Psychophysiological indices of Psychophysiological indices of patients with patients with psychotic major psychotic major depressiondepression as compared with as compared with delusional misidentification delusional misidentification syndromessyndromes: A P300 study.: A P300 study.

Ch. PapageorgiouCh. Papageorgiou11, E. Ventouras, E. Ventouras22, G.N. , G.N. ChristodoulouChristodoulou11

11 Department Of Psychiatry, Eginition Hospital, Medical School, Department Of Psychiatry, Eginition Hospital, Medical School, Uninersity of Athens, Greece Uninersity of Athens, Greece

22Department of Medical Instrumentation Technology, Tecnological Department of Medical Instrumentation Technology, Tecnological Educational Institution of Athens, GreeceEducational Institution of Athens, Greece

IntroductionIntroduction• A variety of considerations indicate a close association between psychotic major depression (PMD)

and delusional misidentification syndrome (DMS). Parenthetically, the delusional misidentification he delusional misidentification syndromes (DMS) including the Capgras, the Frégoli, and intermetamorphosis syndrome, are syndromes (DMS) including the Capgras, the Frégoli, and intermetamorphosis syndrome, are characterized by a misidentification delusion of the self or others (Christodoulou 1991).characterized by a misidentification delusion of the self or others (Christodoulou 1991).

• Both entities are presened with delusions (Munro, 2000) and dopamine overactivity is an essential biological substrate of delusional symptoms, for both disorders(Roane et al., 1998; Wood et al., 2002), while antipsychotic medication is effective in treating this symptomatology (Mulsant et al., 1997; Zanker, 2000).

• In a clinical level of analysis both entities demonstrate frequently aggression (Silva et al., 1995; Silva et al., 1997; Brdsky et al., 2001).

• The right hemispheric function and/or interhemispheric transmission has been implicated in the pathogenesis of both nosological entities (Taiminen et al., 2000; Dejode et al., 2001).

• Psychological and especially psychodynamic viewpoints attribute a decisive pathogenetic role to the defence mechanisms splitting and projection for both entities, hypothesizing that this results from ambivalent feelings, induced by overintense affect towards significant others. (Zanker, 2000)

• Here it should be emphasized that recently the significance of psychodynamic suggestions has been weakened owing to the fact that a high proportion of cases of both disorders exhibit significant brain pathology.

• Thus, it seems to be a need for a differential diagnosis in such cases.

• Event-related potentials (ERPs) provide a valuable Event-related potentials (ERPs) provide a valuable means for studying brain-behavior relations (Fabiani means for studying brain-behavior relations (Fabiani et al., 2000). et al., 2000).

• The P300 component of ERPs is thought to reflect The P300 component of ERPs is thought to reflect attentional operation resource when working attentional operation resource when working memory (WM) updating is engaged (Kok, 2001). memory (WM) updating is engaged (Kok, 2001).

• In this context it is worth noting that contemporary In this context it is worth noting that contemporary neuropsychological views define WM as the capacity to keep neuropsychological views define WM as the capacity to keep information ‘on-line’, as necessary for an ongoing task (Baddeley, information ‘on-line’, as necessary for an ongoing task (Baddeley, 1998; Collette and Van der Linden, 2002). 1998; Collette and Van der Linden, 2002).

• In other words, WM is not for ‘memorizing’ per se. It is rather in In other words, WM is not for ‘memorizing’ per se. It is rather in the service of complex cognitive activities, such as reasoning, the service of complex cognitive activities, such as reasoning, problem solving and decision making (Miyake and Shah, 1999; problem solving and decision making (Miyake and Shah, 1999; Glassman, 2000).Glassman, 2000).

Concerning ERP measures in PMD, Santosh et al., (1994), using an ‘oddball’ paradigm, reported that PMD patients showed an attenuation of the P300 amplitude varying in accordance with the severity of psychotic features.

They suggested that smaller P300 amplitude may be a state marker in depression and a trait marker in schizophrenia.

It is notable in this regard that there are studies reporting that PMD patients exhibit deficits of working memory (Pelosi et al., 2000; Slade et al., 2000)

We reported recently (Papageorgiou et al., 200We reported recently (Papageorgiou et al., 20033), that DMS ), that DMS patients, as compared to healthy controls, showed reduced P300 patients, as compared to healthy controls, showed reduced P300 amplitude at right prefrontal region and prolonged latency of amplitude at right prefrontal region and prolonged latency of P300 located at central midline brain area. These findings suggest P300 located at central midline brain area. These findings suggest that surface-recorded event-related potentials may be useful for that surface-recorded event-related potentials may be useful for detecting and monitoring the changes in brain function associated detecting and monitoring the changes in brain function associated with DMS.with DMS.

In view of the above considerations,In view of the above considerations,

it was thought that electrophysiological brain activity, as it was thought that electrophysiological brain activity, as reflected by the P300, in association with WM operations, reflected by the P300, in association with WM operations, could be of value in identifying or discerning possible could be of value in identifying or discerning possible common pathophysiological mechanisms involved in PMD common pathophysiological mechanisms involved in PMD and DMS, and DMS,

and also in evaluating the extent to which such mechanisms and also in evaluating the extent to which such mechanisms may differentiate these two conditions.may differentiate these two conditions.

MMaterials and methodsaterials and methods

  Age Education Medication DurationOf Illness

PMDN=15, (F=8,M=7)

33.7 5.4 years

12.7 2.4years

11 patients= drug free*

8.1 4.4years

DMSN=9 (F=5,M=4)

34.9 7 years

12.9 2.7years

6 patients = drug free**

7.3 4.3years

Healthy controlsN=11, (F=6,M=5)

34.2 6.8 years

13.2 2.5 years

 

• The DMS patients were studied during their delusional The DMS patients were studied during their delusional episode. The sample of patients included four patients episode. The sample of patients included four patients suffering from Capgras syndrome, two patients from suffering from Capgras syndrome, two patients from Frégoli syndrome, two from coexisting Capgras and Frégoli Frégoli syndrome, two from coexisting Capgras and Frégoli syndrome and one patient suffering from Frégoli syndrome syndrome and one patient suffering from Frégoli syndrome and intermetamorphosis. All patients were psychotics of and intermetamorphosis. All patients were psychotics of paranoid type according to DSM-IV criteriaparanoid type according to DSM-IV criteria

• * Medicated DMS patients have taken medication as * Medicated DMS patients have taken medication as follows: The first patient trifluoperazine (30mg/day) + follows: The first patient trifluoperazine (30mg/day) + carbamazepine (600mg/day), the second patient carbamazepine (600mg/day), the second patient risperidone (8mg/day) + gabapentinrisperidone (8mg/day) + gabapentin (800mg/day) and the (800mg/day) and the third patient olanzapine (20mg/day) + oxcarbazepine third patient olanzapine (20mg/day) + oxcarbazepine (600mg/day). (600mg/day).

• **** Three PMD patients Three PMD patients have taken medication as follows: have taken medication as follows: the first patient risperidone (8mg/day) + paroxetine the first patient risperidone (8mg/day) + paroxetine (20mg/day), the second patient olanzapine (10mg/day) + (20mg/day), the second patient olanzapine (10mg/day) + venlafaxine (150mg/day), and the third (olanzapine venlafaxine (150mg/day), and the third (olanzapine 20mg/day) + fluoxetine (20mg/day).20mg/day) + fluoxetine (20mg/day).

Experimental procedureExperimental procedure

Time period Action

AB (100 msec) Administration of warning stimulus (500 or 3000 Hz, 65dB).

AC (1100 msec) Recording of ERPs.

CD (varies) Computerized administration of the set of numbers of the Wechsler Direct Auditory Memory Test. The duration of this period varies depending upon the numbers of digits to be recalled in each trial (from 2 to 9 digits across trials). The time interval between administered digits is 1 sec.

DE (100 msec) Repetition of the warning stimulus.

EF (varies between 15 and 30 sec)

Recording of the memory recall performance, according to the accuracy of responses.

V20

V20

550 msec

Grand average ERP waveforms of the DMS group (red line), the PMD group (blue line) and the normal controls group (black line), at each lead.

Controls PMD DMS

Fp1 16.5±6.2 a 10.3±5.6 a 9.2±10.3 a

F3 16.7±4.6 a 9.2±6.6 b 9.6±7.4 ab

C3-T5/2 12.2±3.4 a 8.9±4.4 a 8.4±6.6 a

C3 15.8±5.4 a 11.9±3.7 a 12.1±7.5 a

Fp2 16.3±5.6 a 10.2±5.3 b 5.9±5.7 b

F4 16.7±4.6 a 11.9±3.1 b 7.2±4.9 c

C4-T6/2 11.0±4.9 a 10.6±2.6 a 6.2±5.8 a

C4 14.0±4.3 a 14.0±2.9 a 8.8±4.1 b

O1 8.5±4.3 a 6.9±6.6 a 9.5±5.2 a

O2 7.2±3.8 a 9.1±3.8 a 10.5±5.8 a

P4 10.2±4.7 a 12.2±4.3 a 9.6±5.2 a

P3 11.9±4.0 a 12.2±3.4 a 11.7±9.3 a

Pz 15.0±4.8 a 14.9±6.1 a 10.7±6.2 a

Cz 17.7±6.0 a 14.1±4.6 a 11.8±5.5 a

Fz 19.5±5.7 a 12.8±4.3 b 8.7±6.7 b

Mean values (±S.D.) in microVolts of the P300 amplitudes for the three groups at each lead. Groups which differ significantly (post-hoc Bonferroni pairwise comparisons, p<0.05) are indicated by the different letters.

Comparison of P300 amplitudesComparison of P300 amplitudes

• Stepwise discriminant analysis applied for the distinction of the Stepwise discriminant analysis applied for the distinction of the three groups, based on the P300 amplitude values, revealed two three groups, based on the P300 amplitude values, revealed two canonical discriminant functions, which correctly classified 80% of canonical discriminant functions, which correctly classified 80% of the cases. the cases.

• The first function is correlated with lead F4 (r=0.806) and, The first function is correlated with lead F4 (r=0.806) and, discriminates the control group from both patient groups. discriminates the control group from both patient groups.

• The second function correlates with lead C4 (r=0.941) and The second function correlates with lead C4 (r=0.941) and discriminates the psychotic depressive group from the DMS group. discriminates the psychotic depressive group from the DMS group.

• Post-hoc Bonferroni comparisons of the discriminant scores derived Post-hoc Bonferroni comparisons of the discriminant scores derived from the two functions confirm the above results.from the two functions confirm the above results.

Mean values in microVolts of the P300 amplitudes for the three groups at each lead. The first group are the controls (white bars), the second group are the PMD group (spotted bars), and the third group are the DMS group (striated bars). An asterisk denotes statistically significant difference between the controls and the PMD group, a triangle indicates the differences between the controls and the DMS group, and a rhombus that between PMD and the DMS groups. Statistically significant differences were computed on the basis of Bonferroni pairwise comparisons.

Fp1

F3

C3-T5/2

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P4P3 Pz

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Fz

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Front

Back

Left Right

5μV

20μV

Controls PMD DMS

Fp1 274±30 a 306±62 a 370±83 b

F3 251±17 a 309±61 ab 354±86 b

C3-T5/2 278±34 a 299±29 ab 336±79 b

C3 269±33 a 297±28 a 368±81 b

Fp2 261±26 a 299±40 ab 354±87 b

F4 256±24 a 294±30 a 355±88 b

C4-T6/2 290±77 a 306±17 a 348±75 a

C4 283±60 a 296±24 ab 357±90 b

O1 320±96 a 337±66 a 390±76 a

O2 357±82 a 332±49 a 363±82 a

P4 312±85 a 325±50 a 374±73 a

P3 270±35 a 311±44 a 372±77 b

Pz 269±35 a 312±39 a 373±80 b

Cz 246±15 a 284±31 a 364±82 b

Fz 250±17 a 289±30 a 352±88 b

Mean values (±S.D.) in msec of the P300 latencies for the three groups at each lead..If two groups do not differ significantly at a specific lead then they have the same letter (a or b) next to their values, while different letters indicate groups which differ significantly (post-hoc Bonferoni paiwise comparisons, p<0.05).

Comparison of P300 latenciesComparison of P300 latencies

• The same stepwise discriminant analysis, applied to distinguish the three The same stepwise discriminant analysis, applied to distinguish the three groups based on the P300 latency values, revealed only one canonical groups based on the P300 latency values, revealed only one canonical discriminant function, which however correctly classified 71.4% of the discriminant function, which however correctly classified 71.4% of the cases. cases.

• The function is formed from the latency values of Cz alone.The function is formed from the latency values of Cz alone. This is due to This is due to the fact that latencies are highly correlated with each other. Post-hoc the fact that latencies are highly correlated with each other. Post-hoc Bonferroni comparisons of the discriminant scores derived from the Bonferroni comparisons of the discriminant scores derived from the function revealed statistically significant differences between the DMS function revealed statistically significant differences between the DMS group and the two other groups. group and the two other groups.

Mean values in msec of the P300 latencies for the three groups at each lead. The first group are the controls (white bars), the second group are the PMD group (spotted bars), and the third group are the DMS group (striated bars). An asterisk denotes statistically significant differences between the controls and the PMD group, a triangle indicates the difference between the controls and the DMS group and a rhombus that between PMD and the DMS groups. Statistically significant differences were computed on the basis of Bonferroni pairwise comparisons.

Fp1

F3

C3-T5/2

O1

Fp2

F4

C4-T6/2

C4

O2

C3

P4P3 Pz

Cz

Fz

240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

1 2 3

240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

1 2 3

240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

1 2 3

240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

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240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

1 2 3

240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

1 2 3

240245250255260265270275280285290295300305310315320325330335340345350355360365370375380385390395400

1 2 3

Front

Back

Left Right

240msec

400mse

• Comparison of memory performance Comparison of memory performance

Post-hoc tests revealed that both patient groups Post-hoc tests revealed that both patient groups had significantly attenuated memory performance had significantly attenuated memory performance compared with healthy controls (p < 0.001, F = compared with healthy controls (p < 0.001, F = 9.31, d.f. = 32), whereas there were no significant 9.31, d.f. = 32), whereas there were no significant differences between the two patient groups. The differences between the two patient groups. The mean values and the standard deviation (S.D.) for mean values and the standard deviation (S.D.) for the three groups, i.e. DMS, PMD and control, were the three groups, i.e. DMS, PMD and control, were 54.4 ± 7.2, 56.06 ± 9.96 and 68.0 ± 4.5, 54.4 ± 7.2, 56.06 ± 9.96 and 68.0 ± 4.5, respectively. More than 149 digits were presented.respectively. More than 149 digits were presented.

DiscussionDiscussion• The amplitude of P300 component is considered as The amplitude of P300 component is considered as

sensitive measure of attentional operation when WM sensitive measure of attentional operation when WM updating is engaged (Coull, 1998; Kok, 2001). updating is engaged (Coull, 1998; Kok, 2001).

• It is believed that frontal generators are more involved in It is believed that frontal generators are more involved in automated orienting, automated orienting, while temporoparietal generators are while temporoparietal generators are more responsive in effortful responding to evoked stimuli more responsive in effortful responding to evoked stimuli (Winterer et al., 2001). (Winterer et al., 2001).

• The reduction in P300 amplitude is also thought to reflect The reduction in P300 amplitude is also thought to reflect gray matter abnormalities (Martin-Loeches et al., 2001). gray matter abnormalities (Martin-Loeches et al., 2001).

Consequently, the obtained pattern of differences in the amplitude of P300 could imply that both DMS patients and patients suffering from PMD may be associated with defects in the WM, being connected to the automatic nature of information processing and mediated by the right frontal area.

With regard to PMD patients, our results appears to be in agreement with recent studies (Santosh et al., 1994; Pelosi et al.,

2000; Slade et al., 2000), indicating that the dysfunction of these brain areas may be implicated in PMD.

Within this framework, it is worth noting that current brain models of emotion processing hypothesize that positive (or approach-related)

emotions are lateralized towards the left hemisphere, whereas negative (or withdrawal-related) emotions are lateralized towards the right

hemisphere (Fossati et al., 2003).

Similarly, as far as the DMSs are concerned, there are also studies providing evidence of dysfunctional connections among frontal cortex,

multimodal association areas and paralimbic structures, resulting in cognitive-perceptual-affective dissonance, which under specific

conditions may lead to positive delusional formation (Fleminger and Burns, 1993; Paillere-Martinot et al., 1994; Mentis et al., 1995; Feinberg,

1997; Joseph et al., 1999).

The two disorders appear to be distinguishable with regard to the ‘effortful’ nature of information processing involving or affecting the right parietal area.In this case the DMS group is afflicted.

The importance of this finding may be better understood considering anatomicoclinical evidence indicating that activation of this region during working memory tasks has conceived responsible for the coordination of concurrent processing of disparate sensory and cognitive events [Collette F& Van der Linden, 2002].

In this context it is reasonable to keep in mind that lesion studies [Karnath, 2001 ] indicate that this region plays a crucial role in spatial neglect.

However, it would be useful to discuss the specificity of the attenuation of the P300 amplitude with respect to other psychiatric disorders. Alcoholics also exhibit attenuated P300 (Enoch et al., 2001), as do schizophrenics (Mathalon et al., 2000) and Alzheimer patients (Daffner et al., 2001).

An alternative explanation may be that these nonspecific abnormalities are mediated by complex brain networks, requiring the integration of multiple cognitive activities involving multiple brain areas (Tracy, 1995).

Moreover, these nonspecific findings may indicate that, in addition to disease-specific processes, disease general processes exist, which could represent ‘an ordered pathway in the brain’s adaptation to many central nervous system diseases’ (Tracy, 1995).

The P300 latency is considered to be a measure of stimulus classification speed (Polich, 1986), reflecting the rapidity of allocation of attentional resources for memory processing (Polich and Martin, 1992; Reinvang, 1999).

Thus, it has been argued that prolonged P300 latency may reflect a failure to allocate attention resources to a stimulus (Coull, 1998; Polich, 1998).

From a neurobiological point of view, prolonged latency may also suggest the involvement of a neurodegenerative process (O’Donnel et al., 1995; Wang et al., 2003), affecting callosal size and the efficiency of inter-hemispheric transmission (Hoffman and Polich, 1999).

Therefore, the differences reported here could imply that DMS patients may have difficulties in allocating attention resources to a stimulus,

possibly due to a neurodegenerative process, involving or affecting an impaired interhemispheric transmission.

This assumption seems to be broadly consistent with the study from Shah et al. (2001), who, exposing healthy volunteers to familiar and unfamiliar faces and voices and employing functional MRI technique, recorded increased activity in the posterior cingulate cortex and the

bilateral retrosplenial cortex.

Based on these findings they suggested that this brain circuitry would account for the judgment of familiarity, which is a substantial issue of

DMS.

Our hypothesis is also compatible with observations in the classic disconnection syndrome called pure word blindness or alexia without agraphia, resulting from disruption of the corpus callosum, which interconnects the two hemispheres (Nolte, 1999).

Patients with this rare condition can write (thus no agraphia) but are unable to read (alexia) even words they have just finished writing. Additionally, this assumption is supported by the study of Sergent (1990), who found that callosal defects may be involved in DMS processes.

• The memory performance of the two groups was significantly The memory performance of the two groups was significantly compromised. This agrees with studies reporting that both DMS compromised. This agrees with studies reporting that both DMS patients and PMD patients show memory deficits (Feinberg et al., patients and PMD patients show memory deficits (Feinberg et al., 1999; Verdoux and Liraud, 2000). 1999; Verdoux and Liraud, 2000).

ConclusionConclusion

• Our results should be interpreted with caution due to the Our results should be interpreted with caution due to the smallness of the test sample and that post-hoc assignation smallness of the test sample and that post-hoc assignation of psychological function to regional activation is of psychological function to regional activation is hypothetical. hypothetical.

• Future studies attending to these issues are warranted to Future studies attending to these issues are warranted to build on these initial findings indicating that PMD and DMS build on these initial findings indicating that PMD and DMS patients share similar psychophysiologic alterations connected to patients share similar psychophysiologic alterations connected to the right frontal region, mediating automatic processes, while DMS the right frontal region, mediating automatic processes, while DMS are associated with dysfunction of effortful mechanisms and are associated with dysfunction of effortful mechanisms and allocation of attentional resources involving the right parietal allocation of attentional resources involving the right parietal and the interhemispheric circuitry. and the interhemispheric circuitry.