DELUSIONAL MISIDENTIFICATION SYNDROMES II

Novel approaches in delusional misidentification syndromes (DMS): Psychophysiological findings. Ch. Papageorgiou, G.N. Christodoulou Department Of Psychiatry, Eginition Hospital, Medical School, Uninersity of Athens, Greece Introduction • The delusional misidentification syndromes (DMS) including the Capgras, the Frégoli, and intermetamorphosis syndrome, are characterized by a misidentification delusion of the self or others (Christodoulou 1991). dissociation between recognition and identification processes, associated with defects in the right hemispheric function and/or interhemispheric transmission (Edelstyn and Oyebode, 1999; Joseph et al. 1999 ; Luaute and Bidault, 1994; Mentis et al., 1995). • It has been suggested that the disturbance in DMS is a • It is debatable whether the key features of DMS are specific to this condition or are common to other psychiatric disorders, particularly schizophrenia (Munro 2000). Consequently, while they are considered to be part of the paranoid spectrum, DMS are not included in DSM-IV or ICD-10 as a distinct disorder. • The brain mechanisms underlying these disorders have not as yet been clarified since their pattern and specificity are still not well understood. • Event-related potentials (ERPs) provide a valuable means for studying brain-behavior relations (Fabiani et al., 2000). The P300 component of ERPs is thought to reflect attentional operation resource when working memory (WM) updating is engaged (Kok, 2001). • We reported recently (Papageorgiou et al., 2003), that DMS patients, as compared to healthy controls, showed reduced P300 amplitude at right prefrontal region and prolonged latency of P300 located at central midline brain area. These findings suggest that surface-recorded eventrelated potentials may be useful for detecting and monitoring the changes in brain function associated with DMS. • Concerning P300 measures in schizophrenia it has been found to be reduced in patients with this disorder. However, a prolongation of P300 latency has not been consistently apparent, ( O’Donnell et al.,1999 ; Shajahan, 1997 ; Frodl et al., 2001 ; Nieman et al., 2002 ). Scalp ERPs are sensitive to only a fraction of the neural activity elicited by a given event. The resolution of this issue requires the use of techniques that have the potential to provide new insights into mental states, allowing non-invasive, real-time assessment of cerebral structure and activity. Such technique may be the low-resolution brain electromagnetic tomography (LORETA), which differentiates between structural and energetic processes related to information processing as revealed by the associated ERP waveform. The structural level, revealed by the location of the local maxima of the current source density distribution, describes the time-dependent network of activated brain areas. The magnitude of the source strength, a measure of the energetic component, describes the allocation of processing resources. • Considering the above, we thought that electrophysiological brain activity, as reflected by the P300, in association with WM operations, could be useful in better understanding the specific mental processes and psychophysiology in schizophrenic patients with DMS and schizophrenic patients without DMS, and, to evaluate whether schizophrenic patients with DMS and schizophrenic patients without DMS are distinct nosological entities. • In this context it is worth noting that contemporary neuropsychological views define Working Memory (WM) as the capacity to keep information ‘on-line’, as necessary for an ongoing task (Baddeley, 1998; Collette and Van der Linden, 2002). In other words, WM is not for ‘memorizing’ per se. It is rather in the service of complex cognitive activities, such as reasoning, problem solving and decision making (Glassman, 2000; Miyake and Shah, 1999). Materials and methods Age Education Medication Schizophrenics with DMS N=9, (F=5,M=4) 34.9  7 years 12.9 2.7 years 6 patients= drug free* Schizophrenics without DMS N=11 (F=6,M=5) Healthy controls N=11, (F=6,M=5) 34.7  7 years 11.6 2.3 years 9 patients = drug free** 34.2  6.8 years 13.2  2.5 years • The DMS patients were studied during their delusional episode. The sample of patients included four patients suffering from Capgras syndrome, two patients from Frégoli syndrome, two from coexisting Capgras and Frégoli syndrome and one patient suffering from Frégoli syndrome and intermetamorphosis. All patients were psychotics of paranoid type according to DSM-IV criteria follows: The first patient trifluoperazine (30mg/day) + carbamazepine (600mg/day), the second patient risperidone (8mg/day) + gabapentin (800mg/day) and the third patient olanzapine (20mg/day) + oxcarbazepine (600mg/day). medication as follows: the first patient risperidone (9mg/day), and the second patient olanzapine (20mg/day). • * Medicated DMS patients have taken medication as • ** Two schizophrenic patients without DMS have taken Experimental procedure Time period Action AB (100 msec) AC (1100 msec) CD (varies) Administration of warning stimulus (500 or 3000 Hz, 65dB). Recording of ERPs. 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. Repetition of the warning stimulus. DE (100 msec) EF (varies between 15 and 30 sec) Recording of the memory recall performance, according to the accuracy of responses. Blue: DMS Fp1 Red: Schizophrenics Black: Controls Fp2 F3 Fz F4 C3 Cz C4 (C3-T5)/2 (C4-T6)/2 P3 Pz P4 O1 O2 -18μV msec 0 100 200 300 400 500 18μV Front 16, 8 16,8 11, 8 11,8 6, 8 6,8 16, 8 1, 8 1 2 3 1,8 1 2 3 Fp1 11, 8 Fp2 1 2 3 16, 8 6, 8 16, 8 11, 8 1, 8 11, 8 6, 8 6, 8 F3 1 2 3 1, 8 Fz 16, 8 F4 1, 8 1 2 3 Left 16, 8 Right 11, 8 6, 8 16, 8 1, 8 1 11, 8 11, 8 2 3 6, 8 6, 8 1, 8 1 2 3 C3-T5/2 Cz C4-T6/2 1, 8 1 2 3 16, 8 16, 8 16, 8 11, 8 6, 8 C3 1 2 3 11, 8 C4 1 2 3 11, 8 6, 8 6, 8 1, 8 1, 8 1, 8 1 2 3 20μV 1.8μV 16, 8 16, 8 P3 O1 Pz O2 Back 1 2 3 16, 8 P4 11, 8 6, 8 1, 8 1 2 3 11, 8 6, 8 1, 8 1 2 3 16, 8 11, 8 11, 8 6, 8 6, 8 1, 8 1, 8 1 2 3 Amplitudes (V; mean) of the P300 amplitude waveform for the three groups, at each lead. A square shows statistically significant differences between the schizophrenia group (white bars) and the controls (spotted bars), a triangle, those between the schizophrenia group and the DMS group (striated bars) and an asterisk , those between the controls and the DMS group. 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 Front 391 386 381 376 371 366 361 356 351 346 341 336 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 Fp1 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 Fp2 291 286 281 276 271 266 261 256 F3 Fz 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 F4 251 246 1 2 3 Left 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 Right 391 386 381 376 371 366 361 356 351 346 341 1 2 3 336 331 326 321 316 311 306 301 296 291 286 296 291 286 281 276 271 266 261 256 251 246 C3-T5/2 Cz 281 C4-T6/2 276 271 266 261 256 251 246 1 2 3 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 391 386 381 376 371 366 361 356 351 346 341 391 386 381 376 371 366 361 356 351 C3 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 C4 391 386 381 376 371 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 391ms 246ms 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 P3 O1 Pz O2 Back 391 386 381 376 371 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 P4 366 361 356 351 346 341 336 331 326 321 316 311 306 301 296 291 286 281 276 271 266 261 256 251 246 1 2 3 Latencies (msec; mean ) of the P300 latency waveform for the three groups, at each lead. A square shows statistically significant differences between the schizophrenia group (white bars) and the controls (spotted bars), a triangle , those- between the schizophrenia group and the DMS group (striated bars) and an asterisk , those between the controls and the DMS group. Compared with control subjects, the two patient groups showed significantly lower amplitudes at the Fp1 and Fp2 leads, corresponding to the prefrontal brain area (bilaterally). However, compared with the DMS group, the schizophrenia group without DMS showed a significant reduction in P300 amplitude in the left prefrontal region (lead Fp1). Concerning the P300 latency, our study revealed that patients with DMS, compared to the other two groups, showed significant prolongation in the central midline brain region (lead Cz). Figure 2. P50 The utilized LORETA version was registered to the Talairach brain atlas. The solution space consisted of 2394 voxels with a spatial resolution of 7 mm. Average LORETA images were constructed across subjects of both compared groups. The voxel-by-voxel t test differences carried out between groups. The structure-Probability Maps atlas was used to assess which brain regions were involved in P300 waveforms as well as in differences between the compared groups. Brodmann area(s) and brain region closed to the observed locations identified by the Talairach coordinates are reported (Talairach, 1988; PascualMarqui et al., 1994;Lancaster et al., 1997). 0.9 0.8 0.7 0.6 p value (t-test) 0.5 0.4 0.3 0.2 0.1 0 240 280 320 360 Time (msec) 400 440 480 Figure 1. p-values of the TANOVA independent groups procedure versus time. The horizontal dotted line signifies the level (0.01) at which differences between the two groups are regarded as statistically significant and the vertical dotted lines designate the time segment (400-466msec) at which significant differences are observed. Figure 1. Results of the voxel-wise t-statistics between the two groups, averaged within the time window (400-466msec.). The bold blue colour signifies statistically significant differences for the t-threshold for p between 0.01 (t=-3.5) and 0.05 (t=-2.8). A=Anterior, P=Posterior, L=Left, R=Right. X Y Z t-value BA Anatomical region 1 Anatomical region 2 67 67 -18 -25 36 36 -2.99 -2.98 BA3 BA1 Postcentral Gyrus Postcentral Gyrus Parietal Lobe Parietal Lobe 60 60 67 -25 -18 -32 36 36 36 -2.97 -2.96 -2.96 BA2 BA4 BA40 Postcentral Gyrus Precentral Gyrus Inferior Parietal Lobule Parietal Lobe Frontal Lobe Parietal Lobe 60 60 -18 -11 29 29 -2.96 -2.95 BA2 BA4 Postcentral Gyrus Precentral Gyrus Parietal Lobe Frontal Lobe 60 67 67 -25 -39 -18 29 36 29 -2.95 -2.95 -2.94 BA40 BA40 BA1 Inferior Parietal Lobule Inferior Parietal Lobule Postcentral Gyrus Parietal Lobe Parietal Lobe Parietal Lobe Table 1. Results of the voxel-by-voxel LORETA t statistics (corrected for multiple comparisons) comparing the two groups within the time frame 400-460msec of the P300b component. Coordinates in mm origin at anterior commisure. X=left(-) to right(+); Y=posterior(-) to anterior(+); Z=inferior(-) to superior(+). Broadman areas (BA) and both descriptions of the anatomical regions are shown. The tvalues correspond to p<0.05, since the corresponding threshold t-value for p=0.01 is -3.5. • Comparison of memory performance Post hoc tests revealed that both patient groups had significantly attenuated memory performance compared with healthy controls (p < 0.001, F = 15.07, df = 28). No significant differences were found between the two patient groups. The mean values and the standard deviation (S D) in the three groups, i.e. DMS patients, schizophrenics and controls, were 54.4 ± 7.2, 52.4 ± 8.4 and 68.0 ± 4.5, respectively. It should be noted that the presented digits for each subject were 149 . Discussion • The amplitude of P300 component is considered as sensitive measure of attentional operation when WM updating is engaged (Coull, 1998; Kok, 2001). • It is believed that frontal generators are more involved in automated orienting, while temporoparietal generators are more responsive in effortful responding to evoked stimuli (Winterer et al., 2001). • The reduction in P300 amplitude is also thought to reflect gray matter abnormalities (Martin-Loeches et al., 2001). Consequently, the differences found here suggest that schizophrenic patients with and without DMS may both be associated with defects in WM and/or automatic orienting, possibly mediated by gray matter abnormalities in the bilateral prefrontal cortex. However, compared to those with DMS, schizophrenic patients without DMS had significant attenuation in the P300 amplitude in the left prefrontal region, and consequently it is this region that might be more involved in the automatic orienting deficits of schizophrenic patients. This hypothesis appears to be in accordance with recent studies, providing evidence of deficits of prefrontal cortex, in various levels of analysis, which have been implicated in the pathophysiology of both schizophrenia and DMS. Recent works report association between reduced gray matter volume of left frontal lobe and schizophrenia (Salokangas et al., 2002), also impairment of automatic responses in connection with dysfunction of activity of left dorsolateral prefrontal cortex (McDonald and Carter, 2003), and failure in the memory strategies of patients with schizophrenia, associated with a disruption of left dorsolateral prefrontal and temporal-limbic structures (Ragland et al., 2004). 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-perceptualaffective 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 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. However, the suggestion that DMS are associated with interhemispheric transfer deficits is not supported by the findings of Ellis et al. (1993). Methodological differences, such as differences in diagnostic subgroups and in experimental procedures (i.e. facial and non-facial stimuli presented tachistoscopically in either or both visual fields vs administered procedure in the present study) may explain the discrepancies in findings. 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 LORETA analysis concerning the two patient groups showed that DMS patients exhibited reduced activation of the right hemisphere particularly with regard the right parietal lobe. 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]. On the other hand lesion studies [Karnath, region plays a crucial role in spatial neglect. 2001 ] indicate that this • The memory performance of the two patient groups was significantly compromised. This agrees with studies reporting that both DMS and schizophrenic patients show memory deficits (Feinberg et al., 1999;Morrison and Tarter, 1984, (Perry et al. 2001). • Our results should be interpreted with caution due to two limitations of the study. • Firstly, sample sizes were inevitably small (since DMS are rare) and the main findings need to be replicated in independent samples. • Secondly, post hoc assignation of psychological function to regional activation is hypothetical, and more experiments with other neuroimaging (MRI) and/or metabolic techniques are warranted to address the role of specific psychological processes in relation to the functional anatomy and pathology of DMS and schizophrenia. Conclusion The present study compared schizophrenics with and without DMS and healthy controls during the performance of a WM test. The results may indicate abnormalities in both allocation of attentional resources and automatic orienting in schizophrenic patients with DSM, possibly due to degenerative deficits in interhemispheric and prefrontal circuitry. Additionally, schizophrenic patients with DMS exibit deficits in conjunction with brain regions and neural circuits being associated with the neglect syndrome. In contrast, even though schizophrenic patients without DMS exhibit partial similarities with patients suffering from DMS, they show excessive reduction of P300 amplitude located at the left frontal area. Future studies with other neuroimaging and/or metabolic techniques are needed to clarify these issues.