Schizophrenia Research Forum - A Catalyst for Creative Thinking

SfN Atlanta: Probing Functional Deficits in Schizophrenia

29 November 2006. The neuropsychological problems associated with schizophrenia, including deficits in attention, cognition, and learning and memory, are most acutely felt as functional deficits. Auditory hallucinations, indecisiveness, delusions, and other functional problems conspire to make normal daily activities a living nightmare. Understanding the components of these functional deficits at the level of simple measurable deficits, or endophenotypes (see SRF Live Discussion), is key to the accurate, early diagnosis and management of this disease. This focus was reflected in a slide session dedicated to functional deficits at this year’s annual meeting of the Society for Neuroscience held last month in Atlanta, Georgia.

Despite having to battle with 70,000 plus raucous fans on their way to the adjacent Georgia Dome for the Atlanta Falcons, New York Giants football game, Susan Rossell from the Mental Health Research Institute, Melbourne, Australia, managed to get the session started on time. Appropriately enough, she got the ball rolling by sharing some data on auditory processing.

While there is some evidence that Heschl’s gyrus (HG) in the primary auditory cortex and the planum temporale (PT) in the secondary auditory cortex are altered in schizophrenia patients, this has been a difficult area to study because the two regions can vary tremendously in size and location among different people. Even after normalizing there can be considerable difference in residual variability in shape and location of these regions, and the more subjects studied, the poorer the overlap, said Rossell.

To overcome this limitation, Rossell and colleagues have used accurately defined regions of interest in MRI scans. By calculating the number of voxels activated in subjects presented with semantically neutral words in a passive listening task, she has been able to more accurately map these regions. Her data suggest that the HG and PT are, in fact, activated differently in schizophrenia patients, who showed a greater tendency toward symmetrical activation (in the left hemisphere, reduced activation in HG and greater activation in the PT) than normal subjects. This effect was even greater in schizophrenia patients who experience auditory hallucinations. The finding could help to pinpoint specific groups of neurons that are affected in schizophrenia or even lead to diagnostic tests for the disease.

The auditory theme was continued by Kevin Spencer, Harvard Medical School, Brockton, who addressed the problem of sound-driven EEG responses, which in chronic schizophrenia patients are typically impaired in the so-called gamma band (30 to 100 Hertz) but not at lower frequencies (see SRF hypothesis paper). The question Spencer asked is whether this “gamma driving deficit” is also present at the very onset of schizophrenia. The answer could help doctors distinguish schizophrenia from other psychiatric syndromes such as affective psychosis and bipolar disorder, which often emerge with very similar initial symptoms. Spencer and colleagues studied gamma deficits in a total of 68 volunteers, 13 first-episode schizophrenia patients, 16 first episode affective disorder patients with psychosis, and 39 healthy controls. With stimuli at 40 Hertz, both sets of patients had reduced “phase locking,” a measure of whether neurons are firing in synchrony. For the schizophrenia patients the phase locking was deficient only in the left hemisphere of the brain, whereas for affective disorder patients the problem manifested in both hemispheres. The results suggest a relatively simple way to distinguish schizophrenia from affective disorder patients in the very earliest manifestation of disease.

Patricia Pardo, University of Minneapolis, reported that a combination of neuropsychological tests and MRI measurements can differentiate schizophrenia and bipolar disorder in their earliest manifestations. She reported results from a small pilot trial to test if any combination of 22 neuropsychological variables and 23 MRI variables can distinguish the two disorders. Pardo enrolled eight healthy controls and 10 each of schizophrenia and bipolar patients to take part in the test. She used the “leaving out one subject method” to generate sets of data based on 27 subjects, then compared that data with data from the person left out and tried to assign a diagnosis in that basis. She reported that nine different sets of 12 of the variables were 96 percent correct in giving a diagnosis. Pardo claimed that by combining those sets, a fully accurate diagnosis can be achieved. But she emphasized that this study needs to be replicated. If it holds up, she said that the results argue that schizophrenia and bipolar disorder are two distinct and separable diseases, which has been somewhat of a contentious issue.

The gamma band deficiencies were also the theme of Anna Kuznetsova’s talk. Gamma band oscillations are thought to emanate from GABAergic inhibitory neurons as they fire in synchrony (see SRF related news story), and Kuznetsova, from Indiana University-Purdue University Indianapolis, has modeled how D4 dopamine receptors might modulate that activity.

There are numerous reasons to link D4 receptors with gamma band abnormalities and schizophrenia: drugs that block the D4 receptors reduce gamma activity; D4 receptors are also most abundant in the prefrontal cortex and medium spiny neurons in the striatum, two areas believed to be most affected in schizophrenia; and polymorphisms in the D4 gene have been linked to schizophrenia. But determining how the various cortical and subcortical neural networks are modulated by D4 receptors is a major challenge.

Kuznetsova suggested a new model in which activation of D4 receptors induces methylation of cell membrane phospholipids. This affects the fluidity of the membrane surrounding ion channels and increases their open/close rate, resulting in increased firing in neurons of the prefrontal cortex to gamma band frequencies.

Mihoko Otake from the University of Tokyo, Kashiwa, Japan, described another type of modeling system, one that addresses the problem of abnormal sense of agency, meaning the tendency for schizophrenia patients to attribute their actions to someone else (overattribution) or feel they have no control over their own movements (underattribution). An important part of the model is a “comparator,” a center that can compare actual sensory feedback with predicted feedback. A comparator that functions properly facilitates a normal sense of agency according to Otake’s model. Overattribution in schizophrenia may occur when the comparator is inhibited during a voluntary movement. In this case, the movement may be “overattributed” to someone else. In contrast, when a schizophrenia patient has an involuntary movement, the model predicts that the comparator has no predicted sensory feedback and therefore underattributes the movement. As these models become more sophisticated, they may be able to help scientists understand what abnormal neuronal networks are at play in schizophrenia patients with altered sense of agency.

Overattribution can even extend to the feeling that there is a totally different “presence” in the room as recently reported by Shahar Arzy and colleagues at the Swiss Institute for Technology, Lausanne (see SRF related news story). In an attempt to identify regions of the brain that might be responsible for these feelings, Arzy and colleagues have had normal, healthy subjects carry out a mental imagery task called an own body transformation. In this task patients are asked to transform themselves into the position of an image that they see in front of them, while their brain activity is measured with high-density EEG. Arzy reported that the tempo-parietal junction (TPJ) was the one region that was consistently associated with perceptual aberrations. Duration, but not strength, of TPJ activation significantly correlated with these perceptions, suggesting that in schizophrenia patients, disturbances in self-awareness may be related to prolonged activation of this region.

Neuronal networks were also discussed by Grega Repovs, Washington University, St. Louis, Missouri, who presented data on the link between working memory problems and abnormal neural connectivity. Repovs has used functional MRI to study neuronal activation during working memory tasks. She presented data on two basic approaches, studying neural activity changes over time in individual subjects, and comparing changes between subjects. A comparison of fMRI data from a set of 11 distinct cortical and subcortical brain regions from 38 normal controls and 38 schizophrenia patients suggests that in schizophrenia there is reduced and enhanced connectivity, respectively, between the right and left dorsolateral PFC and the thalamic regions. The enhanced connectivity of the left DLPFC is possibly as a compensatory mechanism, suggested Repovs. The within subject tests also indicated reduced connectivity between the DLPFC and other cortical regions during both word and facial recognition tasks.

Connectivity was also addressed by Robert Welsh, University of Michigan, Ann Arbor. Welsh used fMRI to scan the brains of 17 stable schizophrenic subjects and 15 healthy controls to compare default state activation. The default state refers to correlated neuronal activity during the resting state that decreases when attention is directed to an external task. Welsh reported that both groups of subjects exhibited the expected default state map showing activity in the ventral medial prefrontal cortex, the PCC/precuneus and bilateral parietal areas. But in addition, the schizophrenia subjects also had activation in the left amygdala/hippocampus that was significantly greater than controls and also less activation of the left lateral parietal region. The finding pinpoints areas where default state connectivity is abnormal in schizophrenic patients.

Gabriel Dichter, University of North Carolina, Chapel Hill, used the same fMRI technique to examine emotion and attention interactions in schizophrenia patients. Poor attention control and affective dysregulation are major aspects of cognitive neuroscience in schizophrenia, and researchers have begun to explore the neural circuitry that might be the root cause of problems in these domains. Dichter tackled the question using a visual oddball task, where subjects are shown neutral images, rare aversive scenes, and target images and are required to press one button when the target image is displayed and another button for all other images. The MRI images obtained from 13 control subjects replicated previous findings—that there is a dorsal/ventral difference with the ventral (including amygdala and ventral frontotemporal cortices) being activated in response to aversive stimuli and the dorsal (including frontoparietal and anterior cingulated cortex) being activated in response to standard events. The pattern was different in patients however, who had dorsal activation in response to both target and aversive stimuli, particularly the anterior cingulate gyrus, which was only activated in response to target stimuli in control subjects. The findings suggest that anomalous dorsal activations in response to aversive stimuli might mediate the effects of affective dysregulation on attentional control.

Attention was also broached by Jun Wang from the University of Georgia, Athens, who has tested schizophrenia patients for visual attention performance. Wang and colleagues used a sophisticated test where subjects viewed superimposed images of five horizontal or five vertical bars and were asked to identify width changes in a) the central bar only, b) the three central bars, and c) only the two peripheral bars. Brain activity was monitored by EEG.

Wang reported that both control and schizophrenia patients showed the same response when asked to focus attention on the three different sets of bars, namely, activation of specific occipital sensors. But in addition, schizophrenia patients also had higher low frequency (delta and theta band) brain activity and different target detection rates and reaction times. Based on the data, Wang suggested that visual attention dysfunction in schizophrenia is based in neural abnormalities that lie upstream of the sensory cortex.

Visual stimuli were also used by Henry Holcomb, Maryland Psychiatric Research Center, Baltimore, to probe spatial memory and learning in schizophrenia patients. Although schizophrenia patients are able to learn new skills much like normal healthy subjects, they tend to do so at a slower pace. To try to understand why this is, Holcomb correlated learning with brain activation as seen using functional MRI images. He tested 22 control subjects and 20 medicated schizophrenia patients in a delayed match-to-sample test using a classic A-B-A experimental design, where subjects receive no feedback in the A trials but do receive feedback in the B trials. Subjects were all given six trials, two A trials followed by two B, and then two more A.

Holcomb reported that schizophrenia patients perform just like normal controls in the A1/A2 trials and the B1/B2 trials (accuracy rates for A’s and B’s were 0.53 and 0.59, respectively, for controls, and 0.53 and 0.62 for patients). However, in the final two trials the schizophrenia subjects scored significantly lower (0.58 vs. 0.65 for controls). While in the normal subjects fMRI signals suggested that the dorsolateral prefrontal cortex and the medial temporal lobe were active in the last two trials, in the schizophrenia patients the occipital lobe was primarily active in those tests, suggesting that once feedback is removed, there is a tendency to default back to the visual system in schizophrenics.

What exactly is the cause of schizophrenia? While that is hotly debated and it is likely that there may be many different correct answers, some speakers addressed specific etiologies of the disease. Speaking to the neurodevelopmental theory, Alan Brown, New York State Psychiatric Institute, addressed the subject of prenatal exposure to infection and risk for the disease (see SRF related news story). Brown and colleagues have examined data from the Kaiser Permanente Child Health and Developmental Study cohort of more than 12,000 children born between 1959 and 1967 and for whom prenatal exposure to influenza or toxoplasmosis is documented. From the cohort, 71 cases of schizophrenia have been identified and tested for executive function. Brown reported that those who had been exposed to prenatal infection had significantly more errors in the Wisconsin Card Sort Test and took significantly longer to complete the Trails B test. The findings suggest that exposure to prenatal infection can lead to poorer executive function in later life.

Paolo Brambilla from the University of Udine, Italy, suggested that a vascular component may be added to the theory of schizophrenia. Cortical lobe atrophy has been documented in both schizophrenia and bipolar disorder, and Brambilla and colleagues have addressed whether this may be due to altered cerebral blood flow. The researchers recruited patients from the Udine and Verona region of Italy and conducted perfusion-weighted MRI scans of the brain to measure cerebral blood volume (CBV) in 54 schizophrenia patients, 15 bipolar patients, and 30 normal control subjects. They found that in the schizophrenia patients the CBV was lower in the left parietal and temporal lobes but higher in the occipital lobe than in controls, while in bipolar patients CBV was increased in the left temporal and frontal lobes and in the prefrontal/limbic system during emotional tasks. The data suggest that alterations in blood flow may contribute to the pathophysiology of both diseases.

Last but not least, Lucas Kempf, NIMH, Bethesda, Maryland, presented data on the role of genetic polymorphisms in disease etiology. Kempf used a multimodal imaging/genetic approach to address whether a single nucleotide polymorphism (SNP) that leads to a premature stop codon in the ZDHHC8 gene has any impact on schizophrenia. The gene, located on chromosome 22q11, has been linked to schizophrenia and to velocardiofacial syndrome, which often co-segregates with schizophrenia.

Kempf and colleagues tested 125 healthy volunteers in face matching and shape matching tests combined with a working memory test (the N-back test) while measuring brain activation with voxel-based morphometry. They found that volunteers who are homozygous for the SNP have significantly lower activation of the thalamus and also lower activation of the posterior cingulate which reached significance during the emotional matching test. The finding suggests that ZDHHC8 is involved in the thalamus-cingulate memory loop and warrants further investigation as a schizophrenia risk gene. ZDHHC8 is believed to be a palmitoyl transferase that may be involved in modulating synaptic strength.—Tom Fagan.

Comments on Related News


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Comment by:  Kevin Spencer (Disclosure)
Submitted 9 February 2006
Posted 9 February 2006
  I recommend the Primary Papers

Related News: Bad Timing: Prenatal Exposure to Maternal STDs Raises Risk of Schizophrenia

Comment by:  Paul Patterson
Submitted 22 May 2006
Posted 22 May 2006

Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory disease, vaginitis, syphilis, condylomata, “venereal disease,” and gonorrhea. Strengths of the study include physician documentation of the infections and face-to-face assessments of schizophrenia. Although sample size was modest, these results extend a prior finding that elevated maternal anti-herpes simplex type 2 antibodies are associated with increased risk of psychotic disorders, including schizophrenia (Buka et al., 2001).

The mechanism of how maternal infection increases risk for schizophrenia could involve pathogens invading the fetus. Although this is certainly possible in the case of some of the infections studied by Babulas et al., in the case of a respiratory virus such as influenza, this explanation appears unlikely. A more parsimonious mechanism would involve activation of the maternal immune system, and action of soluble mediators such as cytokines at the level of the placenta or the fetus. Support for this hypothesis comes from animal studies. An antiviral immune response can be evoked in the absence of the pathogen by injection of synthetic double-stranded RNA (polyI:C). When this is done in pregnant rats or mice, the adult offspring display a number of behavioral abnormalities reminiscent of those observed in schizophrenia. These include deficits in prepulse inhibition, latent inhibition, and social interaction, as well as enhanced amphetamine-induced locomotion and anxiety under mildly stressful conditions (Shi et al., 2003; Zuckerman et al., 2003; Ozawa et al., 2005). Moreover, some of these deficits are ameliorated by treatment with antipsychotic drugs and exacerbated by psychotomimetics (Shi et al., 2003; Ozawa et al., 2005), and the offspring also exhibit dopaminergic hyperfunction (Zuckerman et al., 2003; Ozawa et al., 2005). Some of these abnormalities are also seen in the offspring of influenza-infected mothers or mothers injected with the bacterial cell wall component, LPS (Borrell et al., 2002; Fatemi et al., 2002; Shi et al., 2003).

The most recent advance in this growing cottage industry is the finding that there are critical periods of maternal immune activation that determine the type of adult behavioral dysfunction and neuropathology found in the offspring (Meyer et al., 2006). Injection of polyI:C during stages of mouse gestation corresponding to first-to-second versus second-to-third trimesters of human pregnancy yields different deficits in exploratory and perseverative behavior, postnatal reelin expression, and hippocampal apoptosis. Moreover, these two different stages of injection evoke diverse cytokine responses in the fetal brain. It would further be interesting to know which of these abnormalities is specific to the period corresponding to the human second trimester, as this is the key time of vulnerability for risk of schizophrenia associated with maternal infection.

Other fascinating questions for this increasingly popular model are, what mediates the effects of maternal immune activation (e.g., cytokines, antibodies, corticosteroids), and do they act directly on the fetus or via the placenta? Can imaging be used with the rodents to explore dopamine receptor occupancy? Which of the observed pathologies are most relevant for each of the behavioral abnormalities?

References:
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract Borrell J, Vela JM, Arevalo-Martin A, Molina-Holgado E, Guaza C. Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology. 2002 Feb;26(2):204-15. Abstract Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006 Apr;32(2):200-2. Epub 2006 Feb 9. Abstract Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001 Nov;58(11):1032-7. Abstract Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol. 2002 Feb;22(1):25-33. Abstract Meyer U, Feldon J, Schedlowski M, Yee BK. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci Biobehav Rev. 2005;29(6):913-47. Abstract Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry. 2006 Mar 15;59(6):546-54. Epub 2005 Oct 26. Abstract Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003 Jan 1;23(1):297-302. Abstract Zuckerman L, Rehavi M, Nachman R, Weiner I. Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology. 2003 Oct;28(10):1778-89. Abstract

View all comments by Paul Patterson

Related News: Bad Timing: Prenatal Exposure to Maternal STDs Raises Risk of Schizophrenia

Comment by:  Jürgen Zielasek
Submitted 3 June 2006
Posted 3 June 2006

Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.

Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and astrocytes also express functional TLR3 (Farina et al., 2005; Park et al., 2006; Town et al., 2006). Thus, TLR3 plays an important role in immune responses, and its natural function appears to be immune activation in addition to cross-priming the immune system to virus-infected cells (Schulz et al., 2005). Given the expression of TLR3 at the maternal-fetal interface and on glial cells, the polyI:C-TLR3-model appears to be useful to study the basic mechanisms of viral infections and their consequences for brain development in animal models.

However, several limitations are evident: PolyI:C is not a virus, and different immunological pathways may be activated by intact viruses after binding to their appropriate receptors. Findings from the immune system of rodents cannot be directly transferred to humans, and it may be difficult to dissect—on a molecular level—the protective aspects of an immune response against a viral infection from its putative detrimental effects on human neurodevelopment. Still, such mechanisms may now be studied in the rodent models used by Meyer and coworkers and other groups, and this will help to pave the way for future studies in humans. This will hopefully lead to a better understanding of the role of the immune system and viral infections in the pathogenesis of schizophrenia.

References:

Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol. 2005 Dec 15;175(12):8096-104. Abstract

Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E. Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol. 2005 Feb;159(1-2):12-9. Epub 2004 Nov 11. Abstract

Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K, Kim JS, Lee SJ. TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia. 2006 Feb;53(3):248-56. Abstract

Salem ML, Kadima AN, Cole DJ, Gillanders WE. Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity. J Immunother. 2005 May-Jun;28(3):220-8. Abstract

Schaefer TM, Fahey JV, Wright JA, Wira CR. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J Immunol. 2005 Jan 15;174(2):992-1002. Abstract

Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature. 2005 Feb 24;433(7028):887-92. Epub 2005 Feb 13. Abstract

Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006 Mar 15;176(6):3804-12. Abstract

View all comments by Jürgen Zielasek

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Comment by:  Carol Tamminga, SRF Advisor
Submitted 21 September 2006
Posted 21 September 2006

There is an interesting old neurosurgury literature that shows findings like this. The limitation is that the findings are always in single patients, and hard to interpret because one cannot do real manipulations. An interesting follow-up would be some kind of research using TMS.

View all comments by Carol Tamminga

Related News: Me and My Unpleasant Shadow—A Substrate for Paranoia and Outside Control?

Comment by:  Avi Peled
Submitted 29 September 2006
Posted 29 September 2006

You do not need fancy direct brain stimulation to fool the brain into illusion or delusion-like activity. You can use external (indirect) manipulations. Examples are many: the “McGurk effect,” where conflicting auditory-visual stimuli cause fusion effects to make patients hear something that is not there, and the rubber hand illusion initially described by Botvinik and Cohen (1) and replicated by us (2) in schizophrenia patient literature and later imaged with EEG (3).

More interestingly, this finding adds to the growing knowledge that mental disorders can be reconceptualized as disorders of brain organization (4). It is about time that psychiatrists start to build a brain-related diagnostic system, even if it is currently hypothetical. The benefits of such a diagnostic system are detailed in a dedicated website for the future of psychiatry; see www.brainoptimizers.org.

References:

1. Botvinick M, Cohen J. Rubber hands 'feel' touch that eyes see. Nature. 1998 Feb 19;391(6669):756. Abstract

2. Peled A, Ritsner M, Hirschmann S, Geva AB, Modai I. Touch feel illusion in schizophrenic patients. Biol Psychiatry. 2000 Dec 1;48(11):1105-8. Abstract

3. Peled A, Pressman A, Geva AB, Modai I. Somatosensory evoked potentials during a rubber-hand illusion in schizophrenia. Schizophr Res. 2003 Nov 15;64(2-3):157-63. Abstract

4. Peled A. Brain profiling and clinical-neuroscience. Med Hypotheses. 2006;67(4):941-6. Epub 2006 May 15. Abstract

View all comments by Avi Peled

Related News: Me and My Unpleasant Shadow—A Substrate for Paranoia and Outside Control?

Comment by:  Daniel Wolf
Submitted 6 October 2006
Posted 6 October 2006
  I recommend the Primary Papers

I wonder whether temporoparietal dysfunction and the phenomenon reported in this paper may relate to auditory hallucinations. It seems that sensing a "shadow person" might dramatically increase the tendency to misattribute inner speech to an outside source.

View all comments by Daniel Wolf

Related News: Me and My Unpleasant Shadow—A Substrate for Paranoia and Outside Control?

Comment by:  Chloe Farrer
Submitted 19 December 2006
Posted 19 December 2006

One important comment to make when one compares the study of Blanke and colleagues with our study (Farrer et al., 2004) is that we scanned patients while they were not experiencing any delusion of control, although patients were selected on the basis of their symptoms (they had a high delusion of control score). Our approach was complementary to the one of Spence and colleagues (Spence et al., 1997, who scanned patients while they were experiencing a delusion of control. These authors found hyperactivation of the right inferior parietal lobule (IPL) when patients were moving a joystick and also experienced a delusion of control. IPL was much less activated when the same patients were scanned a few months after, while they were doing the same task but did not experience any delusion. By consequence, these studies show that abnormal activation either artificially induced (like in the stimulation study) or pathologically induced (like in schizophrenic patients) is associated with abnormal attribution that either concerns one's own body or one's own actions. In our study conducted in healthy subjects by Farrer et al., 2003, IPL activity was maximal when subjects experienced that someone else was controlling the movements of the joystick. However, we found that contrary to healthy subjects, this region was poorly modulated as a function of the experience of agency in patients. In addition, in the condition of "maximal agency," the IPL area was highly activated even though patients did not report any delusion of control. What needs to be discovered is how these abnormalities (poor modulation of IPL) become exaggerated so that they lead to the manifestation of symptoms.

View all comments by Chloe Farrer