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0362-1197/01/2703- $25.00 2001 MAIK Nauka/
Interperiodica0294
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.
Studies of cognitive impairments, designated in theRussian
literature as disturbances of higher psycholog-ical functions, are
very important in both medical andsocial respects. According to
data reported byA.S. Henderson [1], dementia is diagnosed in 1%
ofsubjects at the age of 65 years and older. Dementia isdefined as
acquired impairment of memory and intelli-
gence which detrimentally affects the daily life of thesubject.
The basic diagnostic criteria are deficiencies ofcognition and
memory. Agnosia, apraxia, disturbancesof speech and orientation,
etc., are considered as auxil-iary symptoms [1].
The application of neurovisualisation techniques inneurological
practice caused a substantial interest in thestudy of the
structural bases of cognitive impairments,including dementia, with
cerebrovascular disorders.However, the pathophysiological
mechanisms of theirdevelopment still remain poorly understood.
Because cognitive disturbances and dementia incerebrovascular
disorders are potentially curable (i.e.,
it is possible to prevent their further development[2, 3]),
their early diagnosis and objective detection atearly stages become
especially important. Electrophys-iological methods, in particular
P
300, as well as com-mon neuropsychological assessment, are used
for thispurpose.
The method of cognitive evoked potentials or P
300[4] allows objective assessment of cognitive
functionsassociated with perception and processing of informa-tion.
The essence of this approach is that the experi-
menter analyzes complex endogenous events occurringwithin the
brain and associated with recognition andremembering of significant
stimuli, i.e., the basic cog-nitive processes in the brain [46],
rather than a simpleresponse caused by the incoming afference. In
1978,Gudin and coworkers [7] first offered this approach forthe
assessment of dementia. Subsequently, cognitive
evoked potentials have become widely used for theassessment of
cognitive functions in clinical studies[4, 6, 810]. The most
diagnostically informativeparameters of the P
300 are an increase in its latencyand the absence or instability
of the response.
It has been shown [11] that temporal and parietalareas of the
cortex are involved in generation of the
P
3 (
P
300). The P
3(300) peak is associated with thefunction of the frontal lobe.
The role of subcorticalstructures in the generation of the P
300 was shown byYu. Kropotov and V. Ponomarev [12].
An increase in P
300 latency is observed not only incognitive impairments. A
consistent increase in the
P
300 latency also occurs with age. Regression curves,reflecting
the relationships between the latency andage, have been determined
in healthy subjects. Thisrelationship is often called the aging
curve and is usedfor adequate assessment of the P
300 parameter changesin subjects with cognitive impairments.
These relation-ships are useful for objective assessment of aging
pro-cesses [4, 6, 810].
The latency and amplitude of the P
300 wave vary inhealthy subjects, depending on individual
differences
Differences in theP
300 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
Abstract
In this study we analyzed the parameters of auditory evoked
potentials in a stimulus recognitiontask (the P
300 method) and nonspecific visual response to a light flash 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 cog-nitive impairments of various degrees
(cerebrovascular disorder) with different neuropsychological
profiles. Itwas shown that parameters of the P
300 complex depend on both the subject age and his/her cognitive
functionsand can be used for objective analysis of cognitive
impairments. An inverse relationship between the P
3 (
P
300)peak latency and the volume of short-term and operative
memory in subjects with cognitive impairments wasfound. The
parameters of the nonspecific visual response (duration and the
maximum amplitude), reflecting
functioning of the arousal systems of the brain, depended on the
type and severity of cognitive impairments butdid not depend on the
subjects age. Differences in the neuropsychological profiles of
cognitive impairmentsand the pathophysiological mechanisms of their
development, reflected by parameters of the evoked potential,as
well as differences between the brain structures involved in these
process, substantiate the discrimination oftwo types of cognitive
impairmentscortical and subcorticalin subjects with cerebrovascular
disorders.
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DIFFERENCES IN THE P
300 PARAMETERS 295
of their cognitive function, as well as in subjects
withcognitive impairments [5, 10, 1315]. A shorter latencyand
higher amplitude of the P
3 peak are observed insubjects with higher cognitive abilities
[13, 14]. Theamplitude is considered proportional to the attention
ofthe subject to the task, and the latency is thought
tocharacterize the speed of the stimulus classificationwithin the
series presented [4, 16]. In 1995 and 1996,
J. Polich [4, 16] reviewed more than 100 studies con-cerned with
normative data on cognitive evoked poten-tials and the effects of
various cognitive and biologicalfactors on the P
300 parameters. The author pointed outthat most investigators
agree that the peak parameters ofthe P
3 reflect the characteristics of operative memory.
Thus, the P
300 method can be used for verificationof cognitive impairments
and dementia, for assessmentof their severity, for distinguishing
cognitive impair-ments and depression, for objective assessment of
thedynamics of cognitive dysfunction during curing, andfor
assessment of the secondary action of drugs. Thismethod also
facilitates the assessment of cognitivefunctions in children with
retarded mental developmentand can be used for screening when
neuropsychologi-cal assessment is difficult. According to the
theory ofD. Hebb [17], sensory input has two basic functions. Itnot
only provides information about the environmentbut also creates
conditions for the processing of thisinformation. The latter
includes the arousal system ofthe brain stem and thalamus. The
development of visualresponse components involves not only specific
sen-sory systems but also nonspecific components, provid-ing
additional activation of various brain regions. Thisallows the use
of visual evoked potentials to a lightflash for the assessment of
pathologies of specific andnonspecific visual afference in subjects
with the dys-
function of consciousness [18]. L. Ciganek [18] sug-gested that
later components (>100 ms) of the visualresponse to the light
flash are associated with the brainstem and thalamus activating
systems and reflect thereactive characteristics of the whole brain
[19].
Thus, evoked potentials assess regulatory homeo-static
mechanisms of the brain (i.e., cortical-subcorticalhomeostasis)
that maintain the reactive properties ofthe brain and cortical
arousal [2022]. Therefore, theyreflect integrative functioning of
the whole brain ratherthan only the sensory systems. This allows
using a non-specific visual response in the central area, in
additionto the P
300, for assessment of brain arousal systemsand assessment of
their roles in the genesis of variouscognitive impairments.
MATERIALS AND METHODS
The study group consisted of 70 subjects (35 menand 35 women,
mean age 51
6.2 years) with cere-brovascular disorders and symptoms of
cognitiveimpairment. Two groups of patients were distinguishedon
the basis of brain magnetic resonance tomography(MRT). The first
group (20 men and 13 women, mean
age 51.2
6.7 years), with a predominant disturbanceof subcortical
structures of the brain, consisted ofpatients with subcortical
arteriosclerotic encephalopa-thy (26 subjects) and infarcts in the
frontal-medial areasof the thalamus and thalamofrontal pathways (7
sub-jects). The second group (22 females and 15 males,mean age
51.1
5.2 years) with a predominant dys-function of the cortex,
consisted of 29 patients with
angiocoagulopathy (mean age 45.5
7.7 years) and 8patients with hemodynamic stenosis of the
internalcarotid artery (mean age 56.6
2.6 years).
Neuropsychological assessment of higher psycho-logical functions
of the subjects using the method ofA.R. Luria and the international
diagnostic criteria ofdementia ICD-10 [23] indicated that their
cognitivefunctions involved initial stages of cognitive
impair-ment, not reaching the severity of dementia, and vari-ous
degrees of dementia, from slight to severe.
For objective diagnosis of cognitive impairments, weanalyzed the
P
300 component of the cognitive evokedpotential. Normative data
obtained in 75 healthy sub-
jects from 20 to 70 years old was used for the analysisof the
P
300 in patients with cognitive impairments. Thearousal system of
subjects with cognitive impairmentsin cerebrovascular disorders was
examined using non-specific visual response to a light flash. The
controlgroup consisted of 21 healthy subjects. The visualevoked
potentials were analyzed using a Viking IV neu-roaverager (Nikolet,
USA).
The study ofP
300 was conducted in a situation of asudden event (the oddball
paradigm). It involvedselection of responses by the subject during
recognitionof a rare stimulus (a short tone click with a
frequencyof 2000 Hz) among frequent nonsignificant back-
ground stimuli (1000 Hz). Usually, the sensory part ofthe
response, long-latency auditory evoked potentialsor the V-wave, and
the P
300 complex with theN
2 and
P
3 (
P
300) peaks, reflecting the recognition of rare sig-nificant
stimuli, are distinguished. The duration of thestimulus was 50 ms,
with an intensity of 80 dB. The fre-quency of clicks was 1 per
second. The stimuli werepresented binaurally in a pseudorandom
sequence. Theprobabilities of the significant and insignificant
stimuliwere, respectively, 0.3 and 0.7. We used the C
3
M
1
and
C
4
M
2
derivations, 1020% according to the interna-tional
classification, from the central areas of left andright
hemispheres, with respect to the ipsilateral mas-toid process of
the temporal bone. The ground elec-trode was in the Fpz
position. The sensitivity was5
V/scale unit, the frequency band was 0.230 Hz,and the analysis
epoch was 750 ms. The number ofaveraged presentations of
significant stimuli was 30.The averaging of responses to rare
(significant) and fre-quent (insignificant) stimuli was conducted
separately.To assess the repeatability of the results, the study
ofthe P
300 in each subject was conducted in two inde-pendent time
series. The final scores represent thesuperpositions of these two
repetitions. The primary
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2001
REVENOK et al
.
task of the subject was to recognize and count the num-ber of
significant stimuli. The assessment of patientswith pronounced
impairments of cognitive functionsand incomplete understanding of
the instruction wasconducted with passive perception of the
stimuli.
Nonspecific visual responses were recorded to a
light-emitting diode flash, with an intensity of 300 mcdand a
wave length of 640 nm. The light stimulation wasprovided
monocularly (to the eye with a better acuity ofvision), with the
stimulation period 0.8 Hz, the eyesbeing closed. The number of
averagings was 100, andthe analysis epoch was 1 s. We also analyzed
nonspe-cific afference, in which case the response was recordedfrom
the central area of the brain (
C
3
M
1
, C
4
M
2
). Theconditioned response was the same as in the analysis ofthe
cognitive evoked potential. The following charac-teristics of the
response were analyzed: latency (latencyto the first significant
peak), duration (period of theresponse return to the residual noise
level), and themaximum amplitude (amplitude from the maximum
positive to negative peak).
RESULTS AND DISCUSSION
Comparative Analysis of Cognitive Impairmentsin Dysfunction of
Cortical and Subcortical Brain
Structures in Patientswith Cerebrovascular Disorders
General Characteristics of Cognitive Impairment
Based on the neuropsychological examination con-ducted using
international criteria of dementia, cogni-tive functions in 70
patients were found to be initialstages of cognitive impairment,
not reaching the sever-
ity of dementia (24 patients), and various degrees ofdementia
(33 patients). In 13 patients, regardless ofsubjective complains of
memory loss, lower attention,and slower thinking, no objective
signs of cognitiveimpairment were found (Table 1).
A comparative analysis of cognitive impairmentunder the
predominant disturbance of cortical or sub-cortical brain
structures was conducted between twogroups of patients with
subcortical arterioscleroticencephalopathy and angiocoagulopathies,
which con-
stituted the majority of the assessed groups (26 and29 subjects,
respectively).
The initial stages of the cognitive impairment withpredominant
disturbances of the subcortical structuresand the cortex were
characterized by the impairment ofattention. With more pronounced
deficiencies, dysfunc-
tion of thinking, memory, and attention become moresevere.
Furthermore, disturbances of thinking indicateddementia. Patients
with dominant disturbances of thebrain cortex demonstrated slight
dysfunction of opticaland spatial gnosis.
There were significant differences in the severity ofthe
cognitive impairment between two groups ofpatients with
cerebrovascular disorders. Patients withpredominant disturbances of
the subcortical brainstructures exhibited lower attention, lack of
spontane-ous activity, general deceleration of all
psychologicalprocesses, and reduction of interests in the absence
ofclear local dysfunction of higher psychological func-tions. On
the whole, their changes were similar to thosetypically found in
the lobe syndrome. On the con-trary, even the initial stages of
cognitive impairmentwith a predominant disturbance of the cortex
werecharacterized by local dysfunctions of higher psycho-logical
functions, including apraxia, acalculia andagraphia.
Figure 1 shows significant differences (
p < 0.01)between patients with cognitive impairments in
pre-dominantly cortical and subcortical brain disturbances.
In both groups of patients, memory disturbanceswere
modally-nonspecific; i.e., both auditory-speechand visual memory
were impaired. Furthermore, theperformance in delayed reproduction
tasks was charac-terized by a greater impairment than in direct
reproduc-tion tasks. Additionally, we found an increased effect
ofinterference on memory retention and selectiveretrieval of memory
traces. Patients with predominantdisturbances of the subcortical
structures exhibited rel-atively stronger dysfunction of thinking
than short-termmemory, whereas the reverse was typical for
patientswith predominantly cortical disturbances.
Generally,impairment of short-term rather than long-term mem-ory
was more characteristic of patients with predomi-
Table 1. Characteristics of cognitive functions according to
ICD-10
The condition of cognitive functions
Predominant disturbance of subcortical brainstructures (
n
= 33; mean age, 51.2 years)Predominant disturbance of the
braincortex (
n
= 37; mean age, 51.2 years)
n
mean age
n
mean age
No cognitive impairment 4 50.8 9 44.3
Initial signs of cognitive impairment 12 56.8 12 50.7
Slight dementia 6 54 9 46.7Moderate dementia 6 51.8 5 46.8
Severe dementia 5 58.8 2 41
Note:
n
is the number of patients.
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DIFFERENCES IN THE P
300 PARAMETERS 297
nant disturbances of the brain cortex. Long-term mem-ory was
relatively intact at early stages of the disorderbut significantly
impaired in severe dementia, both cor-tical and subcortical.
These differences can be accounted for by distur-bances of
various brain structures. For example, a pre-dominant disturbance
of subcortical structures (diffuseinjury of the white substance of
the brain hemispheres
or infarcts in the frontalmedial areas of the thalamus)causes
interruption of the thalamocortical pathwaysand impairment of
arousal with secondary inactivationof anatomically unaffected
cortical regions. This causesgeneral disorganization of all
psychological activityand secondary memory impairment. In contrast,
inpatients with cortical cognitive impairments that devel-oped as a
consequence of primary injury of the braincortex (significantly
involved in remembering), mem-ory impairment was of a primary
character. The lesserimpairment of thinking in this group of
patients wascaused, most probably, by the relatively better
integrityof the frontal lobe (MRT data indicated that
temporalparietaloccipital areas suffered to a greater extent),
theassociative pathways between various areas of the braincortex,
and the links between the cortex and reticularformation.
Impairment of Counting, Praxis, Speech, Writing,and Reading in
Cognitive Impairments of the Cortical
and Subcortical Types
Significant differences in the severity of localimpairments of
higher psychological functions werefound between patients with
predominantly corticaland subcortical disturbances (Table 2).
Local impairments of higher psychological func-
tions (aphasia, agraphia, alexia, acalculia, apraxia)occurred in
all patients with a predominant disturbanceof the brain cortex and
appeared even at initial stages of
cognitive impairments. The primary cause of theirdevelopment was
local injury of the brain. The severityof the local impairment of
higher psychological func-tions significantly increased with
increasing severity ofcognitive impairments (
p < 0.05). On the whole, thesedeficits pointed to predominant
impairment of the tem-poralparietaloccipital areas of the
brain.
The results of computer tomography showed goodcorrelations with
neuropsychological data (Fig. 2
A
).
Cognitive impairments of the cortical type were charac-terized
by broadening of the subarachnoidal space ofthe brain hemispheres,
which was observed in 71% of
Table 2. Comparative characteristics of the localized impairment
of higher psychological functions in patients with corticaland
subcortical cognitive impairments
Impairment of higher psychological functions
Subcortical cognitive impairments(
n
= 23)Cortical cognitive impairments
(
n
= 25)
n
%
n
%
Aphasia 1 4.3 22 88
Moderate and pronounced 1 4.3 13 52
Impairment of serial counting 17 73.9 11 44
Acalculia 3 13 12 48
Alexia 1 4.3 7 28
Opticospatial deficits 0 0 14 56
Spatialconstructional apraxia
spatial type 0 0 18 78.3
dynamic type 19 82.6 6 24
Note:
n
, number of patients
. All differences in the table are significant.
0.5
0
Rating scale
I II
1.0
1.5
2.0
2.5
a
b
c
Fig. 1.
Comparative assessment of the severity of thinkingand memory
impairment in patients with cortical and sub-cortical types of
cognitive impairments (median values).
I
, cortical; II
, subcortical type; a
, thinking; b
, short-term
memory; c
, long-term memory.
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REVENOK et al
.
patients with dementia and in only 22% patients withinitial
signs of cognitive impairments (
p < 0.035). Mul-tiple infarcts in the cortex, predominantly
in the tempo-ralparietaloccipital area, were found in 86%
ofpatients with moderate and severe dementia, but theywere not
discovered at the initial stages of cognitiveimpairment (
p < 0.002).
Local impairments of higher psychological func-tions were not
characteristic of cognitive impairmentassociated with disturbances
of the subcortical brainareas. They were observed at later stages
of the defi-ciency and did not reach such severity as in
patientswith predominant disturbances of the brain
cortex.Impairments of counting, writing, and praxis wereassociated
with general impairment of psychological
processes. They were dynamic in nature and arose as aconsequence
of general slowing of the dynamics ofpsychological processes. With
increasing severity ofcognitive impairments, they became
significantly morepronounced (
p < 0.05).
The severity of cognitive impairments of the subcor-tical type
correlated (
p < 0.05) with decreases in thedensity of the white substance
in the brain hemispheres,
as well as with widening of the lateral cerebral ventri-cles
(Fig. 2
B
). In contrast, there was no relationshipwith the occurrence of
lacunar infarcts. The dataobtained by computer tomography support
the mecha-nism of segregation of the cortex and subcorticalbrain
structures, particularly the thalamus and reticularformation, in
the genesis of cognitive impairments ofthe subcortical type. This
mechanism has been pro-posed earlier by Tatemichi [24].
Thus, our neuropsychological assessment revealedsignificant
differences in cognitive impairments andtheir dynamics in patients
with predominant distur-bances of the cortical or subcortical brain
structures,
which substantiates the distinction between these twotypes of
cognitive impairment in patients with cere-brovascular
disorders.
Analysis ofP300 in Healthy Subjects and Patientswith Cognitive
Impairments
in Cerebrovascular Disorders
Analysis of Sensory and Cognitive Componentsof P300 in Healthy
Subjects
An analysis of the evoked potential during the rec-ognition of a
significant stimulus and averaging ofresponses to an insignificant
stimulus revealed a classi-
cal long-latency auditory evoked potential with theNP (V-wave)
components. Its parameters (latency andamplitude) coincided with
the common auditoryevoked potential isolated in a series of
homogenousauditory stimuli (Fig. 3A). Averaging of the responsesto
rare significant stimuli brought about an additionalwave complex
with the average latency equal to300 ms, in addition to the V-wave.
This would representthe cognitive component of the response.
The parameters of the V-wave (sensory response)both to
significant and insignificant stimuli did not dif-fer in 60 healthy
subjects 3570 years old and were asfollows: 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 Spearmanrank
correlation coefficients for the latency of theNcom-ponent were
0.37 (p < 0.004) and 0.27 (p < 0.036) forthe insignificant
and significant stimuli, respectively.The Spearman correlation for
the P2 peak of the signif-icant stimulus was 0.31 (p <
0.018).
The parameters of the P300 complex depended onthe subjects age:
the latency tended to become longer,and the amplitude also reduced
(Figs. 3B, 4). The max-imum rank correlation coefficient was
obtained for the
A
B
Fig. 2. Computer tomography of the brain in (A) cortical and(B)
subcortical types of cognitive impairments. (A) Com-puter
tomography of patient B., male, 46 years, with severedementia.
There is a pronounced broadening of the sub-arachnoidal space of
the brain hemispheres, more than the
occipital and parietal lobes. (B) Computer tomography ofpatient
K., male, 64 years, with severe dementia. Pro-nounced diffuse
reduction of white substance density, pre-dominantly around the
ventral horns, with localities ofreduced density and clear
broadening of the lateral cerebralventricles, can be distinguished
in both hemispheres.
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DIFFERENCES IN THE P300 PARAMETERS 299
latency of the P3 (P300) component (r = 0.53, p
