CLINICAL EEG and NEUROSCIENCE - Dynamic Memory Lab

More documents

Recommendations

Info

CLINICAL EEG and NEUROSCIENCE ©2007 VOL. 38 NO. 1Figure 2.Grand averagewaveforms forincongruous words(initial and repeatedpresentations) fromYear 1 for normalold controls (n=16),and from Years 1and 2 for MCI-stable(n=10; meanMMSE=28.0 at Year1) and MCI-to-ADconverters (n=16;mean MMSE=27.3at year 1). The N400is indicated on righttemporalchannels.The incongruousrepetition effect (dueto a diminishedN400 to repeatedwords) is shadedbetween 300-600ms where present.0 400 800 0 400 800 0 400 800 ms 0 400 800 0 400 800 msearly latency windows (300-500 ms) showed a distinctlyfrontal distribution. The authors attributed this frontal old/newe ffect to familiarity because of its resemblance to an eff e c tfound in a prior study. 5 5 Furthermore, patients’ source memorywas at chance, suggesting that their above-chancerecognition performance (62%) was due to a sense of familiarity(or another such implicit process) and not to recollectionof the study event. Schnyer et al 6 4 found further evidencefor deficient ERP word repetition effects in AD. Usinga continuous lexical decision task with incidental repetition atlong lags (>90 items or >7.5 minutes), Schnyer et al found arepetition positivity from 300 to 650 ms in controls, but nodiscernable effect in AD patients.A study in our laboratory 65 applied the same semanticcongruity-plus-repetition paradigm described in the previoussection 2 to patients with mild AD. As in patients withchronic amnesia, patients with mild AD had significantlyreduced P600 word-repetition effects (see Figure 1). Inaddition, patients with mild AD showed a significant diminutionof the N400 word-repetition effect. In fact, both theP600 and N400 repetition effects were “absent” in the ADgroup, in that there were no statistically significant effectsfor these potentials. The loss of the N400 repetition effectmay correspond to abnormal semantic/conceptual priming,as has been found in several behavioral studies of mildAD. 66 Furthermore, when 10th percentile (in normal elderly)cutoffs for the P600 and N400 word-repetition effectswere applied, all 11 mild AD patients were correctly classifiedas abnormal on one or both measures (sensitivity:100%; specificity: 82%), suggesting that this paradigm haspromise for use in the diagnosis or early detection of AD.N400/P600: repetition effects inMild Cognitive ImpairmentAnother study in the authors’ laboratory used the congruity-plus-repetitionparadigm to evaluate N400 and P600repetition effects in MCI. 67 In MCI, target words that followedcongruous category statements elicited a robustpositive shift in N400 amplitude relative to incongruouspairings. Analysis of the fractional area latency of this N400congruity effect showed that it was delayed in MCI relativeto controls. The N400 repetition effect, initial vs. repeatedincongruous pairings, was present but delayed in MCI. TheP600 repetition effect, initial vs. repeated congruous pairings,was not significantly different from zero in the MCIgrand average (see Figure 1). Post-hoc analyses revealedthat in MCI individuals who were subsequently diagnosedwith probable AD (n=7; “converters”), the P600 repetitioneffect was virtually absent, whereas in the MCI participantswho remained at risk (n=6; “MCI stable”) the effect waspresent but delayed relative to controls. Longitudinal ERPstudy of this cohort has shown that the N400 repetitioneffect is diminished and spatially restricted in converters atbaseline (Year 1), then absent in the group average data 1year later (Year 2; see right column in Figure 2). It is noteworthythat the P600 repetition effect at baseline could beused to discriminate MCI-to-AD converters from MCI-stablecases over the next 3 years with high accuracy (e.g.,85% or 11 of the 13 MCI participants included in Olichney14
CLINICAL EEG and NEUROSCIENCE ©2007 VOL. 38 NO. 1et al 67 ), despite statistically indistinguishable MMSE scores(means 26.6 and 27.5 respectively).Summary: N400/P600 repetition effectsRecent work dissociating N400 and P600 repetitione ffects has found that MTL amnesics, whose ability toencode events into long term memory is compromised,show intact N400 but impaired P600 effects. This pattern offindings supports the notion that implicit and explicit retrievalprocesses are indexed by N400 and P600, respectively. InAD, both N400 and P600 repetition effects are severelydiminished. In MCI, the conjunction of reduced N400 andP600 repetition effects may be useful in identifying thoseindividuals at highest risk for subsequent conversion to A D .CONCLUSIONIntegrating across the ERP studies reviewed above,some useful generalizations can be made. The sensitivityof cognitive ERPs can be greatly increased by looking atmodulations of components, rather than expecting anabsence or near ablation of late components such as theP300, N400, and P600, all of which have multiple, distributedneural generators. Patients with a “pure” amnesticsyndrome usually have normal P300s (at least on the auditory“oddball” paradigm), but occasionally, abnormal P300shave been observed among those with more diffuse braininjuries. While memory was the only cognitive domain witha clinical deficit, the P300 abnormalities likely reflect subclinicalabnormalities in attention and working/immediatememory. Amnesic patients usually have normal N400effects, but an important exception is that of MCI “converters”with incipient AD. In contrast to the relatively normaleffects of word repetition on the N400, severe decrementsof the P600/LPC word repetition effect are present in wellcircumscribedamnesia.Patients with mild AD can usually generate reasonablysized P300 and N400 amplitudes, but quantitative analysesoften show subtle abnormalities beyond that attributableto aging. Across N400 experiments, the precise paradigmused appears to be very important and may lead todifferential sensitivity to amplitude or latency abnormalities.In mild AD, both N400 and P600 components demonstratea loss of normal word repetition effects. This suggests amore generalized failure of synaptic plasticity than inpatients with pure amnesia. Biomarkers of failed synapticplasticity should be of great value in AD, a disease thatsome leading investigators view as a primary disorder ofsynaptic function. 68,69 Studies of transgenic AD animal modelsoften find synaptic dysfunction prior to the appearanceof amyloid plaques or extensive neurofibrillary pathology.70,71 Clinico-neuropathological studies have found thatthe density of cortical presynaptic terminals is one of thestrongest predictors of dementia severity. 72ERPs may also provide a useful non-invasive tool forstaging the extent of AD pathology. In the mild to moderatestages of AD, the P300 and N400 potentials usually deterioratemarkedly, but with relative sparing of earlier sensorycomponents. 16 This is as one would predict based on thetypical staged progression of AD pathology. 73 Predilectionsites in early AD include the medial temporal lobe, otherlimbic areas, and multimodal association cortices withsparing of primary sensory areas. Unimodal associationcortex is involved in AD, but not as heavily as multimodalcortex. As more effective treatments emerge for AD, includingsome capable of reducing amyloid burden (e.g., A-βvaccination and γ-secretase inhibitors), biomarkers sensitiveto the reversal of cognitive processing deficits will be ofincreasing importance.ACKNOWLEDGMENTSSupported by National Institute on Aging (NIH grants#R01 AG18442 to J.M.O. and P50 AG05131 to J.R.T. )and the Department of Veterans A ff a i r s .REFERENCES1. Squire LR, Knowlton B, Musen G. The structure and organizationof memory. Annu Rev Psychol 1993; 44: 453-495.2. Olichney JM, Van Petten C, Paller K, Salmon DP, Iragui VJ,Kutas M. Word repetition in amnesia: electrophysiologicalmeasures of impaired and spared memory. Brain 2000; 123:1948-1963.3. Auchterlonie S, Phillips PA, Chertkow H. Behavioral andelectrical brain measures of semantic priming in patientswith A l z h e i m e r’s disease: implications for access failure versusdeterioration hypotheses. Brain Cogn 2002; 48(2-3):2 6 4 - 2 6 7 .4. Donchin E, Coles MGH. Is the P300 component a manifestationof context updating? Behav Brain Sci 1988; 11 ( 3 ) :3 5 7 - 3 7 4 .5. Verleger, R. Event-related potentials and cognition: a critiqueof the context updating hypothesis and an alternative interpretationof P3. Behav Brain Sci 1988; 11: 343-356.6. Johnson R Jr. A triarchic model of P300 amplitude. Psychophysiology1986; 23(4): 367-384.7. Halgren E, Marinkovic K, Chauvel P. Generators of the latecognitive potentials in auditory and visual oddball tasks.Electroencephalogr Clin Neurophysiol 1998; 106(2): 156-164.8. Guillem F, Rougier A, Claverie B. Short- and long-delayintracranial ERP repetition effects dissociate memory systemsin the human brain. J Cogn Neurosci 1999; 11(4): 437-458.9. Yamaguchi S, Knight RT. Effects of temporal-parietal lesionson the somatosensory P3 to lower limb stimulation. ElectroencephalogrClin Neurophysiol 1992; 84(2): 139-148.15
Page 3 and 4: CLINICAL EEG and NEUROSCIENCE ©200
Page 19: CLINICAL EEG and NEUROSCIENCE ©200

CLINICAL EEG and NEUROSCIENCE - Dynamic Memory Lab

Create successful ePaper yourself

Delete template?

Save as template?