, which largely responsible for the observed regional variations in disease-characteristics. Thus, despite MS being more common in women, men are more likely to be genetically-susceptible. This apparent paradox seems to relate to the fact that women are much more responsive than men to the recent changes in environmental-exposure (whatever these have been). These gender-differences may help to explain changes in the sex-ratio and the increasing disease-prevalence, which have both been observed recently. The potential importance of these conclusions regarding the role of environment in MS-pathogenesis is that they open the door to the possibility of pursuing strategies for primary primary disease prevention in the future.

Acute syphilitic meningitis. Its occurrence after clinical and serologic cure of secondary syphilis with penicillin G.

Acute syphilitic meningitis developed in a 36-year-old man three months after apparently successful treatment of secondary syphilis with doses of penicillin G benzathine recommended by the current Centers for Disease Control guidelines. He was then treated with high-dose intravenous penicillin G sodium, with resolution of symptoms and cerebrospinal fluid abnormalities. Although other instances of neurosyphilis following adequate therapy for early syphilis have been reported, in most cases reinfection cannot be convincingly excluded. We believe this patient represents a particularly well-documented example of progression to neurosyphilis, despite recommended therapy with penicillin. A review of recently reported cases suggests that progression of syphilis, despite "appropriate" therapy, is not an isolated event.

Visual evoked potentials in the investigation of "blindsight".

We recorded long-latency visual evoked potentials in four patients with homonymous hemianopias, one of whom had clinical evidence of "blindsight." Stimuli consisted of different words that appeared randomly and at a constant angle to either side of the center of a TV screen, and subjects responded to one previously specified word (the "target") by finger extension. Target stimuli in the intact hemifield elicited a well-formed P3 response in all subjects, whereas stimuli in the blind field produced no such response except in the subject with blindsight. In addition, the earlier potentials in this subject were larger with stimulation of the blind hemifield than the intact field. By contrast, a P100 response was present only with stimulation of the intact field in this subject. These results indicate that cognitive processing of visual stimuli can occur even when subjective awareness of such stimuli is absent, and suggest that such processing occurs independently of the geniculostriate pathway.

Expectancy and response strategy to sensory stimuli.

We investigated the relationship between sensory discrimination and the selection of appropriate responses in subjects performing two different reaction-time tasks, in which three auditory stimuli were presented in random order and with a different likelihood of occurrence. Subjects anticipated the need to make different responses based on the likelihood that a particular stimulus would occur on a particular trial. This was determined by the occurrence and distribution of premovement potentials prior to the stimulus, which were consistent with preparation to respond to the most frequently occurring stimulus. These anticipatory cerebral events, however, could be altered after recognition that this frequent stimulus had not occurred. Thus, after the occurrence of a stimulus other than the anticipated frequent tone, the scalp distribution of cerebral potentials changed in a manner suggesting that the next most frequently occurring stimulus was anticipated. Nonetheless, subjects were able to respond to the least probable stimulus both accurately and rapidly despite a failure to anticipate it correctly, as judged by the cerebral "lateralized readiness potential." These results indicate that stimulus evaluation and response selection are integrated and dynamic cerebral processes, and raise doubt about the functional significance of the so-called premovement readiness potential.

The frontal N30 component of the median-derived SEP in patients with predominantly unilateral Parkinson's disease.

There are conflicting reports concerning attenuation of the frontal N30 component of the median-derived somatosensory evoked potential in patients with Parkinson's disease (PD). We found that the mean N30 latency (28.03 +/- 2.50 msec) and amplitude (2.30 +/- 1.58 microV) obtained with stimulation of the affected arm of 10 patients with predominantly unilateral PD were not significantly different from those obtained from the unaffected arm (mean latency, 28.14 +/- 2.47 msec; mean amplitude, 2.43 +/- 1.65 microV) or from 10 age-matched controls (mean latency, 29.01 +/- 1.88 msec; mean amplitude, 1.92 +/- 0.64 microV). Three patients had an N30 of abnormal amplitude; in two, responses were absent with stimulation of either side, and in one there was a response asymmetry exceeding the normal range, with the smaller response elicited from the affected arm. Thus, only one of 10 patients had a diminished N30 consistent with the clinical findings. We conclude that the N30 is unlikely to be clinically useful in the assessment of patients with PD.

Sequential changes in the P3 component of the auditory evoked potential in confusional states and dementing illnesses.

The P3 component of the auditory evoked potential has been shown to reflect "endogenous" processes related to cognition. This component was measured serially in seven patients who had confusional states or dementing illnesses that fluctuated in severity over time. The latency of P3 component reflected the clinical impression of changes in mental function for each of the patients. These results suggest that the P3 component of the auditory evoked potential provides an objective serial measure of cognitive state that may be useful in following patients with dementing illnesses and in evaluating the effectiveness of any specific therapy.

Task-dependent hemisphere asymmetries of the visual evoked potential.

Stimulus-related and event-related components of the visual evoked potential were recorded in three separate tasks that required language comprehension or spatial discrimination. Task-dependent asymmetries in the evoked potential were found for both the language task and one of the tasks involving spatial discrimination. Moreover, an identical stimulus presented in two different contexts elicited potentials with a significantly different distribution over the two sides of the head. These asymmetries were largely confined to the event-related components and presumably reflect task-dependent differences in neural processing. Reaction-time studies for these tasks, however, indicated that these asymmetries occurred too late to arise from neural structures responsible for language comprehension or spatial discrimination per se, and must therefore reflect subsequent neural events.

Ambulatory EEG recordings in epileptic and nonepileptic children.

We examined the cassette-recorded 24-hour ambulatory EEG findings in children who had either clinically definite seizures or episodic behavioral disturbances not regarded as epileptic on clinical grounds. Among 40 epileptic patients, 22 had one or more attacks during the 24-hour recording session. In 15 of these patients all clinical attacks had appropriate ictal electrographic accompaniments; in another 6 some (but not all) attacks did so. Among 55 children with nonepileptic spells clinically, the 24-hour recording was uninterpretable for technical reasons in one, and in 30 it provided no relevant information because there were no recorded clinical or electrographic attacks. In the remaining 24 patients, one or more clinical attacks were captured, and in no instance was there any accompanying electrographic change. Our findings indicate that the absence of ictal EEG changes during attacks cannot be used in isolation to make a diagnosis of pseudoseizures, but support such a diagnosis made on clinical grounds. The more important role of the ambulatory EEG is to exclude a diagnosis of nonepileptic attacks by demonstrating electrographic seizure activity accompanying typical clinical attacks. Whether the technique will have a useful role in the evaluation of patients when the nature of an episodic disturbance of cerebral function is unclear clinically remains to be established, but will require long-term follow-up to validate any conclusions reached by the electrophysiologic technique.

Side effect profile of interferon beta-1b in MS: results of an open label trial.

To determine which patients are prone to side effects from interferon beta-1b and which side effects are most troublesome, we studied 72 patients with clinically definite MS who were started on interferon beta-1b after its release and found that the side effects significantly associated with treatment included skin reactions, flu-like symptoms, fatigue, leukopenia, new or worsened depression, and new or worsened headache. Of these, only fatigue and depression were significantly associated with discontinuance of therapy. Moreover, the course of disease before initiation of treatment also had a significant impact on the likelihood of discontinuing medication. Thus, despite an apparently similar therapeutic benefit (as judged by the similarly reduced attack rate in each group), patients with a secondary chronic progressive course were more likely to discontinue treatment (63%) than patients with either a relapsing/progressive course (18%) or a remitting/relapsing course (7%). Indeed, in the final regression equation, the only factors significantly related (r = 0.875) to the discontinuance of therapy were fatigue (p < 0.0001), a fatigue-depression interaction (p < 0.0001), and a chronic progressive course of disease (p<0.0001). Thus, if future clinical trials are to provide useful information on the value of interferon beta-1b in progressive MS, the side effects of fatigue and depression will need to be ameliorated to limit the drop-out rate from such trials.

Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial.

BACKGROUND: Interferon beta (IFNbeta) reduces relapses and MRI activity in relapsing-remitting MS (RRMS), with variable effects on disability. The most effective dose regimen remains controversial. METHODS: This randomized, controlled, multicenter trial compared the efficacy and safety of IFNbeta-1a (Rebif) 44 micro g subcutaneously three times weekly (tiw), and IFNbeta-1a (Avonex) 30 micro g IM once weekly (qw) in 677 patients with RRMS. Assessors blinded to treatment performed neurologic and MRI evaluations. The primary endpoint was the proportion of patients who were relapse free at 24 weeks; the principal MRI endpoint was the number of active lesions per patient per scan at 24 weeks. RESULTS: After 24 weeks, 74.9% (254/339) of patients receiving IFNbeta-1a 44 micro g tiw remained relapse free compared with 63.3% (214/338) of those given 30 micro g qw. The odds ratio for remaining relapse free was 1.9 (95% CI, 1.3 to 2.6; p = 0.0005) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeks, favoring 44 micro g tiw. Patients receiving 44 micro g tiw had fewer active MRI lesions (p < 0.001 at 24 and 48 weeks) compared with those receiving 30 micro g qw. Injection-site reactions were more frequent with 44 micro g tiw (83% vs 28%, p < 0.001), as were asymptomatic abnormalities of liver enzymes (18% vs 9%, p = 0.002) and altered leukocyte counts (11% vs 5%, p = 0.003) compared with the 30 micro g qw dosage. Neutralizing antibodies developed in 25% of 44 micro g tiw patients and in 2% of patients receiving 30 micro g qw. CONCLUSIONS: IFNbeta-1a 44 micro g subcutaneously tiw was more effective than IFNbeta-1a 30 micro g IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment.

Electrophysiologic evaluation of lumbosacral radiculopathies: electromyography, late responses, and somatosensory evoked potentials.

We compared the diagnostic utility of EMG, F wave and H-reflex studies, and peroneal and dermatomal SEPs in evaluating 28 patients with clinically unequivocal L-5 or S-1 compressive root lesions. The single most useful electrophysiologic technique was EMG, which often provided evidence of denervation in a myotomal pattern when other electrophysiologic findings were normal. We found abnormal late responses in 14 patients, but always in association with EMG abnormalities. Peroneal-derived SEPs were always normal. Dermatomal SEPs confirmed the diagnosis in seven patients, including two in whom other electrophysiologic studies were normal.

Interferon-beta therapy in multiple sclerosis: evidence for a clinically relevant dose response.

There have been considerable advances made recently in the treatment of multiple sclerosis (MS). In particular, interferon (IFN)beta has been demonstrated in several independent, multicentre clinical trials to lower unequivocally the biological activity of this illness. The results of these trials have been remarkably consistent, demonstrating a reduction in both disease activity and cumulative disability, using a combination of clinical and magnetic resonance imaging outcome measures. Nevertheless, the importance of the total weekly IFNbeta dose in the clinical management of individual patients has been controversial. However, there is considerable information available regarding the effect of IFNbeta dose on the various biochemical and clinical markers that are affected by IFNbeta, which is derived both from pre-clinical studies and multicentre clinical trials. On balance, convincing evidence is provided to support the notion that there is a clinically relevant dose-response in the use of IFNbeta to treat patients with relapsing/remitting MS. However, many of the clinical trials of IFNbeta in MS have confounded the potential effects of dose with the possible effects of frequency of IFNbeta administration. As a result, it is possible that the apparent dose-response observed in these clinical trials may be due, in part, to the more frequent dose administration schedule rather than the total weekly dose.

Therapeutic developments in multiple sclerosis.

Recently there have been considerable advances made in the treatment of multiple sclerosis. For the first time since its initial clinical description in the 1800s, there are now available several medications which unequivocally exert favourable clinical effects through the lowering of the biological activity of the human illness. The therapeutic efficacy of IFN-beta preparations seems particularly well established in this regard on the basis of five large, independent, trials of this agent. These trials have demonstrated remarkably consistent reductions in both attack rates and disability levels using a combination of clinical and magnetic resonance imaging outcome measures. The therapeutic benefit of glatiramer acetate also has been well established, although there is less available data on this agent than there is for interferon. It is important to recognise, however, that, although these agents represent an important first step in the management of patients with multiple sclerosis, they are only partial therapies. In order to actually cure the illness or even to substantially improve patient outcome we need considerably better agents than we have currently. Nevertheless, it is likely that, with improved knowledge of the role that interferon beta plays in the pathogenesis of multiple sclerosis and with better understanding of the mechanism by which glatiramer acetate exerts its therapeutic effect, greatly improved therapeutic agents will be available in the future. In addition, it seems likely that, in the future (by analogy to the experience in oncology), we will begin utilising combinations of therapies in order to better control the biological activity of this debilitating disease. Such combination therapy will almost certainly include combinations of partially effective agents as well as combinations of these agents with other medications (e.g., the immunosuppressive drugs) which, by themselves, have only been demonstrated to exert marginal clinical benefits on the course of illness. Moreover, it also seems likely that, increasingly, therapeutic strategies that enhance or promote myelin repair will become a major focus of clinical research in this area.

The basis and functional role of the late EMG activity in human forearm muscles following wrist displacement.

The present paper examines the hypothesis that the long latency EMG activity produced by muscle stretch is the result of long loop reflex pathways involved in the control of limb stiffness. We recorded the cerebral responses and late EMG activity in agonist and antagonist muscles following sudden stretch of the wrist extensor muscles under 4 experimental conditions in 11 subjects. In each experiment subjects held their right wrist extended isometrically against a constant force of 2.3 N and a trial was begun with a step increase in the force from 2.3 N to 18.4 N, to stretch the extensor muscle. In the first and second experiments the force change occurred unpredictably and subjects had to either oppose the perturbation (Unpredictable Oppose) or relax the forearm muscles once the increase in force was detected (Unpredictable Let-Go). In the third and fourth experiments the force change occurred predictably when subjects pressed a thumb switch with the left hand to cause it. As before, subjects were instructed to either oppose the perturbation (Predictable Oppose) or relax the forearm muscles (Predictable Let-Go). Responses were recorded from the flexor and extensor carpi radialis muscles and from the scalp. When the perturbing force occurred unpredictably, early latency EMG activity (the MI response) was seen in the stretched extensor muscle, and longer latency EMG activity was seen simultaneously in both extensor and flexor muscles. When the force change occurred predictably the late EMG activity was considerably attenuated, especially in the Predictable Let-Go condition. Cerebral responses similarly depended upon the predictability of the perturbation.(ABSTRACT TRUNCATED AT 250 WORDS)