The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis.

BACKGROUND: Amantadine hydrochloride and pemoline, both frequently used to treat the fatigue of multiple sclerosis (MS), may also improve attention and other cognitive functions in MS. To our knowledge, these agents have never been compared in a placebo-controlled trial of patients with MS. OBJECTIVE: To evaluate the effects of amantadine and pemoline on cognitive functioning in MS. METHODS: A total of 45 ambulatory patients with MS and severe fatigue were treated for 6 weeks with amantadine, pemoline, or placebo using a parallel group design. They underwent comprehensive neuropsychological testing to determine treatment effects on cognitive functioning. Primary outcome measures were tests of attention (Digit Span, Trail Making Test, and Symbol Digit Modalities Test), verbal memory (Selective Reminding Test), nonverbal memory (Benton Visual Retention Test), and motor speed (Finger Tapping Test). RESULTS: Fatigue did not significantly correlate with any of the neuropsychological outcome measures at baseline or after treatment. All three treatment groups improved on tests of attention (P < .003), verbal memory (P < .001), and motor speed (P < .002). There were no significant differences between amantadine, pemoline, and placebo. CONCLUSIONS: Cognitive functioning in MS is independent of fatigue. Neither amantadine nor pemoline enhances cognitive performance in MS compared with placebo.

Age effects on central nervous system activity reflected in the olfactory event-related potential. Evidence for decline in middle age.

A series of studies in this laboratory using the olfactory event-related potential (OERP) have examined the underlying central nervous system activity associated with age-related changes in olfactory functioning. Early (sensory) components of the OERP showed reduced amplitude and longer latency in elderly subjects, with larger effects in males. Amplitudes are already decreased in middle age. The late cognitive component, P3, showed a longer latency as well as a decreased amplitude in the elderly, with effect sizes for age significantly larger for the late component than for the early components. We report here the significantly longer latency, particularly for the P3, in middle-aged persons, suggesting age-related slowing of olfactory information processing as early as the 50s. Results suggest that the elderly brain, and indeed, the middle-aged brain shows smaller responses to odors, is less able to allocate attentional resources and slows in its olfactory cognitive processing. The OERP is a potent reflection of these changes.

Traumatic brain injury assessed with olfactory event-related brain potentials.

Olfactory event-related potentials (OERPs) were evaluated to develop an objective, quantitative assessment of sensory and cognitive olfactory loss following traumatic brain injury (TBI). Subjects included 25 TBI patients and 25 age/gender-matched healthy controls. Following standard clinical evaluation of smell function, TBI patients were divided into three groups: 12 anosmics (loss of smell), 6 hyposmics (reduced smell), and 7 normosmics (normal smell). Cognitive ability was assessed using the Trail Making Test (A and B). OERPs were recorded monopolarly from midline electrode sites using an amyl acetate stimulus with a 60-second interstimulus interval; subjects estimated the magnitude of each odor stimulus. Anosmic TBI patients were also tested with OERPs using ammonia to ensure trigeminal nerve function. Amyl acetate OERPs demonstrated that the sensory N1 and P2 amplitudes and the cognitive P3 amplitudes were absent in the anosmic TBI patients and greatly reduced in the hyposmic and normosmic TBI patients compared to healthy controls. The trigeminal OERPs from the anosmic TBI patients were within normal limits, indicating that the primary olfactory deficits were objectively measured with OERPs. The relationship between the OERPs and neuropsychologic test performance supports the cognitive loss associated with TBI. The present study lends support to the utility of OERPs as an objective tool for measuring sensory and cognitive loss after traumatic brain injury.

P300 habituation from visual stimuli?

The P3(00) event-related brain potential (ERP) was elicited with visual stimuli using an oddball task in which the subject indicated with a finger tap response the occurrence of a target stimulus that occurred randomly on 20% of the trials and refrained from responding to a standard stimulus. A total of six trial blocks were collected, with an equal number of artifact-free epochs averaged for both stimulus types. P3 amplitude from the target stimuli did not decrease across trial blocks; P3 amplitude from the standard stimuli did decrease across trial blocks. P3 latency from both the target and standard stimuli increased across trial blocks. No changes in amplitude or latency independent of the P3 effects were obtained for the other ERP components with trial block. The results suggest that P3 components elicited by visual stimuli do not readily habituate for actively discriminated target stimuli. The theoretical implications are discussed in the context of previous findings.

P300 is unaffected by glucose increase.

The effects of glucose ingestion on the P3(00) event-related brain potential (ERP) were investigated by using a visual stimulus oddball paradigm in which subjects discriminated between checkerboard (target) and horizontal line (standard) stimuli. Subjects were assessed for six consecutive trial blocks that were spaced 20 min apart on two different occasions. For the glucose condition, an initial baseline trial block was recorded followed by ingestion of 100 mg of glucose and the remaining five trial blocks recorded. For the water condition, the same procedure was employed with water ingested instead of glucose. Blood glucose levels, heart rate, and body temperature measures also were obtained before each trial block. P3 amplitude and latency did not change across trial blocks for the glucose/water conditions. No glucose/water effects were observed for the N1, P2, or N2 components as well. Blood glucose levels and heart rate increased for the glucose but not the water condition; body temperature decreased with the ingestion of both glucose and water and then returned to baseline levels. These findings suggest that ERPs are not influenced by increases of blood glucose level and are discussed in the context of previous ERP studies employing glucose manipulations.

P300 seasonal variation.

The P300 (P3) event-related brain potential (ERP) was elicited with auditory stimuli in four different groups of normal, young adult subjects (n = 20 in each group) whose ERPs were obtained at different times of the year. P3 amplitude was largest during spring and summer and smaller for the subjects who were assessed during fall and winter. P3 latency was not affected reliably by changes in the seasons. Measurement of the daily sunshine present when each subject was recorded indicated that P3 amplitude is influenced by seasonal variation in the available amount of sunshine. These findings suggest that comparison of P3 amplitude across subject groups must take seasonal differences into account.

P300 and time of day: circadian rhythms, food intake, and body temperature.

The P300 or P3 component of the event-related brain potential (ERP) was obtained from five groups of 24 young adult subjects, with each group measured at a different time of day (8 a.m., 11 a.m., 2 p.m., 5 p.m., 8 p.m.). An activity-preference questionnaire was used to ensure that an equitable number of morning- and evening-preferring subjects were obtained for each testing time. P3 measures, physiological (body temperature, heart rate, subjective alertness), and cognitive performance (digit span, prose memory, digit symbol) variables were assessed. P3 amplitude and latency were not affected directly by the time of day. However, P3 amplitude was smaller in subjects who had not eaten within 6 hours of testing relative to subjects who had a recent meal, and P3 latency was correlated negatively with body temperature. The findings suggest that although the P3 ERP is not influenced by circadian rhythms, it is related to recency of food intake and physiological factors which change with time of day.

Event-related brain potentials to attended and ignored olfactory and trigeminal stimuli.

Event-related brain potentials (ERPs) were recorded from 26 young adults, with equal numbers of male and female subjects, using attended and ignored, olfactory and trigeminal stimuli. The amplitudes and latencies of the N1, P2, and P3 components were recorded using a single-stimulus paradigm, with an inter-stimulus interval of 60 s, employing amyl acetate as the olfactory stimulus and ammonia as the trigeminal stimulus. Subjects estimated stimulus intensity in the attend condition or continued with a visual tracking task in the ignore condition. Results indicate that olfactory information is processed 30-70 ms faster than trigeminal information for the N1 and P2 potential and 100 ms faster for the P3 ERP component. N1/P2 interpeak amplitude was greater for the trigeminal than the olfactory stimuli, and greater in the attended than ignored condition. P3 amplitude was greater in the attend than ignore condition for olfactory information processing and equivalent for trigeminal information processing. These findings suggest that neuronal resource allocation is greatest for attended stimuli and that a painful stimulus demands neuronal resources even when ignored.

P300 from auditory and somatosensory stimuli: probability and inter-stimulus interval.

The P300 (P3) event-related brain potential (ERP) was elicited with auditory and somatosensory stimuli using an easy discrimination task in two experiments. Experiment 1 manipulated target stimulus probability (0.20 vs. 0.80). Experiment 2 manipulated inter-stimulus interval (2 s vs. 6 s) for both stimulus modalities in different conditions while keeping target probability constant. Probability and inter-stimulus interval had similar effects for auditory and somatosensory stimuli, with lower probability and longer inter-stimulus intervals producing larger P3 amplitudes. No statistically reliable differences in scalp distribution between modalities were obtained, with both modalities producing maximal amplitudes at Pz. The results suggest that auditory and somatosensory stimuli when used in a relatively easy discrimination task yield the same overall P3 values.

Normal aging and odor intensity effects on the olfactory event-related potential.

Olfactory event-related potentials (OERPs) were recorded in 14 young and 14 older adults, with odor strength of isoamyl acetate manipulated to assess olfactory stimulus intensity. Young participants produced significantly larger N1/P2, N2/P3 amplitudes and shorter N1, P2 and N2 latencies than older participants. Medium- and high-odor concentrations elicited significantly shorter P2 and N2 latencies than the lowest concentration for both age groups. Odor concentration appears to affect the speed of olfactory stimulus information processing regardless of age.

Olfactory event-related potentials and aging: normative data.

Unlike the clinical usages of evoked potentials (e.g. brain stem auditory evoked potentials for the assessment of auditory function), normative data for the olfactory event-related potential (OERP) have been unavailable. The principal objective was to establish normative data across the human life span for OERPs with a given set of parameters. Participants were 140 persons from seven age groups (16-19, 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years of age), with equal numbers of males and females, screened for nasal health and dementia. The odor stimulus was amyl acetate, presented at nasal temperature in a humidified airstream delivered by an air-dilution olfactometer at a constant flow rate, using a 60-s inter-stimulus interval. OERPs were recorded at Fz, Cz, and Pz electrode sites, amplified and averaged over trials. Amplitudes of the N1/P2 and P3 and latencies of the P2 and P3 were analyzed. Processing speed decreased at a constant rate over decades for the sensory (P2 latency) as well as cognitive (P3 latency) components. Decline in amplitude over decades was also apparent. Normative data will be useful in research on olfactory function and in clinical assessment of olfactory functional status.

P300, food consumption, and memory performance.

The effects of food intake on the P300 (P3) component of the event-related brain potential (ERP) were assessed in two studies. Experiment 1 compared 24 subjects who had not eaten within 6 hours of testing with 24 subjects who had consumed food within 3 hours of testing. P3 target stimulus amplitude was reduced significantly for the subjects who had not eaten relative to those who had eaten, whereas peak P3 latency was only moderately affected by the recency of food consumption over task conditions. In Experiment 2, P3 measurements, memory performance in a word recall task, and blood glucose levels were obtained from 24 subjects at three different times: 1) after a 14-hour fast, 2) 5 min after consuming lunch, and 3) 30 min after consuming lunch. P3 target stimulus amplitude increased initially after food intake and decreased slightly at the third measurement time, while peak P3 latency became somewhat shorter immediately after food intake but then returned to baseline. Recall for recently presented items mimicked the P3 amplitude changes, whereas blood glucose levels increased monotonically across food conditions. The results from both studies suggest that: 1) target stimulus P3 amplitude is affected by the recency of food intake; 2) food-related P3 amplitude changes appear related to memory function; and 3) subjects should eat within several hours before ERPs are acquired to ensure that P3 component measurements reflect values indicative of normal bodily functioning.

P300 and individual differences: morning/evening activity preference, food, and time-of-day.

To determine how individual differences stemming from activity preference, previous food intake, and time-of-day affect the P300 or P3 event-related brain potential (ERP), subject groups who varied orthogonally on these factors were compared using a simple auditory discrimination task to elicit the ERPs. Amplitude of the P3 component for morning-preferring subjects who had eaten recently was relatively large for both the morning and evening measurement time groups. P3 amplitude for the morning-preferring subjects who had not eaten recently was large for those measured in the morning and relatively small for those subjects measured in the evening. For evening-preferring subjects who had eaten recently, P3 amplitude was again relatively large for both the morning and evening measurement time groups. Evening-preferring subjects who had not eaten recently produced very small P3 components for those measured in the morning compared to the large components produced by those subjects measured in the evening. P3 latency tended to be longer for all subjects who had not eaten recently compared to those who had. The results suggest that the P3 component is sensitive to physiological and psychological changes originating from individual differences related to bodily state, which perhaps stems from individual differences in arousal level.

Construct validity in the Trail Making Test: what makes Part B harder?

The Trail Making Test (TMT) is primarily a test of motor speed and visual attention. In Trail Making, Part A, the subject's task is to quickly draw lines on a page connecting 25 consecutive numbers. In Part B, the subject must draw the lines alternating between numbers and letters. To determine what makes Part B harder than Part A, variations of the standard Trail Making Test were assessed. Forty college students (20 male, 20 female) were given four forms of the Trail Making Test. The results show that Trail Making, Part B with just numbers took longer to complete than the standard Part A with numbers. Part B is 56 cm longer and has more visually interfering stimuli than Part A. These results indicate that Part B is more difficult than Part A not only because it is a more difficult cognitive task, but also because of its increased demands in motor speed and visual search.

A developmental study of visual ERP distributions during spatial and phonetic processing.

Ten adults (mean age 19.5 years; S.D. = 1.65) and 10 children (12.2 years; S.D. = 1.28) participated in a choice reaction time study of event-related potential (ERP) correlates of pattern and phonological discriminations of letters. In the form condition, the subjects responded discriminately to letters that did (e.g., b, p) and did not (e.g., f, h) have an enclosed area. Likewise, the subjects responded to letters that did and did not rhyme with "e" in the rhyme task. For both groups, the two late positivities (P600 and P3) were significantly later in the rhyme ERPs than the form as were the RTs associated with the tasks. Distribution and group differences were most notable for the positivity at 380 msec. The P380 distribution did not vary between the conditions for the adults, but there was a more negative distribution in the rhyme condition compared to the form at fronto-central sites for the children. The topographic differences between the form and rhyme tasks at 380 msec were consistent with the involvement of auditory areas in the rhyme task. Generally, however, the children's and adults' wave forms were similar in terms of morphology, peak latency and distribution.

Olfactory P3 in young and older adults.

Olfactory event-related potentials (OERPs) were recorded monopolarly at the Fz, Cz, and Pz electrode sites in 16 young adults and 16 older adults to assess aging effects on the olfactory P3. Amyl acetate was used to elicit the OERPs, with an intertrial interval of 45 s. Young adults produced significantly larger P3 amplitudes and shorter P3 peak latencies than older adults. The olfactory P3 response appears to be sensitive to age-related changes in the olfactory system and may reflect cognitive slowing in the central nervous system.

Neuropsychological performance and cognitive olfactory event-related brain potentials in young and elderly adults.

The P3 event-related brain potential (ERP) reflects neuroelectric activity related to the speed of cognitive processing and allocation of attentional resources. The objective of the present study was to assess the relationship between the P3 and Slow Wave components of the olfactory event-related potential (OERP) with neuropsychological performance in young (n = 16) and elderly (n = 16) adults. OERPs were recorded monopolarly from midline electrode sites while subjects estimated the odor magnitude of each stimulus, eliciting highly reproducible P3s. Results showed that the late cognitive components (P3 amplitude, P3 latency and Slow Wave area) decline with age and that this decreased neuronal efficiency is associated with reductions in the neuropsychological performance indexed by the Trail Making Test and the California Verbal Learning Test.

Olfactory event-related potentials in young and elderly adults: evaluation of tracking task versus eyes open/closed recording.

The purpose of the present study was to evaluate olfactory event-related potentials (OERPs) elicited by amyl acetate from subjects performing a visuomotor tracking task compared with the no-task conditions of eyes open and eyes closed. Task condition did not produce any reliable effects for any amplitude measure. Task type weakly influenced only P2 latency. Elder adults evinced smaller P2 and N1/P2 amplitudes and longer N1 and P2 latencies than young adults. The results suggest that tracking task performance is not necessary to obtain robust OERPs from normal subjects of a wide age range.

Olfactory event-related potentials: older males demonstrate the greatest deficits.

Olfactory event-related potentials (OERPs) were recorded monopolarly at the Fz, Cz, and Pz electrode sites in 16 young adults (8M/8F) and 16 older adults (8M/8F) with inter-stimulus intervals (ISI) of 45, 60 and 90 s using amyl acetate as the odorant stimulus. N1, P2, and N2 peak amplitudes and latencies were measured. Young participants demonstrated significantly shorter peak latencies than older participants. Older males demonstrated significantly smaller peak amplitudes than the other participant groups. Peak amplitudes also increased with longer ISIs for older males. The OERP is compared to traditional olfactory psychophysical testing.