Standardization and Validation of the Flash Visual Evoked Potential-P2 Conversion Scores in the Diagnosis of Amnestic Mild Cognitive Impairment and Alzheimer's Dementia.

Amnestic mild cognitive impairment (aMCI), which is characterized by normal daily activity, but a significant decline in episodic memory, is now widely accepted as a risk factor for the development of Alzheimer's dementia (AD). Research suggests that many of the same neuropathological changes associated with AD also occur in patients diagnosed with aMCI. A recent review of the literature revealed that the latency of the flash visual-evoked potential-P2 (FVEP-P2) may possess pathognomonic information that may assist in the early detection of aMCI. While standards exist for the recording of FVEP-P2, individual clinics often use recording parameters that may differ, resulting in latencies that may not generalize beyond the clinic that produced them. The present article illustrates the process by which the FVEP-P2 latency can be standardized across clinics using FVEP-P2 Conversion Scores. We then demonstrate the diagnostic accuracy of the newly developed scores. Method: In the present investigation, we used the previously unpublished data containing the FVEP-P2 latencies of 45 AD and 60 controls. Result: We were able to demonstrate the process by which individual clinics may first standardize FVEP-P2 latencies and then examine patient performance using FVEP-P2 Conversion Scores, providing clinicians with a richer context from which to examine the patient performance. Conclusion: Consistent with the findings of previous research, the findings of the present investigation support the use of the FVEP-P2 Conversion Scores in the diagnosis of AD. Future directions, including the modification of recording parameters associated with the FVEP-P2, are also discussed.

The effect of wavelength on the variability of the flash visual evoked potential P2: A potential biomarker for mild cognitive impairment and Alzheimer's dementia.

As the number of individuals diagnosed with amnestic mild cognitive impairment (aMCI) and Alzheimer's dementia (AD) increases, a need exists for early detection and treatment of the disorders. A recent review of the literature conducted by Arruda et al. (2020) revealed that the latency of the flash visual-evoked potential-P2 (FVEP-P2) may possess pathognomic information that may assist in the early detection and treatment of each disease. Unfortunately, while group differences in latency are robust, the ability to discriminate between individuals remains difficult due to the natural variability associated with the FVEP-P2 latency. In the current investigation, we examine the role of wavelength of light in the production of the FVEP-P2, with the goal of reducing the variability associated with the FVEP-P2 latency and improving the diagnostic accuracy of the FVEP-P2 evaluation. METHOD: Twenty-four healthy individuals (11 males and 13 females), ages 18 to 36 years (M = 25.00, SD = 5.60), participated in this investigation. Each participant experienced five blocks of 100 strobe flashes (or trials) under two different light conditions (blue filtered light and polychromatic white light) with their eyes closed. The FVEP-P2 associated with each trial was identified and the latency and amplitude of each component was calculated. RESULT: The results of several repeated measures analysis of variance revealed no statistically significant differences in intra- and inter-individual variability associated with the P2 latency or amplitude. However, there was a significant difference in the amplitude of the P2 produced by the two lights, with blue filtered light producing significantly lower amplitudes than the polychromatic white light. CONCLUSION: The results of the present investigation suggest that while imperfect, the current practice of employing polychromatic white light in the production of the FVEP-P2 remains the gold standard and that additional methods of reducing the natural variability of the P2 need to be developed if the FVEP-P2 latency is to be used as a biomarker.

The flash visual evoked potential-P2 and the detection of amnestic mild cognitive impairment: A review of empirical literature.

Amnestic Mild Cognitive Impairment (aMCI) is now recognized as an early risk state for the development of Alzheimer's dementia (AD). Biomarkers, including those that are cerebrospinal fluid or brain imaging based, have yet to provide the ultimate marker variable. A need currently exists for a non-invasive, easy to administer biomarker that contains aMCI/AD specific pathognomic information. OBJECTIVE: The objective of the present investigation was to provide an updated review of the Flash Visual Evoked Potential-P2 (FVEP-P2) as a biomarker for aMCI and AD. The FVEP-P2 has been shown to possess AD specific pathognomic information. METHOD: A review was conducted of all articles published between the years 1976 and 2019 that examined the clinical utility of the FVEP-P2 in the diagnosis of aMCI or AD. Only 17 published investigations met the criteria of the review. RESULT: The weighted average effect size, as measured by Cohen's d, was 1.07, with patients diagnosed with either aMCI or AD exhibiting a significant delay in the FVEP-P2 latency. The weighted mean latency for the controls was 143.92 ms (SD = 17.13). The weighted mean latency for the aMCI/AD was 164.02 ms (SD = 21.33). Estimates of sensitivity, specificity, and accuracy were based on the weighted means and standard deviations and were equal to 0.73. The area under the curve was equal to 0.78. CONCLUSION: The results of the current review suggest that the FVEP-P2 latency possesses AD specific pathognomic information and that it should be included as part of a much larger assessment process that includes neuropsychological, cerebrospinal fluid, and brain imaging findings.

Reliability of the Flash Visual Evoked Potential P2: Double-Stimulation Study.

The flash visual evoked potential P2 (FVEP-P2) has been identified as a potentially useful clinical, diagnostic tool for Alzheimer's dementia (AD) and mild cognitive impairment (MCIa) due to its association with cholinergic functioning in the brain. The FVEP-P2 is the second positive component of the VEP waveform elicited by a single strobe flash. Despite finding a selective delay in the latency of the FVEP-P2 in AD and MCIa groups, adequate levels of sensitivity and specificity have not been achieved due to natural group differences and inter-individual variability. In response, Fix and colleagues introduced a novel, double-stimulation paradigm that contained two strobe flashes (i.e., stimulations). The first stimulation served as a visual challenge while the second stimulation produced the recorded FVEP-P2 component. The results of that investigation indicated that the latency of the FVEP-P2 could be used to reliably discriminate between aMCI and healthy controls when the ISI of the double-stimulation condition was 100 ms or higher. Unfortunately, very little is known regarding the psychometric properties of the FVEP-P2 when produced by a double-stimulation condition. Consequently, we assessed the test-retest reliability of the FVEP-P2 latency produced by a single- and twelve double-stimulation conditions in a sample of young, healthy individuals (N = 20). Results indicated that while the FVEP-P2 latencies produced by the single- and double-stimulation paradigm were reliable, the intra-individual variability continued to be too high for the FVEP-P2 latency to be used clinically. Methods of reducing the intra-individual variability are discussed, including the use of monochromatic light.

Modeling cyclic variations in sustained human performance as measured by reaction time and the flash visual evoked potential-P2.

Recent research suggests that sustained attention is punctuated by periodic lapses that produce cyclic variations in sustained human performance. Research conducted by our laboratory (Arruda, Zhang, Amoss, Coburn, & Aue, 2009) and by the laboratories of others (Aue, Arruda, Kass, & Stanny, 2009; Smith, Valentino, & Arruda, 2003) suggests that sustained human performance cycles approximately every 1.5 and 5.2min. Further, it has been suggested that a norepinephrine based arousal system may be responsible for these variations. Unfortunately, both cholinergic and noradrenergic pathways are known to mediate attention and it is unclear from previous research whether one or both of the identified cycles is related to cholinergic functioning. Consequently, the purpose of the present investigation was to assess the validity of the 1.5 and the 5.2mincycles using both reaction time and a cortical marker of cholinergic activity-the flash visual evoked potential P2 (FVEP-P2). Twenty-seven participants performed a 15-min continuous performance task. A spectral analysis procedure was used to detect the prevalence of the 1.5 and 5.2mincycles in both performance and cortical activity. While the results of these analyses support the validity of the 1.5 and 5.2mincycles in sustained human performance, only the 5.2mincycle was detected in cortical activity (i.e., the FVEP-P2 amplitudes) using model fitting. Consequently, the results of the present investigation support the validity of the 1.5 and 5.2mincycles and extend the findings of previous research by implicating acetylcholine in the 5.2mincycle.

Age-related differences in recall for words using semantics and prosody.

The positivity effect is a developmental shift seen in older adults to be increasingly influenced by positive information in areas such as memory, attention, and decision-making. This study is the first to examine the age-related differences of the positivity effect for emotional prosody. Participants heard a factorial combination of words that were semantically positive or negative said with either positive or negative intonation. Results showed a semantic positivity effect for older adults, and a prosody positivity effect for younger adults. Additionally, older adults showed a significant decrease in recall for semantically negative words said in an incongruent prosodically positive tone.

Using visual evoked potentials for the early detection of amnestic mild cognitive impairment: a pilot investigation.

OBJECTIVE: Amnesic mild cognitive impairment (MCIa) is often characterized as an early stage of Alzheimer's dementia (AD). The latency of the P2, an electroencephalographic component of the flash visual evoked potential (FVEP), is significantly longer in those with AD or MCIa when compared with controls. The present investigation examined the diagnostic accuracy of several FVEP-P2 procedures in distinguishing people with MCIa and controls. METHODS: The latency of the FVEP-P2 was measured in participants exposed to a single flash condition and five double flash conditions. The double flash conditions had different inter-stimulus intervals between the pair of strobe flashes. RESULTS: Significant group differences were observed in the single flash and two of the double flash conditions. One of the double flash conditions (100 ms) displayed a higher predictive accuracy than the single flash condition, suggesting that this novel procedure may have more diagnostic potential. Participants with MCIa displayed similar P2 latencies across conditions, while controls exhibited a consistent pattern of P2 latency differences. These differences demonstrate that the double stimulation procedure resulted in a measurable refractory effect for controls but not for those with MCIa. CONCLUSIONS: The pattern of P2 group differences suggests that those with MCIa have compromised cholinergic functioning that results in impaired visual processing. Results from the present investigation lend support to the theory that holds MCIa as an intermediate stage between normal healthy aging and the neuropathology present in AD. Measuring the FVEP-P2 during several double stimulation conditions could provide diagnostically useful information about the health of the cholinergic system.

The reliability and validity of the Visual Analog Mood Scales in non-English-speaking pain patients.

OBJECTIVES: This study assessed the validity and reliability of the Visual Analog Mood Scales (VAMS) when administered to a non-English-speaking, headache population. METHODS: The VAMS and another frequently administered measure of mood, the Profile of Mood States (POMS), were administered to sixty patients at a headache clinic in Milan, Italy. The VAMS and POMS were both administered before and after a regularly scheduled appointment at the clinic. Multitrait-multimethod analyses were conducted to assess the validity of each subscale comprising the VAMS. RESULTS: All subscales comprising the VAMS possessed high test-retest reliability, and the "confused,""sad,""angry,""energetic," and "tired" subscales of the VAMS were shown to be valid when administered to a non-English-speaking pain population. Further, compared to age-matched controls (from available normative data), pain patients reported being significantly more confused, sad, and tense on the VAMS and significantly more tired, confused, depressed, and tense on the POMS. DISCUSSION: Given the evidence of strong reliability and validity, the VAMS may be useful as a clinical diagnostic tool when administered to non-English-speaking pain populations.

The effects of EEG data transformations on the solution accuracy of principal component analysis.

Principal component analysis (PCA) is a commonly used multivariate procedure that reduces the dimensionality of a data set. When applied to quantitative electroencephalogram (qEEG) data, PCA produces components that may represent functional systems within the brain. Unfortunately, qEEG, like many other physiological measures, produce distributions that are positively skewed. In response, researchers often transform qEEG data prior to conducting a PCA, which does not require univariate or multivariate normality. Despite this, researchers continue to transform qEEG data with limited knowledge of how such transformations will affect the accuracy (precision) of their component solutions. The purpose of the present investigation was to examine the effects of several commonly used data transformation procedures on PCA solution accuracy.

Age differences in cognitive and psychomotor abilities and simulated driving.

The current study investigated the relationship between drivers' abilities in various cognitive and psychomotor domains and their driving performance. The goal was to identify test measures that could be used to develop a fitness-for-driving test battery, particularly for older drivers. Licensed drivers over 40 years of age (M=65.56 years, SD=13.02) were recruited from university leisure courses (n=18) and drivers under 40 (M=22.20 years, SD=3.79) were recruited from undergraduate and graduate courses (n=44). Participants were given a battery of standard neuropsychological tests used to assess ability in the domains of cognitive processing speed, psychomotor functioning, visuospatial performance, sustained attention, and executive functioning. Participants' driving ability was assessed in a simulator with data collected in three categories of driving performance: (a) driver control maintenance behaviors, (b) accidents and violations, and (c) attention and reaction time. Younger participants outperformed older participants in 4 out of the 5 domains of neuropsychological testing (all but sustained attention). Age differences were found in simulator driving accidents and violations and driving performance was significantly correlated with neuropsychological test performance. The results are discussed in terms of the potential to use these tests to assess older drivers seeking license renewal or for selecting professional drivers for the transportation industry.

Cyclic variations in sustained human performance.

Biological rhythms play a prominent role in the modulation of human physiology and behavior. [Smith, K., Valentino, D., & Arruda, J. (2003). Rhythmic oscillations in the performance of a sustained attention task. Journal of Clinical and Experimental Neuropsychology, 25, 561-570] suggested that sustained human performance may systematically fluctuate in a cyclic manner with periods of 1.5 min and 5.2 min. The current series of investigations sought to manipulate those periodicities by altering task difficulty, administering caffeine, and testing on a more ecologically valid task. Strong evidence of a 1.5 min periodicity was found across studies. Most participants did not demonstrate the 5.2 min periodicity. Moreover, the 1.5 min periodicity was resistant to task manipulations and appeared in similar levels across conditions in all three experiments. These rhythms may be indicative of an endogenous system that modulates sustained attention in humans. Evidence supporting this idea and implications of the research are discussed.

Rhythmic oscillations in quantitative EEG measured during a continuous performance task.

The objective of the present investigation was to determine if cyclic variations in human performance recorded during a 30 min continuous performance task would parallel cyclic variations in right-hemisphere beta-wave activity. A fast fourier transformation was performed on the quantitative electroencephalogram (qEEG) and the performance record of each participant (N = 62), producing an individual periodogram for each outcome measure. An average periodogram was then produced for both qEEG and performance by combining (averaging) the amplitudes associated with each periodicity in the 62 original periodograms. Periodicities ranging from 1.00 to 2.00 min and from 4.70 to 5.70 min with amplitudes greater than would be expected due to chance were retained (Smith et al. 2003). The results of the present investigation validate the existence of cyclic variations in human performance that have been identified previously (Smith et al. 2003) and extend those findings by implicating right-hemisphere mediated arousal in the process (Arruda et al. 1996, 1999, 2007). Significant cyclic variations in left-hemisphere beta-wave activity were not observed. Taken together, the findings of the present investigation support a model of sustained attention that predicts cyclic changes in human performance that are the result of cyclic changes in right-hemisphere arousal.

A quantitative electroencephalographic correlate of sustained attention processing.

The objective of the present investigation was to develop a quantitative electroencephalographic measure (qEEG) that is sensitive and specific to changes in sustained human performance. A principal components analysis (PCA) was performed on the qEEG obtained from participants during a continuous performance test. Measures of sensitivity (proportion of correctly identified correct responses, or hits) and specificity (proportion of correctly identified incorrect responses, or misses) were calculated to assess the classification accuracy of each newly derived component. PCA solutions produced a right hemisphere component comprised of beta-wave activity measured from four unipolar sites (F8, C6a, C6, and T4) that appeared to be sensitive and specific to changes in human performance. Results provide evidence for the validity of a right hemisphere qEEG measure that is sensitive and specific to changes in sustained human performance. Consistent with the findings of previous research, the present findings implicate the right cerebral hemisphere in the sustained attention process.

Effects of flash mode and intensity on P2 component latency and amplitude.

UNLABELLED: Alzheimer's disease (AD) groups manifest flash visual-evoked potential (VEP) P2 component delays compared to healthy control groups. However, using P2 latency to categorize individual patients and controls yields low accuracy. Additionally, several laboratories have failed to replicate the basic between group P2 latency findings. The sporadic failure to find the P2 delay and, when found, its failure to classify patients and controls accurately may reflect the use of non-optimal stimuli or recording sites. OBJECTIVE: This was a parametric investigation of stimulation and recording methods in healthy college students. METHOD: Using an extended recording montage of 64 electrodes, 10 stimulus conditions (5 flash intensities through open and closed eyes) were evaluated for their P2 effects. RESULT: The optimal recording site (O2) yielded the most reliable latencies and amplitudes across a range of stimulus intensities. Flash intensity did not affect P2 latency or amplitude. Flashes delivered through closed eyelids produced a flash VEP but delivery through open eyes produced a pattern VEP lacking a flash P2 component. CONCLUSION: This accounts for the failure of some laboratories using open eyes to replicate the P2 delay in AD groups. SIGNIFICANCE: Optimal flash VEP conditions include closed eyes and recording from O2. Flash intensity is unimportant.

Assessment of mood state in dementia by use of the visual analog mood scales (VAMS).

OBJECTIVE: The assessment of mood states in individuals with dementia is a challenging yet clinically useful task. The purpose of the present study was to examine the validity of the Visual Analog Mood Scales (VAMS) in individuals with dementia. METHODS: Thirty-one patients who met diagnostic criteria for dementia completed the VAMS and a modified Profile of Mood States. RESULTS: Authors found good convergent validity between all monotrait-heteromethod mood states. Excellent discriminant validity was found for VAMS Happy, Confused, Angry, and Energetic scales. CONCLUSION: These results provide evidence for the validity of the VAMS in patients with dementia.

Rhythmic oscillations in the performance of a sustained attention task.

Attempts to sustain a narrow focus of attention over a long period of time are effortful and are punctuated by lapses. Most studies of sustained attention performance obscure the presence and pattern oflapses by reporting measures that are summed across the entire period of an individual's performance, or that are average scores for blocks of trials across many participants. In the present study we attempted to explore fluctuation in the attention of individual participants over the course of a vigilance task and to quantify its periodicity, if any exists. Normal university students listened to letters of the alphabet, arranged randomly and presented at a rate of 2 per second for 20 min. They were instructed to press a hand-held button when they detected a target two consecutive identical letters). Continuous estimates of performance accuracy (correctly detected targets) at regularly spaced time intervals were created for each participant using a moving time window. The resulting functions were analyzed in order to detect and quantify periodicity using a Fast Fourier Transform (FF). The most often observed rhythms for those participants with adequate FFT power congregated at 1-2 min, 4-7 min and greater than 10 min. Performance functions from 36 of the 40 subjects displayed at least two of these frequencies. Other studies have identified cycles in performance during similar vigilance challenges, but without particular rhythms or with no particular shared frequencies amongst participants. The possible sources of these fluctuations and the differences in the findings of these studies and the present study are discussed.

Diagnostic utility of visual evoked potential changes in Alzheimer's disease.

Previous studies have consistently found a selective delay of the P2 flash visual evoked potential (VEP) component among groups of patients with Alzheimer's dementia (AD) compared with control groups. Several authors have termed the selective P2 delay a "marker" for AD and have called for its use in clinical diagnosis. This study examined the diagnostic utility of the selective P2 delay in a retrospective sample of 45 AD patients and 60 age-equivalent healthy control subjects. Although significant between-group differences were found, classification accuracies for individual patients and controls were too low for the P2 delay to contribute meaningfully to clinical diagnosis.

Measures of variations in performance during a sustained attention task.

In this study the authors developed and explored measures of short-term variations in accuracy on a test of sustained attention, a departure from traditional measures of average performance over long periods. The study participants were normal young adults, actively engaged in a continuous performance test (CPT). Both correct (hits) and incorrect (misses) responses to CPT targets appeared to aggregate in runs (2 or more consecutive hits or misses). Results of a Monte-Carlo procedure indicated that these runs were longer and fewer than would occur if hits and misses were randomly distributed. Average accuracy decreased between the first and second 5-min quarter of the test, then remained level. The length of hit runs followed the same pattern. However, other aspects of performance continued to change. The amount of time participants spent in miss runs began to increase significantly in the third quarter, and the frequency of miss runs did not increase until the fourth quarter. Explanations of these findings based upon changes in perceptual sensitivity or upon phasic increases in arousal caused by hits were rejected by further analysis. There was evidence that the length of miss runs was limited by a target-expectancy effect created by the specific parameters of our CPT. The authors conclude that measures of variations in performance reveal aspects of vigilance that are not tapped by traditional measures, and that factors that initiate, sustain and terminate both hit and miss runs are important targets of future research. Additional research is needed to determine whether or not the particular measures developed in this study may contribute to the understanding of attention problems in clinical populations.