Similarities in the pattern of regional brain dysfunction in negative schizophrenia and unipolar depression: a single photon emission-computed tomography and auditory evoked potentials study

Rug.

Nem-Psychopharmacol.

& Bol.

Psychid. Copyright

2001, 0 2001

Vol. 25, pp. 993-1009 Ekvier

Sueme

Inc.

Pmlted in the USA. Au nghts reserved 027%5846/01/$-see front matter

ELSEVIER

PII:

80378~5846(01)00172-5

SIMILARITIES IN THE PATTERN OF REGIONAL BRAIN DYSFUNCTION IN NEGATIVE SCHIZOPHRENLA AND UNIPOLAR DEPRESSION: A SINGLE PROTON EMISSION-COMPUTED TOMOGRAPHY AND AUDITORY EVOKED POTENTIALS SSTUDY VESNA MEDVED’, RATKO PETROVIC’, VELIMIR ISGUM3, LAJOS SZIROVICZA4 and LJUBOMIR HOTUJAC’

‘Psychiatric Clinic, *Nuclear Medicine Clinic and 3Neurological Clinic, University Clinical Hospital Centre Rebro, 41nstitute for Anthropological Research, Zagreb, CROATIA

(Final form, April 2001)

Abstract

Vesna Medved, Ratko PetroviC, Velimir ISgum, Lajos Szirovicza and Ljubomir Hotujac: Similarities in the Pattern of Regional Brain Dysfunction in Negative Schizophrenia and Unipolar Depression: A Single Photon Emission-Computed Tomography and Auditory Evoked Potentials Study. Prog. NeuroPsychophurmacol. & Biol. Psychiut. 2001,2& pp.

993-1009.82001

Elsevier Scimce

Inc.

1. Negative schizophrenic and unipolar depressive patients were clinically assessed. In addition to this SANS and HRSD tests were administered. 2. SPECT and AEP measurements were provided. SPECT resulted in quantified brain blood perfusion, by means of average “count/pixel” values in the brain regions of interest, AEPs resulted in stored multichannel signal waveforms. 3. Statistical analyses of blood perfusion measurement data revealed an overall similarity between these two disorders in the majority of brain regions. An exception to this are the regions: inferior temporalis, inferior occipitalis, hippocampus and the anterior basal ganglia. Both diagnostic groups manifested hypofrontality. In general, hypoperfusion of the left hemisphere was found, albeit displaying different patterns in the two groups investigated. 4. AEP latencies were prolonged and found to be similar in both diagnostic groups, whilst AEP amplitudes were smaller in schizophrenics compared to depressives.

auditory evoked potentials (AEPs), biological psychiatry, depression, frontal brain regions, schizophrenia, single photon emission-computed tomography (SPECT) Kevwords:

Abbreviations: auditory evoked potentials (AEP), computer tomography (CT), Hamilton rating scale for depression (HRSD), orbitomeatal line (OM), positron emission tomography (PET), regional cerebral 993

V. Medved et al.

994

blood flow (rCBF), region of interest (ROB, single photon emission-computed scale for the assessment of negative symptoms (SANS).

tomography

(SPECT),

Introduction

The clinical depression

overlap

between

is an established

following

common

1987), nivelation

symptoms

fact. Reports

symptoms:

of negative indicate

schizophrenia

the existence

loss of energy and willpower,

of affect (Boeringa and Castellani

and symptoms

of unipolar

of a partial similarity

anchedonia,

associality

1982), loss of motivation,

between

(Whiteford

the et al.

physical anergy, loss of

recreational interests, diminished

sexual interest, inability to develop intimate relations, as well as to keep

previously

with friends

developed

relations

and peers (Kitamura

question of a possible similarity of patterns in the brain dysfunction

and Suga,

of these two psychiatric

Regional deficit of functional (neural) activity has already been investigated cerebral blood flow using 99mTc-HMPA0

1991). This raises the

single photon emission-computed

disorders.

by measuring the regional tomography

- (SPECT) and

auditory evoked potentials (AEP) - P300, which reflect the metabolic and electrophysiolgical living human brain, SPECT and PET methods resulted

in a number

hypometabolism association Molina

et all.

considered increase depressive

findings.

(Chua and McKemra

between

hypofrontality

of different

negative

1997)

(Vasile

In schizophrenics,

1995, Andreasen

symptoms

whereas

applied to schizophrenic

brain

the general trend accentuates

has been reported

studies

of affective

et al. 1996, Ogura et al. 1998, Galynker

robust for schizophrenia in P300 latency

(Coburn

et al. 1998). Papers

metabolic

schizophrenia

and unipolar

and electrophysiological

psychiatric disorders above.

(Ebmeier

disorders

et al. 1993, postulate

et al. 1998). Furthermore,

findings

reporting

a decrease

in P300 amplitude

(Diner et al. 1985) that the P300 amplitude is influenced,

in not

latency is also usually found

et al. 1998).

In this study we examine the relationship with negative

frontal

rarely

only by cognitive, but also by emotional factors. Apart from this, prolonged (Vandoolaeghe

have

include a decrease in P300 amplitude (Salisbury et al. 1998) and an

disorders lead to the conclusion

in depressives

patients

et al. 1997, Spence et al. 1998) and a strong

and hypofrontality

functional

and depressive

status of the

between regional cerebral blood flow and P300 in patients depression.

dysfunctions,

The aim was to research

and their possible

similarities,

the topography

of

in view of the two

SPECT and AEPs in negative schizophrenia

and unipolar depression

995

Methods

Patient Ponulation

Subjects

for the study were recruited

Zagreb, Croatia. All subjects

at the Psychiatric

met the DSM-III-R

1987). Psychopathological

during a semi-structured

interview using SANS (Andreasen

psychopathology

level was 12 years for schizophrenics

Depressives

were

anxiolytics.

undergoing

treatment

Patients had not previously

patients were righthanded.

According

that might induce EEG-changes, dependencies

and 10 for depressives.

received

The mean duration of

The subjects

All schizophrenic

(mean chlorpromazine consisting

(mean age 32.1,

(mean age 47.8, ranging from 33 to 55). The

and 8 years for depressives.

of typical antipsychotics

(American

1983) and Hamilton rating scales (Hamilton

and were not regarded as being in remission.

treatment consisting

or depression

20 female patients diagnosed with negative schizophrenia

illness was 7 years for schizophrenics

Centre Rebro,

data were obtained by the first co-author of this paper

ranging from 24 to 40), and 13 with unipolar depression mean educational

Hospital

criteria for schizophrenia

Psychiatric Association,

1960). The study encompassed

Clinic, University

manifested

current

subjects were receiving

- equivalent dose = 959.37 mg/day).

of tricyclic

atypical neuroleptic

or tetracyclic

antidepressives

or electroconvulsive

and

therapy. All

to the set criteria, those over 55 years of age, those taking drugs

and those with a history

of neurological

illnesses,

alcoholism

were excluded from the study. All subjects featured an average IQ and readily consented

or in

writing to participate once the aims and procedures of this study had been explained to them.

Study Design

The study was carried out during a period subsequent the patient’s

state had stabilized.

Each participant

to one to two weeks of stay in the hospital, once was subjected

to the two assessment

mentioned

above. The findings for five (AEPs) and four (SPECTs) for different

depressive

patients

were excluded

from the study due to technical

problems.

and two

Rating scales and AEP

recordings were made for each patient on the same day; SPECT was administered

Assessment

schizophrenic,

methods

a day later.

Instruments

The SPECT procedure

was carried out in a darkened sound-proof

room. Image acquisition

min after an i.v. radiotracer injection of 15 mCi (550 Mbq) of Tc99m-HMPA0.

Measurements

began 15 were made

V. Medved et al.

996

using the double-headed

rotating scintillation

gamma camera Siemens ZLC 37, and lasted for 20 minutes.

Brain slices, 4.6 mm apart, parallel to the orbitomeatal 120 projections

processing.

was done in

(60 from each camera head) at 3 distances. Data obtained were stored in an ADAC 33000

computer which provided visualization Quantification

line (OM), were recorded. Recording

was performed

of perfusion records and numerical processing

in the following

of digitized data.

manner, and included four slices chosen for numerical

The first slice was 2.5 cm above the OM line, with ROB for the inferior temporalis

the hippocampus

(IT) and

(HI). The second slice was 5 cm above the OM line with ROIs for the gyms frontalis

superior (SF3), the gyms frontalis inferior (IF), the superior temporalis

(ST), the inferior occipitalis

(IO),

the anterior basal ganglia (BG) and the thalamus (TH). The third slice was 7.5 cm above the OM line with ROIs for the gyms frontalis superior (SF2), the gyms frontalis medialis (C2), the inferior parietalis (IP) and the superior occipitalis OM line with ROIs for the gyms frontalis

superior

(MF), the central region

(SO). The fourth slice was 9 cm above the

(SFI),

the central region (Cl)

and the superior

parietalis (SP) (32 regions in all). During the process of image quantification,

the number of pixels in each ROI was counted,

“count/pixel” for a particular region were chosen as raw measurement fact, average determine possible.

values of perfusion

measures

the dosage of radioactivity “Count/pixel”

as raw measurement

of raw measurement

between

(amounting

measurement

comparisons

ROIs). Since it was not possible on an absolute

data were suitable for some quantitative symmetry. In some other quantitative

data applied is as follows.

divided by the average value for the corresponding in this manner

variables. (These quantities are, in

entering brain cells, measurement

instance, when evaluating brain hemispheric normalization

for corresponding

to approximately

hemisphere,

scale was not

comparisons,

regions were

to draw inter-subject

comparisons

in this way also made it possible

to draw

for each patient.

placed at: FPZ, FPl, FP2, F7, F3, FZ, F4, F8,

T3, C3, CZ, C4, T4, T5, P3, PZ, P4, T6, 01, OZ and 02 locations, according to the International system (Brain Atlas 2.30 System by Bio-Logic

lo/20

Systems Corp.). AEPs were obtained using an oddball

task. Stimuli consisted of a 1-kHz tone-burst (frequent, nontarget stimulus) and a 2-kHz tone-burst target stimulus). Stimuli were presented

for

analyses, the mode for

The values for particular

between particular regions in the sense frontal-occipital

Scalp EEGs were recorded using Ag-AgCl electrodes

to

at a certain slice level. Values normalized

1) made it possible

results. Further, values normalized

so that

(rare,

binaurally in random order at 70 dB. The stimulus plateau was

90 ms, with rise and fall times of 10 ms. Patients were instructed to count the number of rare tones and to report their count for each trial. Analysis time was 512 ms. AEPs were averaged separately for rare and frequent stimuli. Multichannel memory for further processing.

AEP curves thus obtained,

expressed

in pV, were stored in computer

SPECT and AEPs in negative schizophrenia

and unipolar depression

997

Data Analysis

Due to the complex and multivariable several signal processing

methods,

nature of the interrelationships

and a battery of parametric

methods were applied in their comprehensive analysis

followed

measurement

only after testing

variable,

(distribution

so that

analysis (Medved

the character

one

among

and non-parametric

testing

distribution

(normal

of the corresponding

distribution)

or

non-parametric

level criterion.

Global scores of rating scales applied were compared

using the Student-t

test, provided

global scores had been previously tested for normality using the Smimov-Kolmogorov To provide quantitative between the two diagnostic provided

for each identified

variables,

as explained corresponding

insight into the possible

cerebral

previously regions

region. Normalised

(Assessment

between

homogeneity

of variance has been established

hemispheres

was determined

in the arithmetic

the measured

means

of two

previously.

section - by direct comparison comparison

t-test

for differences

in paired

samples

Comparisons

were done separately for subsample

procedure

independent

samples, in perfusion

values (“count/pixel”) of perfusion

was

were used as in rCBF

test was used to determine

The differentiation

of mean perfusion

significance

values for regions

values of rCBF

In order to evaluate differences

groups, a Student-t

based on raw measurement

brain regions. In the statistical

perfusion

Instruments).

in two diagnostic

of differences

Instruments

differences

the same

test.

groups, a univariant analysis of variance with discriminating

significance

Assessment

statistical

deviating from normal) methods were able to be used. In all analyses, 0.05 has been used as

the significance

between

variables,

1995). The choice of a certain method of

of probability

parametric

between measurement

provided

that

between brain

- as explained

values of corresponding

values of particular

the

left-right

in the

left-right regions the

was used, with an 0.05 level of significance.

shizophrenia

(SCH) (N=l5) and subsample

depression

(DEP) (N=ll).

Multichannel waveform.

AEP signals in each individual recording were processed by calculating the mean square

This in turn served as the basis for finding the latency value for each particular record, which

was done in an interval ranging from 250 to 512 ms (Regan 1987) using the software algorithm. at each particular electrode position, called grand-average

waveforms).

average waveforms

Further,

for SCH and DEP groups were calculated (so-

V. Medved et al.

998

Results

The average total score on SANS for the group of schizophrenic

patients was 87.43, and 54.54 for the

group of depressive patients. The average total score on the Hamilton scale for the group of schizophrenic patients was 27.93, and 26.81 for depressives. form normality.

The difference

It was determined

that there were no significant

in the total score on SANS between

statistically (p < O.OOl), whereas the difference

deviations

groups was highly significant

in the Hamilton score was not (p > 0.05). This confirms

that SANS generally allows for good discriminability

for the two diseases concerned,

unlike the Hamilton

scale.

SPECT Results

Table 1 shows the overall results of determined

significances

of differences

in rCBF measured values

between the two diagnostic groups and includes the values of particular arithmetic means. This shows that 8 out of 32 brain regions differ significantly, displayed a significant difference -

whilst the remaining 24 do not. Regions that

in perfusion between the SCH and DEP groups are:

the IT and IO regions, which displayed a significantly

lower perfusion

in SCH in relation to DEP

bilaterally, -

the HI region, which displayed a significantly

-

the right BG region which displayed

higher perfusion in SCH in relation to DEP bilaterally,

a significantly

higher perfusion

in SCH in relation to DEP,

whilst at the left side the difference being in the same sense, albeit not significant -

the right ST region which displayed a significantly Distributions

of normalised

(p=O.O6),

lower perfusion in SCH in relation to DEP.

rCBF values in particular brain regions for each diagnostic

category are

graphically presented in Fig. 1 (taken as an example), which serves to illustrate data in Table 1. In Table 1, the SF2 and SF3 values for both left and right show that hypofrontality

is present in both

disorders. Table 2 shows the results of differentiation groups, respectively.

hemisphere.

in SCH and DEP

Arithmetic mean values are included.

A significant asymmetry are regularly

in perfusion between brain hemispheres

appeared in a large number of regions. The perfusion values for the left side

lower than those for the right side. This indicates

a global hypoperfusion

of the left

SPECT and AEPs in negative schizophrenia and unipolar depression

Table 1

Differentiation

in Cerebral Blood Perfusion in Particular Regions Between Schizophrenia Depression (DEP) Groups

Right Hemisphere Region Gyrus frontalis superior (SFl) Gyrus frontalis superior (SF2) Gyrus frontalis superior (SF3) Gyrus frontalis medialis (MF) Gyrus frontalis inferior (IF) Central region (C 1) Central region (C2) Superior parietalis (SP) Inferior parietalis (IP) Superior temporalis (ST) Inferior temporalis (IT) Superior occipitalis (SO) Inferior occipitalis (IO) Anterior basal ganglia (BG) Thalamus (TH) Hippocampus (HI) a p denotes the degree of significance

(SCH) and

Left Hemisphere

SCH

DEP

pa

SCH

DEP

pa

0.9956 0.9818 1.0471 1.0037 1.0078 1.0276 1.0205 0.9768 0.9889 1.0078 0.9976 1.0051 0.9523 1.0488 0.9362 1.0024

0.9604 0.9656 0.9814 1.0058 1.0125 1.0840 1.0147 0.9556 0.9798 1.0615 1.0593 1.0341 1.0520 0.9619 0.9307 0.9407

0.338 0.711 0.111 0.948 0.873 0.056 0.826 0.458 0.798 0.024b 0.014b 0.349 0.001 b 0.015b 0.925 0.014b

1.0225 1.0115 1.0547 1.0074 0.9846

0.9779 1.0197 0.9895 0.9887 1.0499 1.0402 0.9984 0.9819 0.9571 1.0467 1.0448 1.0361 1.0698 0.9143 0.9298 0.9552

0.274 0.865 0.085 0.510 0.135 0.755 0.915 0.375 0.567 0.054 0.018b 0.830 0.009b 0.006b 0.743 0.018b

< < < > >

of differences;

1.0299 0.9958 0.9476 0.9386 0.9855 0.9780 1.0467 0.9625 1.0638 0.9488 1.0220

< <

>

b denotes that p < 0.05

AEP Results

AEP measurement

results encompassed

particular individual recordings group, respectively, In both groups depressives

a total of 16 SCH and 11 DEP patients.

are presented

together with corresponding the dispersion

in Table 3 for the SCH group and in Table 4 for the DEP group mean values and ranges.

of P300 latency

are longer, the between-group

Latency values for

difference

values

is considerably

is statistically

increase in latency with age further supports this conclusion.

insignificant

high. While

latencies

in

(~~0.05). The biological

1000

V. Medved et al.

Table 2

Hemispheric

(left-right) Differentiation of Cerebral Perfusion for each Region in the Schizophrenia (N=lS) and Depression (N=l 1) Groups

Schizophrenic

Depression

Region

Right

Left

Gyrus frontalis superior (SFl) Gyrus frontalis superior (SF2) Gyrus frontalis superior (SF3) Gyrus frontalis medialis (MF) Gyrus frontalis inferior (IF) Central region (Cl) Central region (C2) Superior parietalis (SP) Inferior parietalis (IP) Superior temporalis (ST) Inferior temporalis (IT) Superior occipitalis (SO) Inferior occipitalis (IO) Anterior basal ganglia (BG) Thalamus (TH) Hippocampus (HI)

458.8 480.2 525.1 489.8 505.1 478.8 495.1 448.5 477.7 504.0 487.9 482.0 480.2 528.2 471.4 484.7

467.9 467.8 511.1 465.1 480.7 479.3 460.3 434.4 430.5 476.8 475.5 468.9 467.1 519.3 461.3 490.5

a p denotes the degree of significance

When comparing difference

grand-averaged

> > > >

of differences;

waveforms

was found; in SCH the amplitudes

Figure 2 illustrates grand-average

>

pa 0.188 0.100 0.064 0.030b 0.091 0.953 O.OIOb 0.131 O.OOob 0.022b 0.170 0.025b 0.103 0.410 0.414 0.541

Right

Left

pa

418.8 447.6 457.0 466.8 471.4 469.4 470.8 413.9 454.6 494.2 499.3 479.2 490.4 447.4 432.2 441.9

397.2 449.1 446.1 438.8 473.0 420.7 442.0 397.5 424.9 471.4 480.0 458.9 483.0 411.8 415.4 437.6

0.129 0.880 0.252 0.021b 0.943 0.003b 0.05 1 0.172 0.092 0.043b 0.191 0.071 0.367 0.017b 0.323 0.663

> >

>

>

b denotes that p < 0.05

for each channel

between

the groups,

a systematic

(max. 3 uV, typically 2 uV) were smaller than in DEP.

waveform for the FPl electrode position.

Discussion

Methodolonical

Consideration

It is widely abnormalities. standard

accepted

that

schizophrenia

is associated

There are similar findings for depression

clinical

evaluation

methods,

in our research

with

functional

and

structural

however, they are less consistent. of schizophrenia

and unipolar

brain

In addition to depression

we

SPECT and AEPs in negative schizophrenia and unipolar depression

1001

applied two kinds of functional brain imaging techniques; data on cerebral blood metabolism was obtained by applying SPECT, and data on bioelectrical manifestation of brain function by applying AEP. It is clear that, due to the enormous complexity of CNS, it is not possible to draw direct parallels between these empirical data spaces. However, presuming that both biological measures manifest local properties reflected in the topography of the brain, it is acceptable for corresponding features be put into relation. In view of our results, both clinical entities manifested the following similar features: hypofrontality, a decrease in perfusion in the hypothalamic region bilaterally, hemispheric asymmetry, an increase in P300 latency and a decrease in P300 amplitude.

1.3

1.2

1.1

1.0

m XST-R &j XST-L

.9

.8 N=

15

15

15

Schizophrenic

15

11

11

11

H

XIT-R

m

XIT-L

11

Depressive

Fig. 1. Graphical representation of the range of normalized perfusion values in the regions superior and inferior temporalis for each patient group. The median, interquartal range (coloured) and total range are shown. * denotes numbers of patients with extreme values; ’ denotes outliers. XST-R/L denotes arithmetic mean of superior temporalis (right/left) and XIT-R/L denotes arithmetic mean of inferior temporalis (right/let?).

1002

V. Medved et al.

Table 3

Table 4

P300 Latency Values in all Measurement Recordings and Corresponding Arithmetic Means in the Schizophrenia Group

P300 Latency Values in all Measurement Recordings and Corresponding Arithmetic Means in the DepressionGroup

Patient No.

T300 lat (ms)

Patient No.

Patient No.

01 05 06 07 09 14 15 20 22 23 25 26 27 29 30 31

344 474 392 414 386 312 304 402 332 442 294 324 334 322 336 282

02 03 08 10 11 12 13 16 19 28 32

420 466 436 410 494 264 330 350 408 328 330

N=16, ~“355.9,

sb=55.8, Min=282, Max=474

a arithmetic mean; b standard deviation

At the same time, we found differences right ST region (lower perfusion

N=ll,

a arithmetic mean; b standard deviation

in brain perfusion in the IT and IO regions, bilaterally, and the

in SCH), and in the HI region, bilaterally,

perfusion in DEP). Further, grand average AEP-waveform A possible weakness

xa=385.1, sb=69.7, Min=264, Max=494

in the interpretation

and the right BG (lower

amplitudes were smaller in SCH than in DEP.

of our results may be due to the fact that the statistical

data

analysed was obtained for multiple brain regions in a limited number of subjects by applying multiple comparisons.

Brain Blood Perfusion

Although our findings for hypofrontality

in unipolar depressive

and negative schizophrenic

similar to those in the majority of existing reports, there are reports which postulate regions. If it is assumed that hypofrontality

in schizophrenia

is a convincing

hypothesis,

patients is

the role of other smaller regions

SPECT and AEPs in negative schizophrenia

and unipolar depression

1003

of interest inside the frontal cortex itself are postulated, and weak activation of dorsolateral prefrontal

cortex in both the resting state and the state of cognitive activation is found (Buchsbaum et al. 1990). Hypofrontality is associated with particular psychopathological phenomena, psychomotor poverty for instance, i.e. it is in correlation with the degree of pronounced negative schizophrenic symptoms (Medved and Petrovic 1993).

5

4

1

_________________________________________________________________

_________________________________________~~~,~~“_,~,,,__________________

SCH _3__________________________________________________________________ DEP

-4 z

“e J+ e,

% +> “se /Bp -+. -=Lc23 +& +? -%. $

--?$ ‘ie 46 ?$o %c

Time (ms)

Fig. 2. Grand average AEP curves for the schizophrenic (SCH) group and depressive (DEP) group, at the FPl electrode position.

There are also findings which indicate that hypofrontality is in remission among patients with schizophrenia with symptomatic improvement; this would indicate that that it is a state and not a trait factor @pence et al. 1998). Our findings for hypofrontality in schizophrenic patients are not consistent with the findings by Erkwoh et al. (1999) who found hypofrontality and hypertemporality to be part of the active

phase

of

schizophrenia.

During

remission

hypofrontality

partially

disappeared

and

hypertemporality disappeared completely. The question most often posed is whether hypofrontality results from the influence of disease over time or in consequence of medication. In an attempt to find an answer, the Scottish Schizophrenia Research Group (1998) found that patients displayed hypofrontality

1004

V. Medved et al.

compared to a control group in a first episode of schizophrenia prior to drug treatment. Reduced blood flow was observed after six months of antipsychotic drug treatment. Evidence from neuroimaging studies has linked negative symptoms to dysfunctional circuits in the prefrontal cortex, the limbic system and the basal ganglia (Andreasen et al. 1997, Goff and Evins 1998, Zakzanis and Heinrichs 1999, Sabri et al. 1997). However, there are studies which do not find hypofrontality (Widen et al. 1983, Wiesel et al. 1987, Cohen et al. 1989, Szechtman et al. 1988, DeLisi et al. 1989, Russel et al. 1997). Among subcortical structures, the basal ganglia is the one most often associated with schizophrenia, like in patients who have never been medicated (Sheppard et al. 1983, Hawton et al. 1990). There is less consistency in research results of regional cerebral blood flow in depression. Buchsbaum et al. (1984) first reported hypofrontality. Both a regional and a global decrease in brain metabolic activity in depressives are mentioned (Warren et al. 1984). Schroeder et al. (1989) found hypofrontality to be specific for the diagnostic spectrum which includes schizophrenia, schizoaffective psychosis and major depression. Unlike schizophrenia, which tends towards chronicity, a bipolar affective disorder is a state that alternates between disease and health, even in the absence of treatment. Blood flow and metabolic data demonstrate that major depression is accociated with reversible mood state-dependant neurophysiological abnormalities (Drevets 1998). Baxter et al. (1985) pose the question whether different affective states in the same patients also have different metabolic patterns as a consequence. Biver et al. (1994), however, find that two opposite processes occur in the frontal cortex in unipolar depression at the same time: an increase in metabolic activity in the lateral and medial area of the basal frontal cortex, and a reduction of metabolism in the dorsolateral prefrontal cortex. Neuropsychologic research in patients with frontal lesions, as well as animal studies, indicate that lesions of particular substructures of the frontal cortex cause a disturbance in various behavioural, cognitive and emotional functions (Mesulam 1986). A lesion of the dorsolateral prefrontal cortex creates a state termed “frontal retardation”, which includes apathy, a nivelation of affect, loss of interest and apragmatisme. Our findings for bilateral hypofrontality are consistent with the actual concept (Grasby 1999, Drevets 1998), and partially consistent with the findings by Kishimoto et al. (1998) who found hypometabolism

in the let?

anterolateral prefrontal cortex in patients with unipolar and bipolar depression. In a more elaborate study by (Galynker et al. 1998), which examined the relations between regional cerebral flow, depressive symptoms and negative symptoms in patients with major depressive disorder, decreased perfusion in the left dorsolateral prefrontal cortex was found to be related to negative symptoms, in particular. The study by Klemm et al. (1996) found left temporal and left frontal hypoperfusion in 17 patients

SPECT and AEPs in negative schizophrenia with schizophrenia

and unipolar depression

1005

and 12 patients with major depression in concordance with our model of limbic and

frontal dysfunction. In our research in the SCH group, significant asymmetry appeared in regions MF, C2, IP, SO and ST.

The first four regions all belong to the third level, which reflects a significant hypoperfusion of the left hemisphere exactly at this anatomical location. In the DEP group significant asymmetry was found in regions MF, Cl, ST and BG, where a different, more “vertically” oriented anatomical pattern of hypoperfusion of the left hemisphere can be seen. Furthermore, brain laterality in schizophrenia and depression was demonstrated in our research. In general, literature implies abnormalities in the activity of the left hemisphere in schizophrenic patients (Gur and Chin 1999), but the notion of lateralization in connection with depression is uncommon. In addition to this, our finding of hypoactivity in the hypothalamic region in schizophrenic patients has confirmed findings by Min et al. (1999) who have shown that a significant correlation exists between negative symptoms and a decreased level in perfusion in the left thalamic region.

Auditorv Evoked Potentials

From a psychological point of view, prolongation of P300 may be interpreted as a decrease of cognitive processing speed (Cobum et al. 1998). Prolonged latency may indicate the neurodegenerative nature of brain processes since it occurs in dementia, but also during normal ageing (O’Donnell et al. 1995). In our research, the AEPs provided subtle differentiation between groups; P300 latencies were prolonged in both groups examined, consistent with an increase in the P300 latency in schizophrenic and depressive patients (Weir et al. 1998, Laurent et al. 1999), while schizophrenic patients displayed smaller amplitudes as reported by Salisbury et al. (1998), and negative symptoms are related to an increase in latency (Keefe et al. 1991). However, Wagner and colleagues have found that there are no significant differences in the amplitudes of P300 averaged signals between schizophrenic and depressive subjects (Wagner et al. 1997). A reduced P300 amplitude coincides with the diagnosis of schizophrenia, however, severely afIJ.icted patients had smaller P3OOs than those moderately ill. Among moderately ill patients, P300 was related to symptom withdrawal. A sophisticated study designed by Shajahan et al. (1997) examined schizophrenic patients while performing an auditory two-tone oddball discrimination task using SPECT. Patients activated the left superior temporal gyrus during the task, as well as the right caudate. There was a negative correlation

V. Medved et al.

1006

between the P300 amplitude and perfusion during the activation procedure in both caudate nucleii and in the left lingual gyrus. No P300 latency correlations

were observed and there was no frontal activation

during the task. In general, reduction in frontal and thalamic rcBF may be more likely in patients with an impoverished mental status. Patterns

of cerebral

dysfunction

in schizophrenia

and depression

topographically

show

partial

similarity. It may be assumed that lesion patterns have a common topography in part, whereas they do not necessarily

share a common physiology.

depression

is an interesting

question

The nature of physiological which

remains

dysfunction

to be answered

through

in schizophrenia the development

and of

functional brain imaging studies.

Conclusion

In the two disorders the measured brain blood perfusion was found to be similar, with differences appearing only in certain brain regions. Hypoperfusion

of the left hemisphere

was found in both groups.

AEPs led to the detection of a general decrease in cognitive process speed in both disorders, increase in latency. AEP amplitudes depressives.

were found to be smaller in the schizophrenia

These findings may bear to both clinical and neuro-scientific

through an

group than among

relevance which will need to be

studied in future.

References

AMERICAN PSYCHIATRIC ASSOCIATION (1987) DSM-III: Diagnostic and Statistical Manual of Mental Disorders. 3rd rev. edn. American Psychiatric Press, Washington, DC. ANDREASEN, N.C. (1983) Scale for the Assessment of Negative Symptoms (SANS). University of Iowa. ANDREASEN, N.C., O’LEARY D.S., FLAUM, M., NOPOULOS, P., WATKINS, G.L., BOLES PONTO L.L. and HICHWA, R.D. (1997) Hypofrontahty in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 349 (9067): 1730-1734. BAXTER jr., W.E., PHELPS, M.E., MAZZIOTTA, J.C., SCHWARTZ, J.M., GERNER, R.H., SELIN, C.E. and SUMIDA, R.M.(1985) Cerebral metabolic rates for glucose in mood disorders studied with positron emission tomography (PET) and (F-18)-fluoro-2-deoxyglucose (FDG). Arch. Gen. Psychiatry 42: 441-447.

SPECT and AEPs in negative schizophrenia

and unipolar depression

1007

BIVER, F., GOLDMAN, S., DELVENNE, V., LUXEN, A., DeMAERTELAER, V., HUBAIN, P., MENDELEWICZ, J. and LOTSTKA, T. (1994) Frontal and parietal metabolic disturbances in unipolar depression. Biol. Psychiatry 36: 381-388. BOERINGA, J.A. and CASTELLANI, S. (1982) Reliability and validity of emotional blunting as a criterion for diagnosis of schizophrenia. Am. J. Psychiatry 139: 133 I- 1335. BUCHSBAUM, M.S., DeLISI, L.E., HOLCOMB, H.H., CAPPELLETTI, J., KING, AC., JOHSON, J., HAZLETT, E., DOWLING-ZIMMERMAN, S.,POST, R.M., MORIHISA, J., CARPENTER, W., COHEN, R., PICKAR, D.,WEINBERGER, D.R.,MARGOLIN, R. and KESSLER, R.M. (1984) Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders. Arch. Gen. Psychiatry 41: 1159-l 170. BUCHSBAUM, M.S., NEUCHTERLEIN, K.H. and JAAIER, R.J. (1990) Glucose metabolic rate in normals and schizophrenics during the continuous performance test assessed by positron emission tomography. Brit. J. Psychiatry 156: 216-227. COBURN, K.L., SHILLCUTT, S.D., TUCKER, K.A., ESTES, K.M., BRIN, F.B., MERAI, P. and MOORE, N.C. (1998) P300 delay and attenuation in schizophrenia: Reversal by neuroleptic medication. Biol. Psychiatry 44: 466-474. COHEN, M.B., CAKE, R.R. and GRAHAM, L.S. (1989) Quantitative iodine-123 IMP imaging of brain perfusion in schizophrenia. J. Nucl. Med. 30: 1616-1620. CHUA, S.E. and McKENNA, P.J. (1995). Schizophrenia - a brain disease? Br. J. Psychiatry 166: 563582. DeLISI, L.E., BUCHSBAUM, MS. and HOLCOMB, H.N. (1989) Increased temporal lobe glucose use in chronic schizophrenic patients. Biol. Psychiatry 25: 835-851. DINER, B.C., HOLCOMB, P.J. and DYKMAN, R. (1985) P300 in major depressive disorder. Psychiatr. Research Is: 175-184. DREVETS, W.C. (1998) Functional neuroimaging studies of depression: the anatomy of melancholia. Annu. Rev. Med. 49: 341-361. EBMEIER K.P, BLACKWOOD H.R, MURRAY, C., SOUZA, V., WALKER, M., DOUGALL, N., MOFFOOT, A.P.R., O’CARROLL, R.E. and GOODWIN, G.M. (1993) Single-photon emission computed tomography with ggmTc-exametazine in unmedicated schizophrenic patients. Biol. Psychiatry 33; 487-495. ERKWOH, R., SABRI, O., WILLMES, K., STEINMEYER, E.M., BULL, U. and SASS, H. (1999) Active and remitted schizophrenia: psychopathological and regional cerebral blood flow findings. Psychiatry Res. m: 17-30. GALYNKER, II., CAI, J., ONGSENG, F., FINESTONE, H., DUTTA, E. and SERSENI, D. (1998) Hypofrontality and negative symptoms in major depressive disorder. J. Nucl. Med. 39: 608-612. GOFF, D.C. and EVINS, A.E. (1998) Negative symptoms in schizophrenia: neurobiological models and treatment response. Harv. Rev. Psychiatry m: 59-77. GRASBY, P.M. (1999) Imaging strategies in depression. J. Psychopharmacol. w: 346-351. GUR, R.E. and CHIN, S. (1999) Laterality in functional brain imaging studies of schizophrenia. Schizophr. Bull. m: 141-156. HAMILTION, M. (1960) A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 2: 56-62. HAWTON, K., SHEPSTONE, B. and SOPER, N. (1990) Single photon emission computerised tomography (SPECT) in schizophrenia. Br. J. Psychiatry 35: 27-38. KEEFE, R.S.E., LOBEL, D.S., MOHS, R.C., SILVERMAN, J.M., HARVEY, P.D., DAVIDSON, M., LOSONCZY, M. and DAVIS, K.L. (1991) Diagnostic issues in chronic schizophrenia: Kraepelinian schizophrenia, undifferentiated schizophrenia, and state-independent negative symptoms. Schizopbr. Res. 4: 71-79. KISHIMOTO, H., YAMADA, K., ISEKI, E., KOSAKA, K. and OKOSHI, T. (1998) Brain imaging of affective disorders and schizophrenia. Psychiatry Clin. Neurosci. 52 Suppl:S212-S214. KITAMURA, T. and SUGA, R. (1991) Depressive and negative symptoms in major psychiatric disorders. Compr. Psychiatry 22: 88-94.

1008

V. Medved et al.

KLEMM, E., DANOS, P., GRUNWALD, F., KASPER, S., MOLLER, H.J. and BIERSACK, H.J. (1996) Temporal lobe dysfunction and correlation of regional cerebral blood flow abnormalities with psychopathology in schizophrenia and major depression - a study with single photon emission computed tomography. Psychiatry Res. w: l-10. LAURENT, A., GARCIA-LARREA, L., d’AMAT0, T., BOSSON, J.L., SAOUD, M., MARIECARDINE, M., MAUGIERE, F. and DALERY, J. (1999) Auditory event-related potentials and clinical scores in unmedicated schizophrenic patients. Psychiatry Res. m: 229-238. MEDVED, V. (1995) Topographic differentiation between schizophrenia and depression with respect to auditory evoked potentials and regional cerebral flow. Ph.D. Thesis. Zagreb: Medical School, University of Zagreb. (in Croatian). MEDVED, V. and PETROVIC, D. (1993) Brain metabolism quantification in psychiatric research. Period. Biol. 95: 133-135. MESULAM, M. (1986) Frontal cortex and behavior. Ann. Neurol. 19: 320-325. MM, S.K., AN, S.K., JON, D.I. and LEE, J.D. (1999) Positive and negative symptoms and regional cerebral perfusion in antipsychotic-nafve schizophrenic patients: A high-resolution SPECT study. Psychiatry Res. m: 159-168. MOLINA, R.W., MONTZ, A.R., PEREZ, C.M.J., GUTIERREZ, L.R.,.FERRE,N.F., CARREAS, D.J.L. and RUBIA, V.F.J. (1997) Cerebral perfusion correlates of negative symptomatology and parkinsonism in a sample of treatment-refractory schizophrenics: An exploratory 99mTc-HMPAO SPECT study. Schizophr. Res. 2: 1 l-20. O’DONNELL, B.F., FAUX, SF., McCARLEY, R.W., KIMBLE, M.O., SALISBURY, D.F., NESTOR, P.G., KIKINIS, R., JOLESZ, F.A. and SHENTOM, M.E. (1995) Increased rate of P300 latency prolongation with age in schizophrenia. Arch. Gen. Psychiatry 2: 544-549. OGURA, A., MORINOBU, S., KAWAKATSU, S., TOTSUKA, S. and KOMATANI, A. (1998) Changes in regional brain activity in major depression after successful treatment with antidepressant drugs. Acta Psychiatr. Stand. 98: 54-59. REGAN, D. (1987) Human Brain Electrophysiology. Evoked Potentials and Evoked Magnetic Fields in Science and Medicine. New York-Elsevier. RUSSEL, J.M., EARLY, T.S., PATTERSON, J.C., MARTIN, J.L., VILLANUEVA-MEYER, J. and MCGEE, M.D. (1997) Temporal lobe perfusion asymmetries in schizophrenia. J. Nucl. Med. w: 607-612. SABRI, O., ERKWOH, R., SCHRECKENBERGER, M., CREMERIUS, U., SCHULZ, G., DICKMANN, C., KAISER, H.J., STEINMEYER, E.M., SASS, H. and BUELL, U. (1997) U. Regional cerebral blood flow and negative/positive symptoms in 24 drug-naive schizophrenics. J. Nucl. Med. m: 181-188. SALISBURY, D.F, SHENTON, M.E, SHERWOOD, A.R, FISCHER, LA, YURGELUN-TODD, D.A, TOHEN, M. and McCARLEY, R.W. (1998) First-episode schizophrenic psychosis differs from lirstepisode affective psychosis and controls in P300 amplitude over left temporal lobe. Arch. Gen. Psychiatry 3: 173-180. SCHROEDER, J., SAUER, H., WILHELM, K.R., NIEDERMEIER, T. and GEORGI, P. (1989) Regional cerebral bloof flow in endogenous psychoses: A Tc 99m HMPAO-SPECT pilot study. Psychiatry Res. 29: 331-333. SCOTTISH SCHIZOPHRENIA RESEARCH GROUP (1998). R e g ional cerebral blood flow in Iirstepisode schizophrenia patients before and after antipsychotic drug treatment. Acta Psychiatr. Stand. 97: 440-449. SHAJAHAN, P.M., GLABUS, M.F., BLACKWOOD, D.H. and EBMEIER, K.P. (1997) Brain activation during an auditory ‘oddball task’ in schizophrenia measured by single photon emission tomography. Psychol. Med. m: 587-594. SHEPPARD, G., GRUZELIER, J. and MANCHANDA, R. (1983) Positron emission tomographic scanning in predominantly never-treated acute schizophrenioc patients. Lancet 2: 1448-1452.

SPECT and AEPs in negative schizophrenia SPENCE,

and unipolar depression

1009

S.A., HIRSCH, S.R., BROOKS, D.J. and GRASBY, P.M. (1998) Prefrontal cortex activity in people with schizophrenia and control subjects. Br. J. Psychiatry 172: 3 16-323. SZECHTMAN, N., NAHMIAS, C. and GARNE’IT, S. (1988) Effect of neuroleptics on altered cerebral glucose metabolism in schizophrenia. Arch. Gen. Psychiatry 45: 523-532. VANDOOLAEGHE, E., van HUNSEL, F., NUYTEN, D. and MAES, M. (1998) Auditory event related potentials in major depression: prolonged P300 latency and increased P200 amplitude. J. Affect. Disord. 48: 105-l 13. VASILE R.G., SCHWARTZ R.B., GARADA, B., LEONARD HOLMAN, B., ALPERT, M., DAVIDSON, P.B. and SCHILDKRAUT, J.J. (1996) Focal cerebral perfusion defects demonstrated by ggmTc-hexamethylpropyleneamine oxime SPECT in elderly depressed patients. Psychiatry Res.: Neuroimaging 67: 59-70. WAGNER, P., ROSCHKE, J., FELL, J. and FRANK, C. (1997) Differential pathophysiological mechanisms of reduced P300 amplitude in schizophrenia and depression. Schizophr. Res. m: 221229. WARREN, L.R., BUTLER, R.W., KATHOLI, C.R., MCFARLAND, C.E., CREWS, E.L. and HALSEY jr, J.H. (1984) Focal changes in cerebral blood flow produced by monetary incentive during a mental mathematics task in normal and depressed subjects. Brain Cogn. 3: 71-85. WEIR, N., FIASCHI, K. and MACHIN, D. (1998) The distribution and latency of the auditory P300 in schizophrenia and depression. Schizophr. Res. 3 1(2-3): 15 1- 158. WIDEN, L., BLOMQVIST, G. and GREITZ, T. (1983) PET studies of glucose metabolism in patients with schizophrenia. Am. J. Neurol. 3: 550-552. WIESEL, F.A., WIK, G., SJOGREN, I., BLOMQUIST, G., GREITZ, T. and STONE-ELANDER, S. (1987) Regional brain glucose metabolism in drug free schizophrenic patients and clinical correlates. Acta Psychiatr. Stand. 76: 628-641. WHITEFORD, H.A., RINEY, S.J. and CSERNANSKY, J.G. (1987) Distinguishing depressive and negative symptoms in chronic schizophrenia. Psychopathology 20: 234-236. ZAKZANIS, K.K. and HEMRICHS, R.W. (1999) Schizophrenia and the frontal brain: A quantitative review. J. Int. Neuropsychol. Sot. m: 556-566.

Inquiries and reprint requests should be addressed to:

Dot. dr. Vesna Medved Psychiatric Clinic University Clinical Hospital Centre Rebro KiSpatiCeva 12 10000 Zagreb Croatia