CLINICAL EEG and NEUROSCIENCE - Dynamic Memory Lab

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CLINICAL EEG and NEUROSCIENCE ©2007 VOL. 38 NO. 1and which is related to psychological aspects like cognitionor attention (information processing). There are atleast two distinct P300 subcomponents which overlap atthe scalp. The P3b has a more centro-parietal distributionand corresponds to the classical P300 recorded within anoddball paradigm after rare and task relevant events. T h eP3a occurs after novel events independently of task relevanceand is characterized by a more frontal distribution,a shorter latency and a fast habituation. These subcomponentsreflect functionally different processes. Whereas theP3a has been interpreted as an orienting response, theP3b was related to psychological constructs such as controlledinformation processing, the information content ofthe event, memory processes, the reorganization of aninternal expectancy model (“context updating”) or the“context closure.” 3The physiological interpretation of P300 is limited bythe fact that knowledge about the neuronal structures andprocesses involved in the generation of P300 are still insufficient.However, knowledge has increased considerably inthe last years. Intracerebral recordings in patients withepilepsy have shown that the parietal and temporal cortexare involved in the generation of the auditory P3b.Concerning P3a the superior temporal plane, the associationcortices, limbic structures, and frontal as well as prefrontalcortices appear to play a major role. 4-6 With localrecording, the hippocampus shows the largest P300.However, because the hippocampus is an electricallyclosed field, this structure probably does not contribute in arelevant manner to the P300 recorded at the scalp.A further progress in this respect might be the simultaneousrecording of ERPs under functional magnetic resonanceimaging (fMRI). Both fMRI and EEG are complementarymethods for the analysis of brain activity witheach method having its strength where the other one haslimits: the spatial resolution in the range of millimeters infMRI and the time resolution in the range of millisecondsin EEG.Mulert et al 7 have shown that high quality EEG recordingsare feasible inside the scanner with adequate eliminationof artifacts (e.g., originating from MR gradients) fromthe EEG signal. Therefore, not only an optimal temporalresolution of brain activity (as recorded via ERPs/EEG fromthe scalp) but also a precise spatial allocation of the underlyingstructures has been made possible.Regarding the neurochemical background, it is widelyaccepted that P300 potentials recorded at the scalp resultfrom intracortical currents induced by postsynaptic potentials.Neuronal cortical processing is influenced by corticallyreleased modulatory neurotransmitters (serotonin,dopamine, noradrenaline, and acetylcholine). Therefore itis not surprising that these transmitters are also related toP300. Because of the close interaction between the differentneuromodulatory systems, a highly specific relationshipbetween P300 parameters and a certain neuromodulatorcannot be expected. Most consistent are the results concerningP300 and the cholinergic system. Anticholinergicinterventions induce a latency increase and amplitudereduction of P300 whereas the opposite is observed aftercholine agonists. 8-15 This is in line with the robust findingthat Alzheimer’s disease, which is associated with cholinergichypofunction, is associated with reduced amplitudeand prolonged latency of P300.Influences of the noradrenergic and the dopaminergicsystem on P300 16-19 have also been described. The serotonergicsystem appears to play only a minor role for thegeneration of the P300. 12,20P 300 in psychiatric disordersSchizophreniaThe heterogeneity of schizophrenic disorders regardings y m p t o m a t o l o g y, course and outcome is expected toreflect heterogeneity of various underlying pathophysiologicalprocesses. In this respect physiological parameterscould be helpful to define subgroups that are more homogeneousnot only concerning clinical and therapeutic variablesbut also the pathophysiological mechanisms. Withrespect to schizophrenic disorders P300 is among themost intensively studied ERPs.It is a robust finding that the P300 amplitude is smallerin schizophrenic patients than in healthy controls. This hasbeen demonstrated in acutely ill, remitted, medicated andunmedicated patients. 21-26 Neuroleptics have only a relativelysmall effect on P300 amplitudes, which is supportedby studies comparing patients with high versus low plasmalevels of neuroleptics or by a longitudinal study in patientswho discontinued neuroleptic treatment. 27The amplitude reduction of the auditory P300 in schizophrenicpatients is not merely reflecting state dependentaspects but also has to be considered as a trait marker.This is supported by studies showing that the reduction ofP300 amplitude is not influenced in a relevant manner byneuroleptic medication and can also be found in remittedschizophrenics. 22 Furthermore, children of schizophrenicparents and other subjects at risk of developing schizophreniashowed P300 abnormalities. Studies in children ofschizophrenic parents showed a prolongation of P300latencies (auditory oddball paradigm) and/or smaller P300amplitudes as compared to matched controls. 28It has been postulated that patients with a neurodevelopmentalschizophrenia form a subgroup characterized bypoor premorbid adjustment with cognitive disturbances,early and insidious onset, a chronic and deterioratingcourse of the disease, negative symptoms and a tendencyto develop tardive dyskinesia. 29 There are several studiessupporting the assumption that schizophrenic patientswith small P300 correspond to this subgroup of schizophrenics.In a study on stabilized schizophrenic patientsthe subgroup with a small P300 showed more residual26
CLINICAL EEG and NEUROSCIENCE ©2007 VOL. 38 NO. 1symptoms, more perinatal complications, poor premorbidadjustment and a higher risk of developing tardive dyskinesia.The majority of patients showing tardive dyskinesiaat the time of the recording also presented with a smallP300. Even more interesting is the finding that patientswho developed tardive dyskinesias during a 2 years follow-upperiod had already significantly smaller P300 at thebeginning of the prospective study. 3 0 A small P300 hasbeen found to predict nonresponse to neuroleptics concerningpositive symptoms and a prolonged P300 latencyhas been found to predict non-response concerning negativesymptoms. 2 3 S i m i l a r l y, Strik et al 3 1 - 3 3 found thatpatients with a “cycloid psychosis” (according to the classificationby Leonhard), which is characterized by a favorabletherapeutic response and long-term prognosis, haveno reduction of P300 amplitude or even an increase inamplitude compared to healthy subjects. Furthermore, instudies on stabilized schizophrenic outpatients it is a quiteconsistent finding that patients with small P300 have moreresidual symptoms, mainly negative symptoms andthought disorders.P300 and psychopathologyFor the evaluation of the relationship between P300and psychopathology, it is of crucial importance to independentlystudy stabilized patients and acutely psychoticpatients. In stabilized patients, it is a quite consistent findingthat P300 amplitude is negatively correlated with residualsymptoms. This association does not reflect statedependent effects of residual symptoms on P300 butrather the poor outcome of a subgroup of patients withsmall P300. This interpretation is supported by a study ofschizophrenic patients, retested after 9 months. Here theintra-individual changes of psychopathology were not relatedto the corresponding changes of P300 amplitude. 27However, the P300 component reflects both trait andstate aspects such as psychopathology. Several studies onacutely psychotic patients reported positive correlationsbetween P300 amplitudes and the severity of positivesymptoms. However, the literature is not entirely consistenton this issue, which can be explained by differences in theseverity of the acute symptomatology. It has to be expectedthat patients with severe acute symptoms leading toimpaired attention, will have difficulties to cooperate and toperform the P300 oddball paradigm. 34-36In summary, a small P300 in schizophrenic patientshas been found to be a vulnerability marker characterizinga subgroup of patients with a poor premorbid adjustment,an enhanced risk of developing tardive dyskinesia, moreresidual symptoms and a poor outcome. Concerning theevaluation of the relationship between psychopathologyand P300, it is of importance to control the studies forremitted versus acutely psychotic patients, predominanceof positive versus negative symptoms and to differentiatethe P300 subcomponents P3a and P3b.Affective disordersAn amplitude reduction of P300 has been found indepressed patients although the literature is not consistenton this issue. Some authors found changes of P300 only ina subgroup of patients, mainly in those with severe or psychoticdepression. 37,38It is a replicated finding that patients with depressive disorderswith suicide attempts showed smaller P300 amplitudesthan depressive patients without suicide attempts. Inaddition a correlation has been reported between acute suicidalityand P300 amplitude. 3 9 A convincing explanation forthis relationship has not been given up to now.Alzheimer’s diseaseP300 is an interesting instrument for studyingA l z h e i m e r’s disease, because latency and amplitude ofP300 are closely related to cognitive processes and tocholinergic function. Furthermore P300 is cortically generatedand A l z h e i m e r’s disease impairs especially cortical functioning.It is therefore not surprising that A l z h e i m e r’s diseaseis related in a consistent manner with smaller P300amplitudes and prolonged P300 latencies. Such changescan be observed even in patients with mild A l z h e i m e r’s disea s e . 4 0 , 4 1 In studies, comparing demented patients with psychiatricand neurological patients without dementia, thespecificity of P300 latencies was above 80 % whereas thesensitivity was relatively poor, ranging between 15 and80%. As expected, studies with more severely dementedpatients reported higher sensitivities. Auditory P300 latencieswere superior to visual P300 latencies concerning therecognition of patients with A l z h e i m e r’s disease.In a prospective, confirmatory study to evaluate the clinicalrelevance of the P300 in the early diagnosis of A D ,Frodl et al 4 2 investigated patients with AD, mild cognitiveimpairment (MCI) and healthy controls (HC) using P300assessments with dipole source analysis. The authorscould demonstrate that the amplitudes of temporo-basaldipoles (equivalent to the P3b subcomponent) were statisticallysignificantly decreased in AD as compared to both HCand MCI. Furthermore, the latencies of superior temporaldipoles (equivalent to P3a) were significantly prolonged inAD compared with HC. The significant differences remainedstable after stratification of the patients regarding the severityof the disease: Even patients with mild AD showedmarked, significant reductions in P300 amplitudes. T h esensitivity and specificity for the differentiation of A Dpatients and HC using temporo-basal P300-amplitudes andsuperior temporal P300-latencies were as high as 86.7%,and 88.5%, respectively, which is comparable to other(often less validated) biological diagnostic markers in A D .The P300 is related to cholinergic neurotransmissionand may therefore be useful to identify subgroups with amore circumscribed cholinergic dysfunction. This subgroupmay turn out to show a favorable response to a treatmentwith cholinesterase inhibitors.27
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