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Mild cognitive impairment (MCI) has gained wide acceptance as a term referring to various forms of cognitive decline that are not attributable to normal, healthy aging (Petersen, 2004). The amnestic subtype of MCI (MCIa), which is characterized by a deficit in episodic memory but the preservation of general cognitive functioning and the absence of dementia (Petersen, 2004; Levey et al., 2006), may be a transitional period between normal aging and more serious pathological conditions, such as Alzheimer's dementia (AD; Grundman, et al., 2004; Levey, et al., 2006). Conversion from MCIa into AD has been demonstrated to occur for about 10–15% per year for patients diagnosed with MCIa as compared with 1–2% per year for healthy, age-matched controls (Gauthier, et al., 2006).
Based on the high rates of conversion for MCIa to AD, researchers have studied MCIa with the hope that an early diagnosis of AD would lead to an increase in potential for treatment options that may delay or even prevent further cognitive decline (Bischkopf et al., 2002). While some progress has been made in developing methods of early detection, very few have proven to be diagnostically useful (Grundman, et al., 2004; Petersen, 2004; Levey, et al., 2006).
One of the earliest neurophysiological changes seen in AD involves a reduction of cholinergic functioning (Moore, 1997). Acetylcholine is a neurotransmitter that plays an important role in cognitive functioning, including memory and some types of sensory processing (Bajalan et al., 1986). It has been hypothesized that the cognitive deficits associated with MCIa and AD are a direct result of the impaired functioning of the brain's cholinergic systems (Bajalan et al., 1986; Reeves, et al., 1999; Gron, et al., 2006; Herholz et al., 2008). Therefore, reliable and valid measures of early visual processing could, in theory, be used to assess the integrity of an individual's cholinergic system and serve as a clinical diagnostic tool when diagnosing MCIa and AD (Givre et al., 1994; Mielke et al., 1995).
Since the early 1990s, research has focused on developing a noninvasive method of assessing cholinergic functioning that could be used to improve the diagnostic accuracy of the more commonly used neuropsychological test battery (Moore, 1997; Babiloni et al., 2004; Moretti et al., 2004; Babiloni et al., 2009). A detachment of this research has focused on the early visual processing deficits seen in AD and found robust statistically significant group differences in evoked potential latencies to simple flash stimuli, but not to pattern reversal stimuli. This pattern of results suggests that the luminance channel of the human visual system is heavily innervated by cholinergic neurons that may be adversely impacted early in the AD disease process.
By measuring the performance of the luminance channel, it may be possible to reliably gauge the health of the brain's cholinergic system. One of the best methods for accomplishing this is with the P2 component of the flash visual evoked potential (FVEP-P2; Coburn, et al., 2005). The P2 is the second positive wave of the visual evoked potential (VEP) detectable with electroencephalography (EEG) and is a prominent feature of early cortical processing. It has been demonstrated repeatedly that people with MCIa and AD exhibit a selective delay in the FVEP-P2 latency while showing no such differences in response to other types of visual stimuli (Swanwick, et al., 1996; Moore, 1997; Coburn, et al. 2003). Despite this consistent pattern of group differences, individual variability contributes to overlapping FVEP-P2 latency distributions between normal, MCIa, and AD groups that reduces the sensitivity and specificity of the FVEP-P2 when used as a clinical diagnostic tool. Consequently, a method of further separating the distributions of FVEP-P2 latencies associated with these groups must be developed in order to increase the sensitivity and specificity of the FVEP-P2 if it is to be used clinically.
One possible modification to the FVEP procedure might be the use of a double flash stimulation, which has been used previously to study the refractory period of the human visual system (Musselwhite & Jeffreys, 1983; Skrandies & Raile, 1989). VEP responses to single and double stimulations have been compared as a way to measure how quickly the visual system could recover from a single flash stimulus. Presenting successive flash stimuli, while varying the inter-stimulus interval (ISI) of each stimulus pair, resulted in little or no response to the second flash stimulus in conditions with an ISI of 50 milliseconds (ms) or less (Skrandies & Raile, 1989). However, a small response was observed in conditions with an ISI longer than the refractory threshold of 50 ms, and it became more robust as the ISI increased in length.
The double flash procedure has yet to be studied in patients with either MCIa or AD. Given the early loss of cholinergic neurons in patients with MCIa and AD, the double stimulation technique may prove useful in further separating normal healthy controls and patients with either MCIa or AD. For example, one might expect the first flash to tax an already compromised cholinergic visual system, leading to an abnormally delayed response to the second flash stimulus.
The purpose of the current study was to evaluate whether a novel double stimulation procedure could be used to distinguish people with MCIa from a group of healthy controls. It was predicted that the P2 latencies of MCIa patients would be significantly longer, on average, than the FVEP-P2 latencies of healthy controls, especially for ISIs approaching the refractory period. Finally, it was predicted that a longer refractory effect would be observed for individuals with MCIa than controls.
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The purpose of the present pilot investigation was to assess the clinical utility of a novel FVEP-P2 procedure for the diagnosis of MCIa. It was predicted that patients who were identified as having MCIa would exhibit longer FVEP-P2 latencies than a sample of healthy controls. Findings of the present investigation provide general support for this prediction and extend it by demonstrating high diagnostic accuracy for both the single and two of the double stimulation procedures.
Consistent with previous research (Swanwick, et al., 1996), individuals identified as being MCIa exhibited FVEP-P2 latencies that were longer than the FVEP-P2 latencies exhibited by healthy controls. Although the main effect was only marginally significant (p = 0.101), the large effect size (d = 1.25) suggests that the difference in luminance channel performance between those with MCIa and healthy controls may be clinically meaningful. Similar to the overall effect of group, the single flash condition also produced a large effect size (d = 2.47) that was statistically significant (p = 0.017), lending stronger support for the main hypothesis of this investigation. These results suggest that the cholinergic dysfunction apparent in AD is manifest in individuals identified as being MCIa, supporting the theory that MCIa may be an intermediate stage in the progression from normal aging to AD.
The double stimulation conditions produced results that partially support the other hypotheses. Contrary to what was predicted, no group differences were observed in P2 latency for the double flash conditions that immediately followed the refractory period (i.e., 60, 70, or 80 ms ISIs). The challenge of two stimuli presented with an ISI slightly longer than the refractory period (i.e., 50 ms) did not result in an increased difference in P2 latency delay. Instead, the two groups displayed more similar P2 latencies than were found in the single flash condition. This similarity did not hold true for all the double flash conditions, though, as significant group differences were found for the 100 (d = 1.60) and 120 ms (d = 1.86) double flash conditions. These results are particularly promising considering that other previously published investigations that have examined AD have reported smaller effect sizes (e.g., d = 0.68) and lower sensitivity and specificity values (Coburn, et al., 2003).
The pattern of group differences observed across conditions may help shed some light on the status of the cholinergic system in individuals identified as having MCIa. The control group displayed a dynamic pattern of responses across ISI conditions that coincided with our predictions concerning the refractory effect, while the MCIa group did not. Compared with the single flash condition, the control group had a P2 latency increase in the double flash conditions with ISIs just longer than the refractory period that eventually returned to baseline in the longer ISI conditions. This pattern is a clear example of a refractory effect, in which responses that are abnormal for conditions more proximal to the refractory threshold return to normal in conditions more distal. The MCIa group did not display the same pattern of selective delays, as their P2 latencies were long and relatively constant across ISI conditions. Taken together, it appears that the challenge of the double stimulation procedure may have had very little effect on an already compromised cholinergic system, producing a pattern of latencies that may be indicative of the early stages of AD.
Limitations and future directions
There are several limitations to consider when interpreting the findings of this study. The most significant limitation was the small sample size, which resulted in low statistical power. However, the present results are not only consistent with the findings of previous research and theory, but the effect sizes obtained in the present investigation were considerably greater than those observed in previous studies involving AD (Coburn, et al., 2003). Because effect size indicators are descriptive in nature, the observed effect sizes reported here suggest that meaningful differences in FVEP-P2 latencies are genuine and not an anomaly. As such, further investigation with larger sample sizes is needed to validate the present findings.
A second limitation involved the FVEP-P2 waveform identification. A semi-automated procedure was used to identify each P2 and to protect against experimenter bias. While this procedure produced numerical latency data, it did not detect the unpredicted amplitude differences that are apparent in the grand average waveforms (Figure 1). The low amplitude second P2 produced by the MCIa group in the double stimulation conditions may be indicative of a profound refractory effect that prolongs the refractory threshold and prevents the compromised visual system from responding to the second flash. Unfortunately, the magnitude of this refractory effect and its influence on P2 amplitude was unexpected, so the range of double stimulation ISI conditions tested in the present investigation was not wide enough to examine how long the refractory period extended and at what ISI a second P2 emerged and returned to a latency and amplitude similar to the single flash condition. Additional studies are needed to verify the present findings and explore the possibility that examining a large spread of ISIs could prove diagnostically useful in determining the health of the cholinergic system by measuring how severe a refractory effect is present and how long it takes the visual system to recover from the challenge of two rapidly presented flash stimuli.
Figure 1. Grand average waveforms depicted as change in millivolts across time (ms) at site Oz. MCIa, amnesic mild cognitive impairment.
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The present study found significant differences in early visual processing between participants identified as having MCIa and healthy controls. Consistent with previous studies, group differences in FVEP-P2 latency were found in the single flash condition. Results from the double stimulation conditions revealed refractory effect differences between the MCIa and control groups, a dynamic that may represent a novel contribution to the literature on MCIa. These findings support the theory that MCIa is an intermediate stage between normal, healthy aging and the more severe pathology of AD.