P300 (neuroscience)

The P300 (EP300, P3) wave is an event related potential (ERP) which can be recorded via electroencephalography (EEG) as a positive deflection in voltage at a latency of roughly 300 ms in the EEG. The signal is typically measured most strongly by the electrodes covering the parietal lobe. The presence, magnitude, topography and time of this signal are often used as metrics of cognitive function in decision making processes. While the neural substrates of this ERP still remain hazy, the reproducibility of this signal makes it a common choice for psychological tests in both the clinic and laboratory.

Elicitation and Acquisition
The P300 was discovered originally by Samuel Sutton, Margery Braren, Joseph Zubin, and E. R. John as noted in Science magazine from November 26, 1965 to unpredictable stimuli presented in an oddball paradigm.

Although the EEG signal is most strongly acquired around the parietal electrodes, interactions involving the frontal and temporal regions as well as several deep brain loci have been suggested. The P300 wave itself is thought to be comprised of two 'wavelets' known as P3a and P3b signals. These components respond individually to different stimuli, and it has been suggested that the P3a wave "originates from stimulus-driven frontal attention mechanisms during task processing, whereas P3b originates from temporal–parietal activity associated with attention and appears related to subsequent memory processing." . The two wavelets are sometimes referred to as 'non-target' (P3a) and 'target' (P3b) ERPs.

The P300 signal is an aggregate recording from a great many neurons. Although typically non-invasive, parts of the signal may be sampled more directly from certain brain regions via electrode (hence, the medial temporal P300 or MTL-P300). This methodology allows for isolation and local recording of one area without the noise from other signals acquired through scalp electrodes. In practice, the P300 waveform must be evoked using a stimulus delivered by one of the sensory modalities. One typical procedure is the 'oddball' paradigm, whereby a target stimulus is presented amongst more frequent standard background stimuli. A distracter stimulus may also be used to ensure that the response is due to the target rather than the change from a background pattern. The classic oddball paradigm has seen many variations, but in the end most protocols used to evoke the P300 involve some form of conscious realization or decision making. Attention is required for such protocols. No subjects have been noted to have fine control over their P300.

Origin
As with any ERP the P300 is produced by electrical currents within the brain. The various inhibitory and excitatory post synaptic potentials of many neurons create these currents, and thus one can discuss the origin of an ERP with respect to the effects of the neurotransmitters that elicit the post synaptic potentials and the anatomical domains in which they work. The wave is directly generated as the result of excitatory post-synaptic potentials (EPSPs) generated via glutamatergic networks, with NMDA type receptors playing an especially important role. GABAergic and cholinergic influences also modulate P300 activity, GABA by producing inhibitory post-synaptic potentials (IPSPs) that tend to lower wave amplitude and increase latency and acetylcholine by acting as a modulator with the opposite effect of GABA. Norepinephrine, dopamine and serotonin have all been implicated in P300 modulation, but the results are inconsistent and these influences may be minor.

There is some controversy over the anatomical substrates of the P300. Candidate structures include deep, closely spaced parts of the brain in the limbic system (e.g. amygdala, hippocampus and parahippocampal gyrus) as well as more widespread regions (e.g. posterior and superior parietal cortices, cingulate gyrus and the temporoparietal cortex). Intracranial recordings have lent credence to the theory of widely distributed contributors. One hypothesis links the P300 to activation of the locus ceruleus, a noradrenergic center of the brainstem found in the pons. In this view, the role of this noradrenergic circuit is to potentiate significant stimuli for executive decision making. The origins of the component waves (P3a and P3b) are still unclear. fMRI studies suggest that these subcomponents may localize to different regions, with the P3a being mainly a phenomenon of the frontal and insular cortices and the P3b stemming from parietal and inferior temporal regions. These distinct regions are proposed to be separate processing sites for “target” and “distracter” stimuli in the oddball paradigm. Research is also divided as to whether ERPs in general are generated in a stimulus induced (neuronal populations react by firing or not firing to the presented stimulus) or a “phase reset” fashion (neuronal population react by focusing firing patterns on a particular phase based on a stimulus). Recent evidence based on studies of the P300 suggests that both methods likely play in leading to an ERP. Thus, the P300 is not distinct from, but neither entirely explained by, the background dynamics of neural activity. It is not singularly caused by the resetting of pre-existing oscillatory activity, but rather it is affected by and affects such activity. Both explanations fit with the leading explanation for gross P300 behavior, the context updating hypothesis. The P300 is thought in this model to represent the physical change undergone when probabilities tied to certain outcomes are refreshed in light of the subject’s most recent contextual information.

Variation in the P300
Many factors have been implicated in the modulation of the P300. Neurological disorders typically show a reduction of the P300 amplitude as a whole, but foremost among these is the change that accompanies schizophrenia. Research measuring the P300 of schizophrenics versus unafflicted controls has shown marked reduction in P300 amplitude suggesting impairment of controlled information processing. Recent studies trying to develop the basis for P300 reduction in schizophrenia have identified a particular single nucleotide polymorphism in a gene coding for catechol-O-methyltransferase (COMT), an enzyme critical in the breakdown of dopamine in the cortical regions of the brain.

Decreases in amplitude and increases in latency time are also observed in normal aging. It is generally accepted that changes in the amplitude of the P300 are related to increases or decreases in the intensity, energy required or level of arousal tied to a specific task. Latency changes are less well characterized but still give a rough correlation to the processing time necessary for task performance. The measurements of the P300 waveform may also vary depending on the time of measurement. Significant variations in the amplitude and latency have been noted based on the diurnal rhythms of subjects. Such variation necessitates great care in the use of the P300 as a diagnostic measurement. It is not known if these changes are directly or indirectly related to attention/wakefulness changes that are well documented throughout the day.

An interesting departure involves measuring the P300 when conscious decision making is thought to be disrupted. Dreaming and hypnotic states are thought to provide good avenues for exploration into this field. People who are more susceptible to hypnosis show changes in ERP amplitude between normal states and states of so-called negative/positive obstructive hallucination. This seems to be in line with the idea that the P300 is related to transmitting decisions to the consciousness, and thus, these results seem to suggest the plausibility of altered-consciousness in hypnotic states.

Alcoholism also tends to correlate with a reduction in P300 amplitude. Comparisons in P300 characteristics can be made between alcoholic subjects and those with frontal brain lesions, suggesting significant long term impairment of frontal functions related to executive control. More investigation is required to ascertain whether or not this type of change to the P300 is specific to alcoholism, rather than a hallmark of addictive behavior in general. Tobacco related addictions are also often related with alcoholic behavior, and this confounding variable has also not yet been ruled out.

The subcomponents of the P300 are also noted to vary with gender, with female subjects displaying larger amplitude and latency than male subjects. There is a significant amount of variation within genders, however, in both the subcomponents and the P300 itself. Much of this may be due to subtle differences in measuring equipment and technique (electrodes, recording location, scalp preparation). Other researchers have attempted to prove that mild traumatic injury to the head is typically followed by deficits in the P300 that outlast behavioral recovery. In one study using healthy university students who had experienced mild head injury in the past, injured subjects performed no differently than controls on tests of memory and attention yet showed reduced amplitudes and increased latency with an oddball paradigm. The effect of head injury was not investigated in previous trials, and stands out as a likely candidate to confound results.

Stimulation sequences more complicated than a simple oddball routine show variation in P300 characteristics. For example, when random choices are assigned positively and negatively perceived gains and losses, the P300 demonstrates variability with reward/loss magnitude. P300 characteristics were shown to be independent of the valence of an outcome (whether it was a gain or a loss). Changes in the P300 were thought to be related to a subject’s evaluation and re-evaluation of selected/unselected choices.

Applications
Since the mid 1980's, one of the most discussed uses of ERPs such as the P300 is related to lie detection. In a proposed "guilty knowledge test " a subject is interrogated via the oddball paradigm much as they would be in a typical lie-detector situation. This practice has recently enjoyed increased legal permissibility while conventional polygraphy has seen its use diminish, in part owing to the unconscious and uncontrollable aspects of the P300. The technique relies on reproducible elicitation of the P300 wave, central to the idea of a Memory and Encoding Related Multifaceted Electroencephalographic Response (MERMER) developed by Dr. Lawrence Farwell.

Scientific research often relies on measurement of the P300 to examine event related potentials, especially with regard to decision making. Because cognitive impairment is often correlated with modifications in the P300, the waveform can be used as a measure for the efficacy of various treatments on cognitive function. Some have suggested its use as a clinical marker for precisely these reasons. There is a broad range of uses for the P300 in scientific research, ranging from study of depression and drug addiction to anxiety disorders (obsessive compulsive disorder, post-traumatic stress disorder, etc).

Applications in brain-computer interfacing have also been proposed. The P300 has a number of desirable qualities that aid in implementation of such systems. First, the waveform is consistently detectable and is elicited in response to precise stimuli. The P300 waveform can also be evoked in nearly all subjects with little variation in measurement techniques, which may help simplify interface designs and permit greater usability. The speed at which an interface is able to operate depends on how detectable the signal is despite “noise.” One negative characteristic of the P300 is that the amplitude of the waveform requires averaging of multiple recordings to isolate the signal. This and other post-recording processing steps determine the overall speed of an interface. The algorithm proposed by Farwell and Donchin provides an example of a simple BCI that relies on the unconscious decision making processes of the P300 to drive a computer. A 6x6 grid of characters is presented to the subject, and various columns or rows are highlighted. When a column or row contains the character a subject desires to communicate, the P300 response is elicited (since this character is “special” it is the target stimulus described in the typical oddball paradigm). The combination of the row and column which evoked the response locates the desired character. A number of such trials must be averaged to clear noise from the EEG. The speed of the highlighting determines the number of characters processed per minute. Results from studies using this setup show that normal subjects could achieve a 95% success rate at 3.4-4.3 chars/min, and trends suggest that 40 chars/min is the maximum theoretical limit achievable. It remains to be shown whether such systems provide similar results in patients suffering from “locked-in” syndrome, the main target population for such brain driven devices.

Again, building from the oddball paradigm, recognition of speech or sound patterns is a well documented method to elicit the P300. Because of this, the waveform has been suggested for use in another field of interfacing: audiology. One can use the P300 as a measure of the quality for cochlear implants, since a target sound will not register an event related potential if it is poorly transferred by external hearing apparatus. Auditory cues may provide a simpler method for generating ERPs as silence is simpler to recreate than complete lack of visual cues. Furthermore, the question of whether the brain is made aware of a visual cue is not simple. If visual processing can occur without the subject's awareness, further measures will need to be taken to determine the extents of the accompanying evoked potentials. One group has provided results from combined ERP and fMRI imaging, which begins to address these issues by probing brain activity outside of subject reporting.