Chapter 10 Visual cognitive ERPs

Disorders of Visual Processing Handbook of Clinical Neurophysiology, Vol. 5 GG Celesia (Ed.) © 2005 Elsevier B.V. All rights reserved.

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CHAPTER 10

Visual cognitive ERPs Mitchell G. Brigell* Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105-1912, USA

With the advent of new technologies to explore brain function comes the expectation of the emergence of new insights into human experience and cognition. Current literature holds such hopes for functional MRI and PET neuroimaging techniques. Similarly, EEG technology has been used to explore cognition and the mind for over 50 years. Despite the current enthusiasm regarding the role of neuroimaging in cognitive neuroscience, new insights into the origins of conscious experience and the code of visual cognition in the human brain are few and far between. This is partially due to the need for an adequate paradigm to address the neural coding mediating consciousness (visual and otherwise). There is probably as little chance that we will obtain a ‘pixel by pixel’ understanding of brain function as there was for phrenologists and skull morphological analysis. Although psychophysiology has not provided the revolutionary insight into brain function that was once expected, a number of paradigms have emerged that provide a novel look at attention, language and memory mechanisms. In this section, the components of visual cognitive event related potentials (ERPs) will be reviewed. An extensive literature on the effects of neurodegenerative and psychiatric diseases on these potentials will also be briefly presented. However, it is important to note at the outset that, to date, these responses have not shown sufficient sensitivity and specificity for use as markers of disease progress or to show effects of therapeutic intervention. 10.1. ERP components Surface recorded ERPs are complex responses involving overlapping contributions from multiple areas of

the brain. Thus, a neuro-anatomical definition of ERP components is fraught with difficulty and tenuous assumptions. However, psychological definition of components proves more approachable. Thus, by manipulation of the task demands of experimental paradigms, components related to such psychological states as attention shift, semantic priming and stimulus evaluation can be isolated. ERPs are termed endogenous in that they are dependent on the internal state of the organism, more than exogenous sensory evoked potentials, which are more dependent on the characteristics of the stimulus. For example, an exogenous component of a visual evoked potential might depend on the wavelength of stimulation, whereas an endogenous component of the response to the same stimulus might depend on whether stimulus wavelength was a criterion that the subject was using to categorize the stimulus. Some of the more common components of visual ERPs are the N200, the P300, the N400 and the late positive component. The N200 is a component that occurs to stimuli that deviate from a pre-existing context. It generally has the highest amplitude over the vertex. The P300, also called the P3b, is a response to infrequent target stimuli in what has been termed an oddball paradigm. It is maximal in amplitude over parietal areas and is thought to represent the time taken to evaluate stimulus information and to update recent event memory (Donchin and Coles, 1988). The P3a is a more frontally dominant response that occurs to novel or unexpected stimuli. This component is probably related to involuntary shifts of attention induced by novel stimuli (Knight, 1991). Examples of P3a and P3b responses are shown in Fig. 10.1. 10.1.1. Methodological considerations

* Tel.: +1 734 622-1852; Fax: +1 734 622-5196; E-mail: Mitchell.Brigell@Pfizer.com

Visual ERPs are recorded using standard electroencephalographic/evoked-potential technology.

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Fig. 10.1. Waveform and topographic distribution of P3a and P3b visual ERPs obtained during an adaptation of the Wisconsin card sorting task. The P3a is obtained to presentation of a novel non-target stimulus. It has a frontal distribution. A P3b component is observed to a rare target stimulus. It has a more posterior amplitude distribution. From Barcelo et al., 2002, with permission.

Electrical activity of the brain is recorded using surface electrodes and differential amplification. Signal averaging, time-locked to a stimulus event, allows the measurement of activity associated to that event. Some special considerations are necessary for ERP studies. First, many cognition related signals are late components (occurring more than 200 ms after the stimulus event), and much of the information is contained in low-frequency EEG bands. The long latency of cognitive ERPs means that motor reactions to the stimulus can interfere with the recording of brain potentials. Study design should avoid confounding of motor preparation with cognitive state. Care should also be taken to exclude traces with muscle artifacts apparent in the recording. The low frequency components of these responses necessitate that filter settings on amplifiers use a low frequency cut-off of 0.1 Hz or lower. Recording of cognitive ERPs most often requires multiple signal averages to be collected during a trial. In oddball experiments responses to frequent and infrequent stimuli must be separately averaged. In attention experiments, responses to attended and unattended stimuli must be separately averaged. In priming studies of short-term memory, averaging

depends upon the number of stimuli intervening between successive presentations of a given stimulus. Criteria for averaging may also depend upon response criteria (e.g. items correctly recalled vs. forgotten items). Thus, in order to best record cognitive ERPs it is usually best practice to store the raw EEG and event markers and perform signal averaging off-line. Only some of the currently available commercial systems have this capability and interested investigators should be aware of the ease with which systems can be adapted to the needs of their studies. Stimulus paradigms used in visual cognitive ERPs are quite varied and there are no established standards. The interested reader is encouraged to refer to the literature cited in this chapter for further methodological details. More comprehensive methodological reviews of cognitive ERP methods are also available (Coles and Rugg, 1995; Heinze et al., 1999; Polich, 1999). 10.2. ERPs and visual attention Perhaps the greatest impact of visual ERP research has been in the area of visual attention. It had long been recognized that attention to a spatial location could decrease reaction time to stimuli presented in this region (Broadbent, 1958; Deutsch and Deutsch, 1963; Posner, 1980). Behaviorally, it was not possible to determine whether this effect reflected a change in early sensory sensitivity or a change in response criterion (Broadbent, 1970; Sperling, 1984; Muller and Findley, 1987). ERPs recorded during a spatial attention task showed increased amplitude of the early sensory components to targets presented in attended locations (Eason et al., 1969; Hillyard et al., 1973; Fig. 10.2). These results unambiguously showed that spatial attention increased the gain of the early sensory response. A great deal of research has followed these early studies. It has been learned that spatial attention occurs earlier in the visual pathway than attention to other features of the visual stimulus such as color or spatial structure (Harter et al., 1982; Hillyard and Munte, 1984). Attention to color produces a ‘selection negativity’ that occurs after the earliest sensory components. When concurrent features are attended to (a red spot at a specific location in the visual field) spatial location takes precedence over stimulus features in that little, if any, enhancement of the ERP is observed when a target stimulus is presented in an unattended location. Single cell recordings from alert monkeys trained in attention tasks have shown modulation of response of cells when attention is directed to a

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Fig. 10.2. The effect of attention on the early components of the visual ERP. The upper panel shows the ERPs obtained from 64 electrodes during attention (red) and passive (green) conditions. Enhancement of P1 and N2 response components is obvious over posterior head regions contralateral to the field of attention. The lower panel shows topographic voltage maps of the difference between attention and passive viewing conditions for the P1 and N2 components. From Woldorff et al., 2002, with permission.

location within the cell’s receptive field in pre-striate (V2), but not primary (V1) visual cortex (Motter, 1993; Luck et al., 1997). Attention to color and motion has been shown to affect response of V4 and MT (Treue and Maunsell, 1996), respectively. In addition to sustained attention effects the dynamics of shifting visual attention have been studied using electrophysiology (Harter and Anllo-Vento, 1991; Mangun and Hillyard, 1991; Yamaguchi et al., 1994), FDG-PET imaging (Posner and Peterson, 1990; Nobre et al., 1997; Coull and Frith, 1998) and fMRI (Beauchamp et al., 2001). These studies used a Posner attention task, in which a central or peripheral cue is used to direct attention. By looking at responses to the central cue, the act of shifting attention can be measured. These imaging studies have shown both frontal and posterior parietal cortical regions to be

involved in this process (Fig. 10.3). It has become clear that shifting attention requires active suppression of attention to the current location and that visual neglect following parietal lobe injury is largely mediated by an inability to suppress the current locus of attention. The voluntary shift of attention mediated by a central cue can be differentiated from an involuntary orienting response to a peripheral cue (Jonides, 1981). Electrophysiologically, this involuntary shift of attention to a peripheral cue is manifested by an enhanced N1 response amplitude (Mangun and Hillyard, 1987). 10.2.1. Visual attention ERPs: aging, disease and pharmacologic effects Effects of age, disease and neuroactive drugs have been observed on attentional effects on ERPs. As is

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Fig. 10.3. Areas of significant fMRI activation during shift of spatial attention in eight individual subjects. Areas of activation are displayed on blown-up surface of a standard brain. Adapted from Beauchamp et al., 2001, with permission.

the case with all cognitive ERPs, the effects are rather small and variable. Thus, although significant effects on group data can be observed, these differences do not translate into diagnostic utility. 10.2.1.1. Age Richards (2000) has reported valid and invalid cueing effects on ERPs and saccadic reaction time in infants as young as 14 weeks of age. This study also showed developmental effects on the cueing effects from 14 to 26 weeks of age. In a study of adult aging, LorenzoLopez et al. (2002) found that a group of older subjects (56–66 years of age) had a smaller effect of peripheral cueing on P1 amplitude than that seen in young adults (19–23 years of age). No effects of age on central cueing were observed. 10.2.1.2. Learning disability Jonkman et al. (1992) measured ERPs during a standard Posner central cue paradigm in 9–12-year-old

children with or without specific reading disability. The reading disabled group was split into perceptual and linguistic typed depending on the results of psychometric testing. Shorter reaction times were found to validly cued locations for all groups. Unlike normal adults, all children showed shorter reaction times to invalid cued locations than to uncued stimuli. This result is often found in children and suggests that the invalid cue serves as a warning signal of an impending stimulus, which activates the system compared to the uncued condition. ERPs to the cue were similar between groups. The increase in amplitude to validly cued stimuli was larger over the right hemisphere, regardless of the field of stimulus presentation, for all groups. In the 100–200 ms following stimulus presentation, results from reading disabled children differed from normals and perceptual and linguistic dyslexics differed from each other. Brigell et al. (1996) studied 8–10-year-old children classified by psychometric tests as having specific reading disabil-

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ity, maths disability, or normal. A sustained attention task was used in which the children attended to one hemifield and responded to a target letter by button press. As in the Jonkman study, normal children showed an effect of attention over right posterior head regions regardless of the field of attention (Fig. 10.4). This result has not been reported in adults, where attention effects are generally contralateral to the field of attention. Maths disabled children showed a robust effect of attention for target stimuli only, whereas normals showed an attention effect for both target and non-target stimuli. Reading disabled children did not show any consistent effects of attention on early ERP components, a result similar to that found for linguistic type dyslexics by Jonkman et al. (1992). 10.2.1.3. Neurodegenerative diseases Early ERP studies of attentional processes in Parkinson’s disease provided inconsistent results, largely due to discrepancies in tasks used and disease severity of the studied population (see Yamada et al., 1990). A more recent thorough investigation by

Fig. 10.4. The effect of attention on the visual P1 response in normal children. Data in the upper row are the response to target stimuli presented in the right visual field and data in the lower row are to non-target stimuli presented in the right visual field. The waves drawn in heavy line are from the right occipital electrode during sustained attention to the right visual field. The topographic voltage maps of the P1 response obtained under this condition are shown in the leftmost column of maps. The light line waveforms and the center maps are obtained during sustained attention to the left visual field. The difference maps, shown in the rightmost column show the effects of attention on the P1 response. Note that attention enhances the response over the right occipital lobe despite stimulus presentation in the right visual field. From Brigell et al., 1996, with permission.

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Yamaguchi and Kobayashi (1998) has given some clarity to the subject. In this study, voluntary (central cues) and automatic (peripheral cues) attention shift paradigms were used. Interval between the cue and target was varied between 200 and 800 ms. Patients with idiopathic Parkinson’s disease of mild to moderate severity were compared to age matched normal controls. Patients were not demented. Behavioral results showed that peripheral cues had similar effects for patients and controls, although patients were generally slower to respond. Central cue validity had little effect on reaction time when the interval between cue and stimulus was long, whereas when shorter intervals were used, the cueing effects were similar between patients and controls. ERPs showed that patients had smaller processing negativities to the cue, and that in the central cue long interval condition, the long-latency negative polarity attention component was reduced over frontal head regions. The authors interpret their results to imply that dopaminergic deficiencies primarily affect the frontal attentional areas. In a study comparing various forms of bradykineticrigid syndromes on attentional ERPs, Pirtosek et al. (2001) reported more severe abnormality of attentional effects for patients with Steele–Richardson– Olszewski syndrome than for those with multiple system atrophy or idiopathic Parkinson’s disease. The attention shift paradigm has also been used to study patients with lateral cerebellar degenerative disease (Yamaguchi et al., 1998). Both behavioral reaction time data and early ERP components showed similar attention effects for patients and age matched controls regardless of whether cues were central or peripheral. The late negativity ERP component to the cue and the late positivity to the stimulus were reduced in amplitude in the patient group. The authors suggest that the lateral cerebellum makes little contribution to attention shift, but may be involved in response preparation and selection. 10.2.1.4. Pharmacologic effects In a single-dose double-blind study in normal young males, Heinze et al. (1994) measured the effects of a benzodiazepine (oxazepam) and a stimulant (kava root) on the visual attention ERP. Oxazepam increased reaction time and error rate, while reducing the amplitude of most post-stimulus ERP components. Kava did not significantly affect performance, but significantly increased the amplitude of many post-stimulus ERP components. In a double-blind randomized crossover placebo controlled study, 24 patients with

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definite MS were treated with amantadine (Sailer et al., 2000). Drug treatment significantly increased the amplitude of a ‘selection negativity’ component occurring 200 ms following stimulus presentation despite no significant effect of treatment on reaction time. This effect was more pronounced in patients with disease duration of greater than 7 years. 10.3. Visual P300 The P300 is the most thoroughly studied of the ERP components. A comprehensive review of the P300 literature is beyond the scope of this chapter, but the interested reader should consult Picton (1992) for a review. Briefly, the P300, or P3b, is a response recorded over the parietal lobe approximately 300 ms following an infrequent target stimulus. This response was first described by Sutton et al. (1965) and was first recorded in a now standard oddball paradigm by Ritter and Vaughan (1969). The response, though generally quite large, is also variable and dependent on task difficulty and age (Picton et al., 1986; Polich, 1987). Thus, although potentially useful in the scientific study of dementia and cognitive processing, the P300 has not been used widely as a clinical tool or as a measure in clinical trials. 10.3.1. P300: aging, disease and pharmacologic effects 10.3.1.1. Age P300 peak latency decreases rapidly with age from 5 years to 12 years. There is a slow decrease from 12 to 16 years of age, followed by a gradual increase throughout adulthood (Taylor, 1988; Johnson, 1989; Polich et al., 1990b). Johnson (1989) has reported that the latency decline with age in childhood is greater for auditory than visual stimuli. Kutas et al. (1994) have reported an increase in P300 latency of 1.4 ms/year throughout adulthood. More recently, Kok (2000) has reported a decrease in amplitude of central and anterior components of the visual search P300 with senescence and an increase in a posterior negative component. Kok speculates that this increase in posterior negativity amplitude reflects a compensatory mechanism. 10.3.1.2. Learning disabilities/attention deficit disorder A number of authors have reported reduced P300 amplitude in patients with LD/ADD (Ollo and

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Squires, 1986; Satterfield et al., 1990). P300 abnormalities can occur in the absence of performance differences between groups, suggesting the use of alternative pathways for stimulus evaluation and orienting. 10.3.1.3. Phenotypic marker for alcoholism The P300 has been reported to be reduced in offspring of alcoholics (Begleiter et al., 1984; Whipple et al., 1988; Van der Stelt, 1999). In addition, in families with a high density of alcoholism, a reduced P300 has been shown to be predictive of future addiction (Berman et al., 1993; Hill et al., 1995). An intriguing study by Noble et al. (1994) has reported an association between the P300, a high risk for alcoholism and the D2 receptor gene DRD2 in children of alcoholics. Van der Stelt (1999) has found normal attentional effects on earlier components of the ERP suggesting that the P300 effect is not simply due to a sensory attentional deficit. Overall, these studies provide fairly convincing evidence that the P300 is a pathophysiologic marker of vulnerability to alcoholism. 10.3.1.4. Neurodegenerative diseases Numerous studies have reported prolonged latency and decreased amplitude of the visual and auditory P300 in patients with Alzheimer’s disease relative to age matched controls (Goodin et al., 1978; Polich et al., 1990a; Saito et al., 2001). Furthermore, two small longitudinal studies have shown that the P300 may be a useful adjunct to track disease progression (St Clair et al., 1988; Cohen et al., 1995). Abnormal P300 results have been observed in non-demented patients with Parkinson’s disease (Sagliocco et al., 1997; Zeng et al., 2002). Sagliocco et al. (1997) reported delayed P300 responses in a visual discrimination oddball task in treated Parkinson’s disease patients. Zeng et al. (2002) did not find an effect on the P300 in a different visual task using a similar population. However, they did find an absent novelty P3 in this same population. Abnormalities in P300 have also been reported in Huntington’s disease (Munte et al., 1997) and multiple sclerosis (Newton et al., 1989; Honig et al., 1992; Slater et al., 1994).

10.3.1.5. Psychiatric diseases A number of studies have suggested that the P300 is both a state and trait marker of schizophrenia (e.g. Pfefferbaum et al., 1984; Blackwood et al., 1991; Ford, 1999). These effects appear to be independent

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of medication effects (Pfefferbaum et al., 1989). Small effects on P300 amplitude and latency have been reported in patients with major depression (Pfefferbaum et al., 1984; Bruder et al., 1991). In general, these effects are smaller than those reported in dementia and a relatively preserved P300 may help in the differential diagnosis. The P300 was reported to be similar to controls in a group of patients with chronic fatigue syndrome (Polich et al., 1995). 10.3.1.6. Pharmacologic effects Many compounds reduce the P300 along with earlier sensory components of the ERP, primarily due to their sedative effects. These non-specific effects will not be summarized here. The anticholinergic drug hyoscine (scopolamine) appears to have an effect on the P300 (reduced amplitude and increased latency) that is independent of effects on earlier components (Callaway, 1984; Meador et al., 1989). In a study on normal children, Peloquin and Klorman (1986) found no effect of a single dose of methylphenidate on the P3 obtained in a Sternberg memory probe task, but did find an increase in P3 amplitude obtained in a continuous performance task. Reaction time measures showed that the drug caused an increase in accuracy and a reduction in variability without any change in mean reaction time. Results were interpreted to suggest that results with methylphenidate parallel those found in ADD children and refute the hypothesis that there is a paradoxical effect in the ADD population.

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items, but rather previous exposure affects subsequent responses to a stimulus. The most prevalent of implicit memory paradigms is the repetition priming effect. In this paradigm the time taken to make a lexical decision of whether a stimulus is a word or non-word is decreased if the stimulus has been presented previously (see Schacter et al., 1993, for a review). The ERP obtained to repeated items is characterized by a slow vertex positivity when compared to that obtained to new items (e.g. Rugg, 1987; van Petten et al., 1991). A related paradigm is semantic priming (Meyer and Schvanevelt, 1971) in which the reaction time to make a word/non-word lexical decision is decreased if the word is preceded by a semantically related word (apple-pear) than an unrelated word (table-pear). Semantic priming ERP effects are similar to that found in other repetition priming paradigms (Bentin et al., 1985). Primed verbal stimuli also produce a reduced amplitude N400 potential, regardless of whether the priming is semantic or repetition (Fig. 10.5). Another robust ERP component is the N400 in response to semantic incongruity in a sentence (Kutas and Hillyard, 1980). In this paradigm, responses are recorded to the last word presented in a sentence. The amplitude of the N400 is largest when this word is semantically incongruous (‘The pizza was too hot to cry’) and is smaller to semantically related words (‘The pizza was too hot to drink’). Sentences that are grammatically correct but semantically meaningless do not generate a N400 (van Petten and Kutas, 1991; Fig. 10.6).

10.4. Memory and language related ERPs PRIMING EFFECTS

Exploration of human memory and language has a long history in experimental psychology. Dichotomies such as short-term and long-term memory, implicit and explicit memory and episodic and semantic memory were first demonstrated to be independent in behavioral studies and have subsequently been validated by studies of patients with dissociated memory loss following discrete cortical lesions and by functional imaging studies. A large literature on memory and language related ERPs has been summarized previously (Osterhout and Holocomb, 1995; Rugg, 1995). In this section, we will focus on responses and paradigms that have been applied clinically. ERPs obtained in implicit memory tasks have contributed to our understanding of these processes and have been applied clinically. In implicit memory tasks the subject is given no instructions to remember

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Fig. 10.5. Reduced N400 response to semantically primed (related) words compared to that obtained from semantically unrelated words. Adapted from Swaab et al., 2002, with permission.

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Fig. 10.6. N400 response to semantically incongruous final word. Words were presented at a rate of one per second on a monitor. The solid wave shows the ERP to all semantically congruous sentences. The dashed wave is the response to all sentences in which the final word was semantically incongruous. A N400 peak is apparent following presentation of the final word. Orthographic incongruity of the final word results in a late positive ‘P560’ component (dotted waveform). From Kutas and Hillyard, 1980, with permission.

10.4.1. Memory and language related ERPs: aging, disease and pharmacologic effects 10.4.1.1. Age Developmental effects on memory and language ERPs have been extensively studied to gain insight into the maturation of these processes (Courchesne, 1983; Friedman et al., 1989; Berman, 1990). Berman et al. (1990) observed developmental effects between children (7–10 years old), adolescents (14–16 years old) and young adults (20–30 years old) on ERPs obtained in an explicit memory task, but no difference between groups was observed for repetition effect ERPs, suggesting that this response was fully developed by 7 years of age. Ford et al. (2001) have reported a difference in scalp topography of the priming N400 between young and elderly adults. The semantic incongruity N400 has been reported to be reduced in amplitude and increased in latency in aged, cognitively normal subjects (Iragui et al., 1996). 10.4.1.2. Priming effects in memory disorders Numerous ERP studies have been performed using semantic priming and word repetition effects in patients with Alzheimer’s disease. These studies have been motivated by behavioral studies showing effects of explicitly forgotten items on subsequently presented repeated or semantically related items (implicit priming). Results of ERP priming studies have been inconsistent with some studies showing intact priming N400 responses (Rugg et al., 1994; Kazmerski and

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Friedman, 1997), whereas other studies show reduced amplitudes and increased latencies in the patient population compared to age matched controls (Friedman et al., 1992; Iragui et al., 1996; Constaneda et al., 1997; Revonsuo et al., 1998). A number of factors may contribute to these discrepancies. Schnyer et al. (1999) found that AD patients showed similar priming ERP effects to normals when the lag between items was short, whereas ERP priming effects were reduced with longer lags between prime and target. Olichney et al. (2002) studied picture/word priming in patients with mild cognitive impairment and age matched controls. When the pictures and words were incongruous, the N400 showed a small increase in latency in the patient group, but was normal in amplitude. The late positive component evoked by congruous picture/word pairs was reduced in amplitude in the patient group. This component was more severely abnormal in patients who subsequently converted to AD. Auchterlonic et al. (2002) segregated items in a picture/word priming study based upon whether AD patients could correctly name the picture. They found normal priming effects for pairs in which the picture could be named, and heterogeneous effects for unnamed picture pairs. In a case study of a patient with hippocampal damage and an amnestic syndrome, Duzel et al. (2001) found intact explicit recognition in a word repetition paradigm. ERP results showed an intact N400 but an absent late positive component to repeated stimuli. They interpret their results as implying intact recollection memory, but impaired familiarity following hippocampal damage. 10.4.1.3. Priming effects in schizophrenia Small effects on priming ERP group mean data have been reported in schizophrenic patients compared to controls. Condray et al. (1999) reported equal amplitude N400 components to repeated and new words in schizophrenic patients, in contrast to the reduced N400 amplitude found in normal subjects to repeated items (N400 priming effect). Kimble et al. (2000) report a reduced N400 in schizophrenic patients, but not in their family members, in a sentence semantic incongruity task. 10.4.1.4. Pharmacologic effects Following clues from long-term potentiation studies in hippocampal slices, Grunwald et al. (1999) examined the effects of N-methyl-D-aspartate (NMDA) inhibition on the N400 obtained in a repitition priming

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study. Responses were recorded from depth electrodes in patients with temporal lobe epilepsy. Ketamine reduced the recognition of repeated words. ERPs were averaged only to words that were correctly identified as new or repeated. NMDA inhibition reduced the amplitude of the N400 to new words and eliminated the reduction in N400 to repeated words. Reduction of the N400 amplitude in a repetition priming study in normal subjects following a single dose of a benzodiazepine has also been reported (Munte et al., 1996). 10.5. Summary In summary, cognitive ERP research has elucidated processes underlying higher order visual cognitive performance. Perhaps the most significant contribution of the field to date has been that the effect of visual attention on reaction time is mediated by changes in early sensory processing rather than a shift in response criterion. The effect of attention on early ERP components has subsequently been confirmed in single neuron recordings from pre-striate cortex in awake monkeys. Although attentional effects on ERPs have not yet been fully clinically exploited, this technique would seem to have good reliability characteristics to detect changes in neurological diseases that affect attentional processes and to detect the effects of therapeutic intervention on these disorders. Similarly, ERPs and behavioral responses in explicit and implicit memory tasks can potentially be of use in refining the definition of the early memory loss that precedes the onset of Alzheimer’s disease. This would be of use in defining a population that could benefit from early therapeutic intervention. To date, however, clinical ERP studies have shown significant group mean effects of neurological disorders, but no studies have shown that these responses have the sensitivity and specificity necessary for diagnostic or therapeutic assessment. References Auchterlonic, S, Phillips, NA and Chertkow, H (2002) Behavioral and electrical brain measures of semantic priming in patients with Alzheimer’s disease: implications for access failure versus deterioration hypotheses. Brain Cogn., 48: 264–267. Barcelo, F, Perianez, JA and Knight, RT (2002) Think differently: a brain orienting response to task novelty. NeuroReport, 13: 1887–1892.

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