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often allows for more detailed conclusions than examining behavioral measures alone. For example, ethanol, which has sedative effects, has been found to decrease P3 amplitude, whereas ► caffeine increases P3 amplitude, suggesting that these drugs affect high-level stimulus-encoding processes. Another example concerns the P50 wave, an ERP component that is used for the assessment of sensory gating - the habituation of responses to repeated stimuli. In healthy subjects there is an inhibition of responsiveness, that is, a diminished P50 to repetitive stimuli - an adaptive mechanism to prevent overstimulation. The NMDA receptor antagonist ► ketamine and the antipsychotic ► haloperidol disrupt P50 suppression, indicating that these drugs modulate sensory gating. Another ERP measure, the loudness dependence of the auditory evoked potential (LDAEP), has been proposed as a valid indicator of central serotonergic function in humans. This measure is assessed using the N1/P2-com-ponent of the auditory evoked potential and reflects the reactivity of the auditory cortex. Thus, this ERP measure is used as a marker of neuromodulatory function, rather than a cognitive function.

Investigating ERPs Using Drug Actions

Since ERPs reflect functional aspects of neurotransmitters and neuromodulators, drugs affecting particular neuro-transmitter or neuromodulator systems are used to investigate the role of these systems in the generation of ERP components (Carozzo et al. 2006; Pogarell et al. 2006). A limitation of this approach is that most available drugs are not selective for a single system, which complicates the interpretation of the results. One exception is a class of drugs, ► serotonin reuptake inhibitors (SSRIs), which selectively increases the amount of serotonin in the brain. Accordingly, SSRIs have often been used to investigate the role of serotonin in the generation of different ERP components. Using this approach, it has been shown that serotonin affects the LDAEP strongly, but is not involved, for example, in the generation of the P3, which is modulated by cholinergic, dopaminergic, and norad-renergic drugs. The mismatch negativity is blocked by ► NMDA-receptor antagonists, indicating that the mismatch negativity critically depends on glutamatergic neurotransmission. These and many other findings have led to an increased understanding of the neural basis of ERP components. This, in turn, has informed theories of their functional significance. For example, the finding that the error-related negativity is modulated by dopaminergic drugs has strengthened existing views that link this ERP component to the literature on dopaminergic reward-prediction errors.

The Role of ERPs in Psychiatry: Sensitivity and Specificity

ERPs are not only important research instruments, but are also useful as clinical instruments in neuropsychiatry (Pogarell et al. 2007). ERPs can be used in the diagnostic workup of a wide range of neuropsychiatric disorders as well as in monitoring the course of the disorders and the prediction of treatment responses. To be useful in the diagnostic workup, an ERP component has to be sensitive enough to detect the disorder, but also sufficiently specific for the disorder to rule out alternative explanations.

► Alzheimer's disease is consistently related to smaller P3 amplitudes and prolonged P3 latencies. Using the P3 component, Alzheimer's patients can be diagnosed with high sensitivity and specificity (up to 88.5%). Furthermore, the P3 is effective in both monitoring and predicting the treatment response of Alzheimer's patients to cholinesterase inhibitors. Thus, the P3 may be an important instrument not only in the diagnostic workup, but also in the monitoring and prediction of the treatment response in Alzheimer's disease. This tool is still underutilized in the clinic, presumably because the P3 has not been generally accepted as a valid biomarker for Alzheimer's disease. Schizophrenic patients also show a decreased P3 amplitude. However, this is generally considered a trait marker rather than reflecting the neurological pathology causing ► schizophrenia, because the P3 amplitude reduction is not affected by neuroleptic medication and can also be found in remitted schizophrenics, relatives of schizophrenic patients, and other subjects at risk of developing schizophrenia. Thus, the P3 amplitude may be a sensitive marker, but is not a specific marker for schizophrenia and is therefore not used in the diagnostic workup. However, there are indications that in schizophrenic patients, the P3 may predict treatment response.

Advantages and Limitations of Event-Related Potentials

The major advantage of ERPs is their fine temporal resolution (on the order of milliseconds), indicating that ERPs reflect what is happening in the brain at the very same moment. Another advantage of ERPs is that electroen-cephalography is noninvasive and cheap compared with other brain-imaging methods. An additional convenience is that there are clear and widely agreed-upon guidelines for how ERP studies should be conducted, analyzed, and reported (Picton et al. 2000). The primary limitation of ERPs is that it is not possible to determine the neuroana-tomical generator of an ERP component from the measured scalp potentials alone. Furthermore, the geometrical orientation of neurons must be more or less parallel in order to detect the neural activity at the scalp. Signals from structures located deep within the brain are particularly hard to measure. Finally, during the averaging procedure for isolating the ERP from the EEG, all activity that is not time-locked to the event-of-interest is lost. In order to examine that information, other electrophysi-ological methods are needed.

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