Human Physiology, Vol. 27, No. 3, 2001, pp. 294305. Translated from Fiziologiya Cheloveka, Vol. 27, No.

3, 2001, pp. 4253. Original Russian Text Copyright 2001 by Revenok, Gnezditskii, Kalashnikova.

Differences in the P300 Parameters, Neuropsychological Profile, and Cognitive Impairments in Patients with Cortical and Subcortical Dementia
E. V. Revenok, V. V. Gnezditskii, and L. A. Kalashnikova
Institute of Neurology, Russian Academy of Medical Sciences, Moscow, 115478 Russia
Received May 29, 2000

AbstractIn this study we analyzed the parameters of auditory evoked potentials in a stimulus recognition task (the P300 method) and nonspecic visual response to a light ash in 75 healthy subjects of various ages (2070 years) and 70 subjects (35 males and 35 females, mean age 51 years) with cortical and subcortical cognitive impairments of various degrees (cerebrovascular disorder) with different neuropsychological proles. It was shown that parameters of the P300 complex depend on both the subject age and his/her cognitive functions and can be used for objective analysis of cognitive impairments. An inverse relationship between the P3 (P300) peak latency and the volume of short-term and operative memory in subjects with cognitive impairments was found. The parameters of the nonspecic visual response (duration and the maximum amplitude), reecting functioning of the arousal systems of the brain, depended on the type and severity of cognitive impairments but did not depend on the subjects age. Differences in the neuropsychological proles of cognitive impairments and the pathophysiological mechanisms of their development, reected by parameters of the evoked potential, as well as differences between the brain structures involved in these process, substantiate the discrimination of two types of cognitive impairmentscortical and subcorticalin subjects with cerebrovascular disorders.

Studies of cognitive impairments, designated in the Russian literature as disturbances of higher psychological functions, are very important in both medical and social respects. According to data reported by A.S. Henderson [1], dementia is diagnosed in 1% of subjects at the age of 65 years and older. Dementia is dened as acquired impairment of memory and intelligence which detrimentally affects the daily life of the subject. The basic diagnostic criteria are deciencies of cognition and memory. Agnosia, apraxia, disturbances of speech and orientation, etc., are considered as auxiliary symptoms [1]. The application of neurovisualisation techniques in neurological practice caused a substantial interest in the study of the structural bases of cognitive impairments, including dementia, with cerebrovascular disorders. However, the pathophysiological mechanisms of their development still remain poorly understood. Because cognitive disturbances and dementia in cerebrovascular disorders are potentially curable (i.e., it is possible to prevent their further development [2, 3]), their early diagnosis and objective detection at early stages become especially important. Electrophysiological methods, in particular P300, as well as common neuropsychological assessment, are used for this purpose. The method of cognitive evoked potentials or P300 [4] allows objective assessment of cognitive functions associated with perception and processing of information. The essence of this approach is that the experi-

menter analyzes complex endogenous events occurring within the brain and associated with recognition and remembering of signicant stimuli, i.e., the basic cognitive processes in the brain [46], rather than a simple response caused by the incoming afference. In 1978, Gudin and coworkers [7] rst offered this approach for the assessment of dementia. Subsequently, cognitive evoked potentials have become widely used for the assessment of cognitive functions in clinical studies [4, 6, 810]. The most diagnostically informative parameters of the P300 are an increase in its latency and the absence or instability of the response. It has been shown [11] that temporal and parietal areas of the cortex are involved in generation of the P3 (P300). The P3(300) peak is associated with the function of the frontal lobe. The role of subcortical structures in the generation of the P300 was shown by Yu. Kropotov and V. Ponomarev [12]. An increase in P300 latency is observed not only in cognitive impairments. A consistent increase in the P300 latency also occurs with age. Regression curves, reecting the relationships between the latency and age, have been determined in healthy subjects. This relationship is often called the aging curve and is used for adequate assessment of the P300 parameter changes in subjects with cognitive impairments. These relationships are useful for objective assessment of aging processes [4, 6, 810]. The latency and amplitude of the P300 wave vary in healthy subjects, depending on individual differences

0362-1197/01/2703-0294$25.00 2001 MAIK Nauka /Interperiodica

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of their cognitive function, as well as in subjects with cognitive impairments [5, 10, 1315]. A shorter latency and higher amplitude of the P3 peak are observed in subjects with higher cognitive abilities [13, 14]. The amplitude is considered proportional to the attention of the subject to the task, and the latency is thought to characterize the speed of the stimulus classication within the series presented [4, 16]. In 1995 and 1996, J. Polich [4, 16] reviewed more than 100 studies concerned with normative data on cognitive evoked potentials and the effects of various cognitive and biological factors on the P300 parameters. The author pointed out that most investigators agree that the peak parameters of the P3 reect the characteristics of operative memory. Thus, the P300 method can be used for verication of cognitive impairments and dementia, for assessment of their severity, for distinguishing cognitive impairments and depression, for objective assessment of the dynamics of cognitive dysfunction during curing, and for assessment of the secondary action of drugs. This method also facilitates the assessment of cognitive functions in children with retarded mental development and can be used for screening when neuropsychological assessment is difcult. According to the theory of D. Hebb [17], sensory input has two basic functions. It not only provides information about the environment but also creates conditions for the processing of this information. The latter includes the arousal system of the brain stem and thalamus. The development of visual response components involves not only specic sensory systems but also nonspecic components, providing additional activation of various brain regions. This allows the use of visual evoked potentials to a light ash for the assessment of pathologies of specic and nonspecic visual afference in subjects with the dysfunction of consciousness [18]. L. Ciganek [18] suggested that later components (>100 ms) of the visual response to the light ash are associated with the brain stem and thalamus activating systems and reect the reactive characteristics of the whole brain [19]. Thus, evoked potentials assess regulatory homeostatic mechanisms of the brain (i.e., cortical-subcortical homeostasis) that maintain the reactive properties of the brain and cortical arousal [2022]. Therefore, they reect integrative functioning of the whole brain rather than only the sensory systems. This allows using a nonspecic visual response in the central area, in addition to the P300, for assessment of brain arousal systems and assessment of their roles in the genesis of various cognitive impairments. MATERIALS AND METHODS The study group consisted of 70 subjects (35 men and 35 women, mean age 51 6.2 years) with cerebrovascular disorders and symptoms of cognitive impairment. Two groups of patients were distinguished on the basis of brain magnetic resonance tomography (MRT). The rst group (20 men and 13 women, mean
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age 51.2 6.7 years), with a predominant disturbance of subcortical structures of the brain, consisted of patients with subcortical arteriosclerotic encephalopathy (26 subjects) and infarcts in the frontal-medial areas of the thalamus and thalamofrontal pathways (7 subjects). The second group (22 females and 15 males, mean age 51.1 5.2 years) with a predominant dysfunction of the cortex, consisted of 29 patients with angiocoagulopathy (mean age 45.5 7.7 years) and 8 patients with hemodynamic stenosis of the internal carotid artery (mean age 56.6 2.6 years). Neuropsychological assessment of higher psychological functions of the subjects using the method of A.R. Luria and the international diagnostic criteria of dementia ICD-10 [23] indicated that their cognitive functions involved initial stages of cognitive impairment, not reaching the severity of dementia, and various degrees of dementia, from slight to severe. For objective diagnosis of cognitive impairments, we analyzed the P300 component of the cognitive evoked potential. Normative data obtained in 75 healthy subjects from 20 to 70 years old was used for the analysis of the P300 in patients with cognitive impairments. The arousal system of subjects with cognitive impairments in cerebrovascular disorders was examined using nonspecic visual response to a light ash. The control group consisted of 21 healthy subjects. The visual evoked potentials were analyzed using a Viking IV neuroaverager (Nikolet, USA). The study of P300 was conducted in a situation of a sudden event (the oddball paradigm). It involved selection of responses by the subject during recognition of a rare stimulus (a short tone click with a frequency of 2000 Hz) among frequent nonsignicant background stimuli (1000 Hz). Usually, the sensory part of the response, long-latency auditory evoked potentials or the V-wave, and the P300 complex with the N2 and P3 (P300) peaks, reecting the recognition of rare signicant stimuli, are distinguished. The duration of the stimulus was 50 ms, with an intensity of 80 dB. The frequency of clicks was 1 per second. The stimuli were presented binaurally in a pseudorandom sequence. The probabilities of the signicant and insignicant stimuli were, respectively, 0.3 and 0.7. We used the C3M1 and C4M2 derivations, 1020% according to the international classication, from the central areas of left and right hemispheres, with respect to the ipsilateral mastoid process of the temporal bone. The ground electrode was in the Fpz position. The sensitivity was 5 V/scale unit, the frequency band was 0.230 Hz, and the analysis epoch was 750 ms. The number of averaged presentations of signicant stimuli was 30. The averaging of responses to rare (signicant) and frequent (insignicant) stimuli was conducted separately. To assess the repeatability of the results, the study of the P300 in each subject was conducted in two independent time series. The nal scores represent the superpositions of these two repetitions. The primary

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Table 1. Characteristics of cognitive functions according to ICD-10 The condition of cognitive functions No cognitive impairment Initial signs of cognitive impairment Slight dementia Moderate dementia Severe dementia
Note: n is the number of patients.

Predominant disturbance of subcortical brain Predominant disturbance of the brain structures (n = 33; mean age, 51.2 years) cortex (n = 37; mean age, 51.2 years) n 4 12 6 6 5 mean age 50.8 56.8 54 51.8 58.8 n 9 12 9 5 2 mean age 44.3 50.7 46.7 46.8 41

task of the subject was to recognize and count the number of signicant stimuli. The assessment of patients with pronounced impairments of cognitive functions and incomplete understanding of the instruction was conducted with passive perception of the stimuli. Nonspecic visual responses were recorded to a light-emitting diode ash, with an intensity of 300 mcd and a wave length of 640 nm. The light stimulation was provided monocularly (to the eye with a better acuity of vision), with the stimulation period 0.8 Hz, the eyes being closed. The number of averagings was 100, and the analysis epoch was 1 s. We also analyzed nonspecic afference, in which case the response was recorded from the central area of the brain (C3M1, C4M2). The conditioned response was the same as in the analysis of the cognitive evoked potential. The following characteristics of the response were analyzed: latency (latency to the rst signicant peak), duration (period of the response return to the residual noise level), and the maximum amplitude (amplitude from the maximum positive to negative peak). RESULTS AND DISCUSSION Comparative Analysis of Cognitive Impairments in Dysfunction of Cortical and Subcortical Brain Structures in Patients with Cerebrovascular Disorders General Characteristics of Cognitive Impairment Based on the neuropsychological examination conducted using international criteria of dementia, cognitive functions in 70 patients were found to be initial stages of cognitive impairment, not reaching the severity of dementia (24 patients), and various degrees of dementia (33 patients). In 13 patients, regardless of subjective complains of memory loss, lower attention, and slower thinking, no objective signs of cognitive impairment were found (Table 1). A comparative analysis of cognitive impairment under the predominant disturbance of cortical or subcortical brain structures was conducted between two groups of patients with subcortical arteriosclerotic encephalopathy and angiocoagulopathies, which con-

stituted the majority of the assessed groups (26 and 29 subjects, respectively). The initial stages of the cognitive impairment with predominant disturbances of the subcortical structures and the cortex were characterized by the impairment of attention. With more pronounced deciencies, dysfunction of thinking, memory, and attention become more severe. Furthermore, disturbances of thinking indicated dementia. Patients with dominant disturbances of the brain cortex demonstrated slight dysfunction of optical and spatial gnosis. There were signicant differences in the severity of the cognitive impairment between two groups of patients with cerebrovascular disorders. Patients with predominant disturbances of the subcortical brain structures exhibited lower attention, lack of spontaneous activity, general deceleration of all psychological processes, and reduction of interests in the absence of clear local dysfunction of higher psychological functions. On the whole, their changes were similar to those typically found in the lobe syndrome. On the contrary, even the initial stages of cognitive impairment with a predominant disturbance of the cortex were characterized by local dysfunctions of higher psychological functions, including apraxia, acalculia and agraphia. Figure 1 shows signicant differences (p < 0.01) between patients with cognitive impairments in predominantly cortical and subcortical brain disturbances. In both groups of patients, memory disturbances were modally-nonspecic; i.e., both auditory-speech and visual memory were impaired. Furthermore, the performance in delayed reproduction tasks was characterized by a greater impairment than in direct reproduction tasks. Additionally, we found an increased effect of interference on memory retention and selective retrieval of memory traces. Patients with predominant disturbances of the subcortical structures exhibited relatively stronger dysfunction of thinking than short-term memory, whereas the reverse was typical for patients with predominantly cortical disturbances. Generally, impairment of short-term rather than long-term memory was more characteristic of patients with predomiHUMAN PHYSIOLOGY Vol. 27 No. 3 2001

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nant disturbances of the brain cortex. Long-term memory was relatively intact at early stages of the disorder but signicantly impaired in severe dementia, both cortical and subcortical. These differences can be accounted for by disturbances of various brain structures. For example, a predominant disturbance of subcortical structures (diffuse injury of the white substance of the brain hemispheres or infarcts in the frontalmedial areas of the thalamus) causes interruption of the thalamocortical pathways and impairment of arousal with secondary inactivation of anatomically unaffected cortical regions. This causes general disorganization of all psychological activity and secondary memory impairment. In contrast, in patients with cortical cognitive impairments that developed as a consequence of primary injury of the brain cortex (signicantly involved in remembering), memory impairment was of a primary character. The lesser impairment of thinking in this group of patients was caused, most probably, by the relatively better integrity of the frontal lobe (MRT data indicated that temporal parietaloccipital areas suffered to a greater extent), the associative pathways between various areas of the brain cortex, and the links between the cortex and reticular formation. Impairment of Counting, Praxis, Speech, Writing, and Reading in Cognitive Impairments of the Cortical and Subcortical Types Signicant differences in the severity of local impairments of higher psychological functions were found between patients with predominantly cortical and subcortical disturbances (Table 2). Local impairments of higher psychological functions (aphasia, agraphia, alexia, acalculia, apraxia) occurred in all patients with a predominant disturbance of the brain cortex and appeared even at initial stages of

Rating scale 2.5 2.0 a 1.5 1.0 0.5 0 c b

II

Fig. 1. Comparative assessment of the severity of thinking and memory impairment in patients with cortical and subcortical types of cognitive impairments (median values). I, cortical; II, subcortical type; a, thinking; b, short-term memory; c, long-term memory.

cognitive impairments. The primary cause of their development was local injury of the brain. The severity of the local impairment of higher psychological functions signicantly increased with increasing severity of cognitive impairments (p < 0.05). On the whole, these decits pointed to predominant impairment of the temporalparietaloccipital areas of the brain. The results of computer tomography showed good correlations with neuropsychological data (Fig. 2A). Cognitive impairments of the cortical type were characterized by broadening of the subarachnoidal space of the brain hemispheres, which was observed in 71% of

Table 2. Comparative characteristics of the localized impairment of higher psychological functions in patients with cortical and subcortical cognitive impairments Impairment of higher psychological functions Aphasia Moderate and pronounced Impairment of serial counting Acalculia Alexia Opticospatial deficits Spatialconstructional apraxia spatial type dynamic type Subcortical cognitive impairments (n = 23) n 1 1 17 3 1 0 0 19 % 4.3 4.3 73.9 13 4.3 0 0 82.6 Cortical cognitive impairments (n = 25) n 22 13 11 12 7 14 18 6 % 88 52 44 48 28 56 78.3 24

Note: n, number of patients. All differences in the table are significant. HUMAN PHYSIOLOGY Vol. 27 No. 3 2001

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processes. They were dynamic in nature and arose as a consequence of general slowing of the dynamics of psychological processes. With increasing severity of cognitive impairments, they became signicantly more pronounced (p < 0.05). The severity of cognitive impairments of the subcortical type correlated (p < 0.05) with decreases in the density of the white substance in the brain hemispheres, as well as with widening of the lateral cerebral ventricles (Fig. 2B). In contrast, there was no relationship with the occurrence of lacunar infarcts. The data obtained by computer tomography support the mechanism of segregation of the cortex and subcortical brain structures, particularly the thalamus and reticular formation, in the genesis of cognitive impairments of the subcortical type. This mechanism has been proposed earlier by Tatemichi [24]. Thus, our neuropsychological assessment revealed signicant differences in cognitive impairments and their dynamics in patients with predominant disturbances of the cortical or subcortical brain structures, which substantiates the distinction between these two types of cognitive impairment in patients with cerebrovascular disorders. Analysis of P300 in Healthy Subjects and Patients with Cognitive Impairments in Cerebrovascular Disorders Analysis of Sensory and Cognitive Components of P300 in Healthy Subjects An analysis of the evoked potential during the recognition of a signicant stimulus and averaging of responses to an insignicant stimulus revealed a classical long-latency auditory evoked potential with the NP (V-wave) components. Its parameters (latency and amplitude) coincided with the common auditory evoked potential isolated in a series of homogenous auditory stimuli (Fig. 3A). Averaging of the responses to rare signicant stimuli brought about an additional wave complex with the average latency equal to 300 ms, in addition to the V-wave. This would represent the cognitive component of the response. The parameters of the V-wave (sensory response) both to signicant and insignicant stimuli did not differ in 60 healthy subjects 3570 years old and were as follows: latency N, 96 15.6 ms; P, 172 14.8 ms; NP, 7 2.6 V. The amplitude of the V-wave had a small inverse correlation with the age. The Spearman rank correlation coefcients for the latency of the N component were 0.37 (p < 0.004) and 0.27 (p < 0.036) for the insignicant and signicant stimuli, respectively. The Spearman correlation for the P2 peak of the significant stimulus was 0.31 (p < 0.018). The parameters of the P300 complex depended on the subjects age: the latency tended to become longer, and the amplitude also reduced (Figs. 3B, 4). The maximum rank correlation coefcient was obtained for the
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B
Fig. 2. Computer tomography of the brain in (A) cortical and (B) subcortical types of cognitive impairments. (A) Computer tomography of patient B., male, 46 years, with severe dementia. There is a pronounced broadening of the subarachnoidal space of the brain hemispheres, more than the occipital and parietal lobes. (B) Computer tomography of patient K., male, 64 years, with severe dementia. Pronounced diffuse reduction of white substance density, predominantly around the ventral horns, with localities of reduced density and clear broadening of the lateral cerebral ventricles, can be distinguished in both hemispheres.

patients with dementia and in only 22% patients with initial signs of cognitive impairments (p < 0.035). Multiple infarcts in the cortex, predominantly in the temporalparietaloccipital area, were found in 86% of patients with moderate and severe dementia, but they were not discovered at the initial stages of cognitive impairment (p < 0.002). Local impairments of higher psychological functions were not characteristic of cognitive impairment associated with disturbances of the subcortical brain areas. They were observed at later stages of the deciency and did not reach such severity as in patients with predominant disturbances of the brain cortex. Impairments of counting, writing, and praxis were associated with general impairment of psychological

DIFFERENCES IN THE P300 PARAMETERS 5 V/scale unit N A N1 I P N2 I P2 N1 N II P P2 P3(300) 75 ms/scale unit N2 P3(300) N3 II B N3

299

75

Fig. 3. P300 in two healthy subjects of different ages (I, 35 years, II, 60 years). Latency of the P3 (P300) I: 327 ms, amplitude 13.6 V; II: latency P3(300) 360 ms, amplitude 8 V. Two responses from various time series of averaging are compared. A, sensory component of the response, averaging of the response to an insignicant stimulus (the NP complex); B, sensory (N1P2) and cognitive (N2P3N3) (P300) components of the response with averaging of responses to the signicant stimulus.

latency of the P3 (P300) component (r = 0.53, p < 0.00005). The relationship was smaller for the N2 peak latency (r = 0.27, p < 0.04). In normal subjects, the P3 (P300) peak latency increased linearly with the slope equal to 0.997 ms per year (curve slope, 0.997 ms/deg). The respective regression equation is P3 (P300) latency = 0.997 ms/year age + 297 ms, with the correlation coefcient r = 0.53 and = 25 ms. The relationship between the P3 (P300) peak and the age is called the aging curve. Other authors [4, 25] obtained similar results. The amplitude of P3 (P300) showed a reverse relationship with the age, which is described by a straight line with the formula P3 (P300) amplitude = 11.4 V 0.09 V age, r = 0.35 (p < 0.0005) and = 1.1 V. The amplitude of the P3 (P300) decreases with age approximately to 1/10 V per year. These data were taken into account during the analysis of changes in the P300 complex parameters in patients with cognitive impairments. Comparative Analysis of Sensory and Cognitive Components of the P300 in Patients with Cognitive Impairments of the Cortical and Subcortical Types The P300 parameters to insignicant stimuli did not differ between healthy subjects and patients with cognitive impairments of the cortical as well as subcortical type. The latency of the NP complex in norm was 96174 ms; in predominant lesions of cortical and subcortical brain structures, 90166 and 97168 ms, respectively. However, the amplitude of the NP complex was signicantly lower in patients with cognitive impairments (6.6 2.9 and 7.1 2.4 V in the two
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groups of patients, respectively) than in the age norm (9.2 3.9 V). Comparison of the V-wave characteristics for the recognition of a signicant stimulus in patients with cognitive impairments of various types revealed the following signicant differences (p < 0.05). The latency of the NV peak to a signicant stimulus was shorter, and the NP inter-peak amplitude was lower in patients with cortical cognitive impairments (p < 0.05). Goodin and Aminoff [9] also reported an increase in the latency of earlier peaks of the N1 and P2 response in patients with subcortical dementia. These data require further analysis of the role of the V-wave parameter differences to a signicant stimulus for verication of cortical and subcortical cognitive impairments in cerebrovascular disorders. The parameters of the cognitive complex P300 in patients with cognitive impairments signicantly differed from those in healthy subjects of the same age. For adequate assessment of the P3 (P300) latency changes in patients, the parameters of their responses were compared with the data obtained in 75 healthy subjects 2070 years old (Fig. 4). Figure 4 shows that 70% of patients with cognitive impairments of the cortical and subcortical type had a P3 (P300) latency signicantly different from that found in normal subjects. The parameters of the P300 complex in patients with cognitive impairments signicantly differed from those in age-matched healthy subjects: there was an increase in the latency and reduction of the amplitude of the P3 (P300), as well as alteration of the wave shape (it became smoother, with worse identication of the response components). However, the P3 (P300) response parameters to an insignicant stimulus were

300 P300 latency, ms 700 650 600 550 500 450 400 350 300 250 20 30 40 50

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60 70 Age, years

Fig. 4. Relationship between the P3 (P300) peak latency and age in a group of healthy subjects and patients with cognitive impairments of the cortical and subcortical type. The black points designate the values of the P3 (P300) latency in healthy subjects of various ages. The regression line and condence interval lines (2.5 SD) are shown. White points designates the P3 (P300) latency in patients with cognitive impairments of the subcortical type. Crosses refer to P3 (P300) latency in patients with cognitive impairments of the cortical type. The size of these signs reects the severity of cognitive impairments, and their minimum sizes represent the value of the latency in patients with normal cognitive functions in predominant disturbances of the brain cortex or subcortical structures.

decrease in the P3 (P300) peak amplitude was signicant in cognitive impairment of the cortical type. In patients with initial signs of cognitive impairments and slight dementia, irrespective of the type of cognitive impairment, the P3 peak latency increased by 1026% as compared to the age norm. The latency increased enormously in severe dementia, by 90% in the cortical and by 53% in subcortical type of the disorder. More signicant changes in the P3 component, such as an increase in the latency and reduction of the amplitude, were observed in patients with a predominant disturbance of the brain cortex, especially with increasing severity of cognitive impairments (p < 0.00005 and p = 0.0005 for cortical and subcortical cognitive impairments, respectively). The relationship between the P3 peak latency and the amplitude was much greater in severe dementia of the cortical type than in the subcortical type. However, this difference was not signicant. Similar patterns were documented by other authors, who noted an increase in the latency and a decrease in the amplitude with increasing severity of cognitive impairments in patients with Alzheimers disease, vascular dementia, and Parkinsons disease [13, 25, 26]. The high informativeness of the P300 method in the diagnosis of various stages of cognitive impairments has been noted by J. Polich [27] in Alzheimers disease and by S. Kigler with coworkers [28] in hemodynamically signicant stenoses of the internal carotid artery. Agreement between Neurophysiological and Neuropsychological Assessment A comparative analysis of quantitative characteristics of neuropsychological and neurophysiological studies is extremely interesting. We found an inverse relationship between the P3 (P300) peak latency and the volume of both short-term and operative memory, assessed using the Wechsler test, in 24 patients with a cerebrovascular disorder and cognitive impairments caused by damage to the brain cortex (Fig. 6A). The respective correlation coefcient was 0.57 (p < 0.001). Unlike this, the relationship between the P3 (P300) peak latency and the volume of short-term and operative memory was not signicant in cognitive impairments of the subcortical type (r = 0.36, p < 0.05, n = 26; Fig. 6B). In patients with cognitive impairments, there was no correlation between the P3 (P300) amplitude, the parameters of the V-wave, and the volume of short-term and operative memory. Thus, we conclude that the P300 peak latency is associated with such neuropsychological measures as the volume of short-term and operative memory. These data point to the primary character of memory impairment in patients with a predominant disturbance of the cerebral cortex, in contrast to the secondary character of such deciency (being a consequence of disrupted dynamics of psychological activity)
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almost the same as in healthy subjects. Figure 5 presents characteristic shapes of the P300 wave in patients with slight dementia in the predominant disturbance of cortical (II) and subcortical (III) brain structures, as well as in a healthy subject of this age (I). Table 3 presents the parameters of the P300 complex recorded in patients with cognitive impairments of various types and in healthy subjects of the same age. Table 3 shows that the latency of P3 (P300) in patients with cognitive impairments of both types was signicantly longer and the amplitude was signicantly lower than in healthy subjects of the same age (p < 0.0005). The differences in the P3 (P300) peak characteristics between patients with cortical and subcortical types of cognitive impairments were not significant. An analysis of changes in the groups in relation to the severity of cognitive impairments revealed a clearer pattern (Table 4). As Table 4 shows, the P3 peak latency correlated with the extent of cognitive impairments. This latency signicantly (p < 0.001) increased already at the initial stages of cognitive impairment. Furthermore, a

DIFFERENCES IN THE P300 PARAMETERS 5 V/scale unit N A N1 I P N II P N III P 75 ms/scale unit P2 P3 75 N1 P2 N2 P3 N3 III P2 N2 N1 N2 B N3 I

301

P3 N3 II

Fig. 5. P300 in a healthy subject, age 40 years (I), and in a patient with slight dementia of the cortical (II) and subcortical (III) types with identication of the response parameters. I, healthy subject, male, 40 years of age, P3 latency 338 ms, P3 amplitude 8.6 V; II, patient L., female, 43 years old, with slight dementia of the cortical type, P3 latency 440 ms, P3 amplitude 2.8 V; III, patient M., female, 47 years old, with slight dementia of the subcortical type, P3 latency 450 ms, P3 amplitude 2.5 V. Other designations as in Fig. 3.

observed in patients with a predominant impairment of subcortical brain structures. Thus, our study of cognitive evoked potentials revealed a relationship between the N2 and P3 components of the P300 complex and age, as well as cognitive functions. The sensory component of the response

associated with the incoming stimulus was less dependent on the age and did not depend on cognitive functions. Already at initial stages of cognitive impairment, there was a signicant increase in the P3 peak latency, and, in cognitive impairments of the cortical type, a decrease in the amplitude was also signicant. The

Table 3. P3 (P300) parameters in patients with cognitive impairments of the cortical and subcortical types and in healthy subjects of the same age (median values) Parameters of the P3(300) peak Age norm (45 years) Latency, ms Amplitude, V Latency/amplitude ratio 338 6.8 55 Cognitive impairments Cognitive impairments Age norm (51 year) of the cortical type of the subcortical type 405 3.2 120 347 6.7 54 417 3.9 94

Table 4. Relationships of P3 (P300) parameters and the severity of cognitive impairments of the cortical and subcortical types (median values) Cognitive impairments of the cortical type Severity of cognitive impairments Initial stages of cognitive impairments Slight dementia Moderate dementia Severe dementia Age norm
HUMAN PHYSIOLOGY

Cognitive impairments of the subcortical type n latency P3, ms 12 6 6 5 47 383 435 513 530 347 amplitude latency/ampliP3, V tude ratio P3 4.9 2.9 2.7 2.8 6.7 81 231 211 236 54

n 9 9 5 2 52

latency P3, ms 381 435 470 641 338

amplitude latency/ampliP3, V tude ratio P3 4.1 3.2 2.9 1.9 6.8 74 135 147 331 55

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302 P3(300) latency, ms 750 A 650 550

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750 650 550

450 350 250 2 3 4 5 6 7 8

450 350 250 un. 2 3 4 5 6 7 8

Fig. 6. Relationship between the P3 (P300) peak latency and the volume of short-term memory in patients with cognitive impairment of (A) the cortical and (B) subcortical types in cerebrovascular disorders.

severity of cognitive impairments in patients with a vascular disorder of the brain correlated with changes of the P300 complex. An increase in the severity of cognitive impairments was accompanied by an increase in the P3 (P300) peak latency and a decrease in its amplitude. There was no relationship between alterations of the P300 complex components and the type of cognitive impairment (cortical or subcortical). Analysis of Nonspecic Components of Visual Evoked Potentials to a Light Flash in Norm and Cognitive Impairments of Various Severity Analysis of the Visual Evoked Potential in Healthy Subjects The arousal systems of the brain stem, called the energetic block by A.R. Luria [29], signicantly affect cognitive functions. This is why the study of the arousal brain systems using nonspecic evoked potentials, recorded in the central area, in addition to the P300 analysis, is so important. In normal subjects, the visual evoked potential to a light ash is very easy to discern, both in the specic occipital area and the nonspecic central area. There was a pronounced individual variability in response patterns. Figure 7 presents a

typical visual evoked potential to a light ash recorded in the central area of the brain in a normal subject (A). On the whole, a nonspecic response of healthy subjects was characterized by the following parameters (median values): response lag, 0.56 ms; the response length or the recovery time to the initial background noise level (this is a characteristic of the efciency of homeostatic regulation), 214.8 ms; and the maximum amplitude of the response, 10.7 V. The Spearman and Kendall rank correlation analyses conducted in the group of healthy subjects did not reveal any signicant relationships between the parameters of specic and nonspecic visual evoked potentials and the subjects age. Comparative Analysis of Nonspecic Components of the Evoked Potential in Patients with Cognitive Impairments of the Cortical and Subcortical Types Our comparative analysis indicated that the integral parameters of the nonspecic visual evoked potential did not depend on the age of healthy subjects. However, patients with cortical and subcortical cognitive impairments were characterized by clear alterations of the visual evoked potential parameters (Fig. 7, Table 3).

Table 5. Parameters of nonspecific visual evoked potentials to a light flash in norm and in cognitive impairments of the cortical and subcortical types Type of cognitive impairment Cortical Subcortical Norm
* p < 0.005, ** p < 0.0005. HUMAN PHYSIOLOGY Vol. 27 No. 3 2001

Parameters of the nonspecific visual response response lag, ms 59.2 62 56 response duration, ms 235 303.8** 214.8 maximum amplitude, V 7.3* 9.4 10.7

DIFFERENCES IN THE P300 PARAMETERS 5 V/scale unit Amax

303

A
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Fig. 7. Nonspecic visual evoked potentials to a light ash in (A) a healthy subject and patients with dementia of the (B) cortical and (C) subcortical types. The following response parameters are presented: response lag is the latency to the rst signicant component; response duration is the total duration of the response (to the recovery of the residual noise level). Amax is the maximum amplitude of the response (from the maximum to the minimum component of the response).

Figure 7 presents typical examples of nonspecic visual evoked potentials in patients with cortical (B) and subcortical (C) dementia. There was a reduction of the maximum amplitude of the response in a patient with the cortical type of dementia and an increase in the response duration in subcortical dementia. Statistical analysis of these results is presented in Table 5. Table 5 shows that the lag of the occurrence of nonspecic activation in cognitive impairments of both types did not differ from values obtained in normal subjects. Signicant reduction of the maximum amplitude, as compared to the normal value, was observed in patients with cognitive impairments of the cortical type. However, the parameters of the response recovery duration were much higher in the subcortical type of cognitive impairments than in normal subjects and patients with cortical cognitive impairments. This increase was associated with the severity of cognitive impairments. Taken together, these results support the opinion of several authors [29, 30] that higher psychological functions depend not only on the condition of the cortex, but also on the activating subcortical and brain stem structures. Thus, the application of nonspecic visual evoked potentials (responses in the central area) to a light ash, allowing determination of the condition of brain activating systems, indicated that the response parameters do not depend on the age but change in cognitive impairments. For example, there was a signicant increase in the response duration in patients with subcortical cognitive impairments, which indicated an impairment of brain activating systems in patients with
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damaged subcortical structures of the brain. Unlike this, reduction of the maximum amplitude of the response was observed only in patients with predominant disturbances of the cerebral cortex, which points to an impairment of its functional activity as a consequence of structural disturbances (cortical infarctions). These differences in the pattern of the nonspecic visual response suggest that pathophysiological mechanisms of cognitive impairments differ in the predominant disturbance of the cortical and subcortical brain structures. This substantiates the distinction between the two types of cognitive impairment, cortical and subcortical, in patients with cerebrovascular disorders. CONCLUSIONS (1) Cognitive impairments represent a common sign of various cerebrovascular disorders. The neuropsychological prole and pathophysiological mechanisms of their development in these disorders depend on the predominant localization of pathological changes in the brain. (2) Cognitive impairments in patients with predominant disturbances of the subcortical structures of the brain are represented by impairment of the dynamics of psychological activity, such as reduced attention, lack of spontaneous activity, slowing down of all psychological functions, narrowing of interests, but a typical absence of any local impairments of higher psychological functions. Cognitive impairments in predominant disturbances of the brain cortex are characterized by the early appearance and progressive local impairment of higher psychological functions, with the development

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REVENOK et al. Principles, Clinical Applications, and Related Fields, 3rd ed., Niedermeyer, E. and Lopes da Silva, F., Eds., Baltimore: William & Wilkins, 1993. Egorov, A.V., Gnezbitsky, V.V., Koptelov, Yu.M., et al., Analysis of Dipole Sources in Cognitive Evoked Potentials (P300) of the Human Brain, in Sovremennoe sostoyanie metodov neinvazivnoi diagnostiki v medicine. Trudy konf. (The Current State of Noninvasive Medical Diagnostic Methods, Proc. Conf.), Ukraine, YaltaGurzuf, 1996, p. 106. Goodin, D.S., Squires, K.S., and Starr, A., Long Latency Event-Related Components of the Auditory Evoked Potential in Dementia, Brain, 1978, vol. 101, p. 635. Gnezditsky, V.V., Vyzvannye potentsialy mozga v klinicheskoi praktike (Brain Evoked Potentials in Clinical Practice), Taganrog: Izd. TRGU, 1997. Goodin, D.S. and Aminoff, M.J., Electrophysiological Difference between Subtypes of Dementia, Brain, 1986, vol. 109, p. 1103. Pfefferbaum, A., Ford, J.M., Wenegrat, B., et al., Electrophysiological Approaches to the Study of Aging and Dementia: Alzheimers Disease: A Report of Progress, in Aging, Corkin, S., et al., Ed., New York: Raven, 1982, vol. 19. Verleger, R., Heide, W., Butt, C., and Kmpf, D., Reduction of P3b in Patients with Temporo-Parietal Lesions, Cognitive Brain Res., 1994, vol. 2, p. 103. Kropotov, J. and Ponomarev, V., Subcortical Neuronal Correlates of Component P300 in Man, EEG Clin. Neurophysiol., 1991, vol. 78, p. 40. Goodin, D.S. and Martin, S., P300, Cognitive Capability, and Personality: A Correlational Study of University Undergraduates, Person. Individ. Diff., 1992, vol. 13, no. 5, p. 533. Polich, J., Cognitive Brain Potentials, Current Directions in Psychological Science, 1993, vol. 2, no. 6, p. 175. Polich, J., Ehlers, C.L., Otis, S., et al., P300 Latency Reects the Degree of Cognitive Decline in Dementing Illness, EEG Clin. Neurophysiol., 1986, vol. 63, p. 138. Polich, J. and Kok, A., Cognitive and Biological Determinants of P300: An Integrative Review, Biol. Psychol., 1995, vol. 41, p. 103. Hebb, D.C., Drives and the CNS (Conceptual Nervous System), Psychol. Rev., 1955, vol. 62, p. 243. Ciganek, L., The EEG Response (Evoked Potential) to Light Stimulus in Man, EEG Clin. Neurophysiol., 1961, vol. 13, p. 165. Shags, Ch., Brain Evoked Potentials in Norm and Pathology, Moscow: Mir, 1975. Gnezditsky, V.V., A Quantitative Analysis of Reactive Changes of the EEG in Norm and in Localized Disturbances of the Brain (Application of Automatic Control Methods), Cand. Sci. (Biol.), Moscow, 1974. Sazonova, O.B. and Gnezditsky, V.V., Comparative Assessment of the Effects of Lesions in Thalamus, Hippocampus, and the Corpus Callosum on Spontaneous and Evoked Electrical Brain Activity in Humans, Elektroziologicheskie issledovaniya statsionarnoi aktivnosti v golovnom mozgu (Electrophysiological Studies of Stationary Activity of the Brain), Rusinov, V.S. and Grindel, O.M., Eds., Moscow: Nauka, 1983, p. 233.
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of apraxia, acalculia, and agraphia. Impairments of short-term memory in this group are more pronounced, but impairments of thinking, emotions, and personality are less pronounced than in patients with predominant disturbances of the subcortical structures. (3) Parameters of the P300 complex recorded during recognition of a signicant auditory stimulus depend on the age and the condition of cognitive functions. They may be used for objective diagnosis of cognitive impairment, which is especially important at its early stages. Increases in the severity of cognitive impairments are accompanied by an increased latency and a reduced amplitude of the P3 (P300) peak. Alterations of the P300 complex do not depend on the type of the cognitive impairment. The P300 peak latency increases with the reduction of both the short-term and operative memory. (4) The parameters of nonspecic components of the visual evoked potential to a light ash, reecting the action of brain arousal systems, depend on the type and severity of cognitive impairments but do not depend on the age. The duration of the visual response signicantly increases in patients with cognitive impairments associated with predominant disturbances of the subcortical structures, which points to malfunctions of brain activating systems. Patients with cognitive impairments associated with predominant disturbances of the brain cortex are characterized by lower levels of the maximum response amplitude, which points to an impairment of the functional state of brain cortex as a consequence of structural alterations (cortical infarctions). (5) Differences in the neuropsychological prole of cognitive impairments, their pathophysiological mechanisms assessed by evoked potentials, and differences in the brain structures involved in the pathological process substantiate the discrimination of two types of cognitive impairments, cortical and subcortical, in patients with cerebrovascular disorders. REFERENCES
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