| 1 | Hum. Mol. Genet. 2000 May 9: 1415-23 |
|---|---|
| PMID | 10814723 |
| Title | Disruption of two novel genes by a translocation co-segregating with schizophrenia. |
| Abstract | A balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypothesize that the translocation is the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation. By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation. These genes have been provisionally named Disrupted-In-schizophrenia 1 and 2 ( DISC1 and DISC2 ). DISC1 encodes a large protein with no significant sequence homology to other known proteins. It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a COILed-COIL by interaction with another, as yet, unidentified protein(s). Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system. The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system. DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene. Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 2 | Genomics 2002 Dec 80: 662-72 |
| PMID | 12504857 |
| Title | Cloning and characterization of Disc1, the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1). |
| Abstract | We cloned the mouse ortholog of DISC1 (Disrupted-in-schizophrenia 1), a candidate gene for schizophrenia. Disc1 is 3163 nucleotides long and has 60% identity with the human DISC1. Disc1 encodes 851 amino acids and has 56% identity with the human protein. Disc1 maps to the DISC1 syntenic region in the mouse, and genomic structure is conserved. A Disc1 splice variant deletes a portion of Disc1 beginning at amino acids orthologous to the human truncation. Bioinformatic analysis and cross-species comparisons revealed sequence conservation distributed across the genes and conservation of leucine zipper and COILed-COIL domains in both orthologs. In situ hybridization in adult mouse brain revealed a restricted expression pattern, with highest levels in the dentate gyrus of the hippocampus and lower expression in CA1-CA3 of the hippocampus, cerebellum, cerebral cortex, and olfactory bulbs. Identification of Disc1 will facilitate the study of DISC1's function and creation of mouse models of DISC1 disruption. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 3 | Hum. Mol. Genet. 2003 Jul 12: 1591-608 |
| PMID | 12812986 |
| Title | DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. |
| Abstract | Disrupted-In-schizophrenia 1 (DISC1) is a novel gene associated with schizophrenia by multiple genetic studies. In order to determine how mutations in DISC1 might cause susceptibility to schizophrenia, we undertook a comprehensive study of the cellular biology of DISC1 in its full-length and disease-associated mutant forms. DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system, including MIPT3, MAP1A and NUDEL; proteins which localize receptors to membranes, including alpha-actinin2 and beta4-spectrin; and proteins which transduce signals from membrane receptors, including ATF4 and ATF5. Truncated mutant DISC1 fails to interact with ATF4, ATF5 or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N-terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central COILed-COIL domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C-terminus of DISC1. In its full-length form, DISC1 protein localizes to predominantly perinuclear punctate structures which extend into neurites in some cells; mutant truncated DISC1, by contrast, is seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms co-localize with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 are found in microtubule fractions, neither form of DISC1 appears to bind directly to microtubules, but rather do so in a MIPT3-dependent fashion that is stabilized by taxol. Based on these data, we propose that DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 4 | Hum. Mol. Genet. 2003 Jul 12: 1591-608 |
| PMID | 12812986 |
| Title | DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. |
| Abstract | Disrupted-In-schizophrenia 1 (DISC1) is a novel gene associated with schizophrenia by multiple genetic studies. In order to determine how mutations in DISC1 might cause susceptibility to schizophrenia, we undertook a comprehensive study of the cellular biology of DISC1 in its full-length and disease-associated mutant forms. DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system, including MIPT3, MAP1A and NUDEL; proteins which localize receptors to membranes, including alpha-actinin2 and beta4-spectrin; and proteins which transduce signals from membrane receptors, including ATF4 and ATF5. Truncated mutant DISC1 fails to interact with ATF4, ATF5 or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N-terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central COILed-COIL domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C-terminus of DISC1. In its full-length form, DISC1 protein localizes to predominantly perinuclear punctate structures which extend into neurites in some cells; mutant truncated DISC1, by contrast, is seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms co-localize with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 are found in microtubule fractions, neither form of DISC1 appears to bind directly to microtubules, but rather do so in a MIPT3-dependent fashion that is stabilized by taxol. Based on these data, we propose that DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 5 | Genomics 2003 Jan 81: 67-77 |
| PMID | 12573262 |
| Title | Evolutionary constraints on the Disrupted in Schizophrenia locus. |
| Abstract | The Disrupted in schizophrenia (DISC) locus on human chromosome 1q42 has been strongly implicated by genetic studies as a susceptibility locus for major mental illnesses. In humans the locus is transcriptionally complex, with multiple alternate splicing events, antisense transcription, and intergenic splicing all evident. We have compared the genomic sequence and transcription maps of this locus between human, mouse, pufferfish (Fugu rubripes), and, in part, zebrafish (Danio rerio). The order and orientation of EGLN1, TSNAX, and DISC1 genes are conserved between mammals and F. rubripes. Intergenic splicing and short intergenic transcripts are not found to be conserved features. DISC2, a putative noncoding transcript partially antisense to DISC1, is not conserved in mouse or F. rubripes. Alternate splice forms of the protein-coding DISC1 gene are conserved even though the genomic structure is not. The amino acid sequence of DISC1 is diverging rapidly, although a putative nuclear localization signal and discrete blocks of COILed COIL are specifically conserved features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 6 | J Can Chiropr Assoc 2004 Dec 48: 273-81 |
| PMID | 17549105 |
| Title | Comparison of a triaxial fluxgate magnetometer and Toftness sensometer for body surface EMF measurement. |
| Abstract | The use of magnetic fields to treat disease has intrigued mankind since the time of the ancient Greeks. More recently it has been shown that electromagnetic field (EMF) treatment aids bone healing, and repetitive transcranial magnetic stimulation (rTMS) appears to be beneficial in treating schizophrenia and depression. Since external EMFs influence internal body processes, we hypothesized that measurement of body surface EMFs might be used to detect disease states and direct the course of subsequent therapy. However, measurement of minute body surface EMFs requires use of a sensitive and well documented magnetometer. In this study we evaluated the sensitivity and frequency response of a fluxgate magnetometer with a triaxial probe for use in detecting body surface EMF and we compared the magnetometer readings with a signal from a Toftness Sensometer, operated by an experienced clinician, in the laboratory and in a clinical setting. A Peavy Audio Amplifier and variable power output Telulex signal generator were used to develop 50 microT EMFs in a three COIL Merritt COIL system. A calibrated magnetometer was used to set a 60 Hz 50 microT field in the COIL and an ammeter was used to measure the current required to develop the 50 microT field. At frequencies other than 60 Hz, the field strength was maintained at 50 microT by adjusting the Telulex signal output to keep the current constant. The field generated was monitored using a 10 turn COIL connected to an oscilloscope. The oscilloscope reading indicated that the field strength was the same at all frequencies tested. To determine if there was a correspondence between the signals detected by a fluxgate magnetometer (FGM1) and the Toftness Sensometer both devices were placed in the Merritt COIL and readings were recorded from the FGM1 and compared with the ability of a highly experienced Toftness operator to detect the 50 microT field. Subsequently, in a clinical setting, FGM1 readings made by an FGM1 technician and Sensometer readings were made by 4 Toftness Sensometer operators, having various degrees of experience with this device. Each examiner obtained instrument readings from 5 different volunteers in separate chiropractic adjusting rooms. Additionally, one of the Toftness Sensometers was equipped with an integrated fluxgate magnetometer (FGM2) and this magnetometer was used to obtain a second set of EMF readings in the clinical setting. The triaxial fluxgate magnetometer was determined to be moderately responsive to changes in magnetic field frequency below 10 Hz. At frequencies above 10 Hz the readings corresponded to that of the ambient static geofield. The practitioner operating the Toftness Sensometer was unable to detect magnetic fields at high frequencies (above 10 Hz) even at very high EMFs. The fluxgate magnetometer was shown to be essentially a DC/static magnetic field detector and like all such devices it has a limited frequency range with some low level of sensitivity at very low field frequencies. The interexaminer reliability of four Toftness practitioners using the Sensometer on 5 patients showed low to moderate correlation. The fluxgate magnetometer although highly sensitive to static (DC) EMFs has only limited sensitivity to EMFs in the range of 1 to 10 Hz and is very insensitive to frequencies above 10 Hz. In laboratory comparisons of the Sensometer and the fluxgate magnetometer there was an occasional correspondence between the two instruments in detecting magnetic fields within the Merritt COIL but these occasions were not reproducible. In the clinical studies there was low to moderate agreement between the clinicians using the Sensometer to diagnosing spinal conditions and there was little if any agreement between the Sensometer and the fluxgate magnetometer in detecting EMFs emanating from the volunteers body surface. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 7 | Psychiatry Res 2004 Jun 127: 9-17 |
| PMID | 15261700 |
| Title | Transcranial magnetic stimulation for auditory hallucinations in schizophrenia. |
| Abstract | It has been suggested that low frequency transcranial magnetic stimulation (TMS) over left temporo-parietal cortex may reduce the frequency and intensity of auditory hallucinations in schizophrenia. Sixteen patients with hallucinations, treatment-resistant for at least 2 months, were randomised into a placebo-controlled crossover study of TMS at 1 Hz and 80% of motor threshold over left temporo-parietal cortex. Treatment periods lasted for 4 days, with daily duration escalating from 4 to 8, 12 and 16 min on subsequent days. Each minute of stimulation was followed by 15 s of rest to check COIL position and allow the patient to move, if necessary. Both patients and symptom raters were unaware of the treatment condition. Patients' hallucination scores improved from baseline with both real and sham TMS, and there was no significant difference between real and sham treatments. There was a trend for second treatments, whether sham or real, to be more effective than first treatments. Other psychopathology scales (apart from positive symptoms) and verbal memory were not affected by real or sham TMS. Previous positive studies could not be replicated with these parameters. TMS is safe if applied within the protocol used. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 8 | J. Biol. Chem. 2004 Mar 279: 10450-8 |
| PMID | 14688250 |
| Title | Myospryn is a novel binding partner for dysbindin in muscle. |
| Abstract | Dysbindin is a COILed-COIL-containing protein that was initially identified in a screen for dystrobrevin-interacting proteins. Recently, dysbindin has been shown to be involved in the biogenesis of lysosome-related organelles and is also a major schizophrenia susceptibility factor. Although dysbindin has been implicated in a number of different cellular processes, little is known about its function. To determine the function of dysbindin in muscle, we performed a yeast two-hybrid screen to identify potential interacting proteins. Here we show that dysbindin binds to a novel 413-kDa protein, myospryn, which is expressed in cardiac and skeletal muscle. The transcript encoding myospryn encompasses genethonin-3, a transcript that is down-regulated in muscle from Duchenne muscular dystrophy patients and stretch-responsive protein 553, which is up-regulated in experimental muscle hypertrophy. The C terminus of myospryn contains BBC, FN3, and SPRY domains in a configuration reminiscent of the tripartite motif protein family, as well as the dysbindin-binding site and a region mediating self-association. Dysbindin and myospryn co-immunoprecipitate from muscle extracts and are extensively co-localized. These data demonstrate for the first time that there are tissue-specific ligands for dysbindin that may play important roles in the different disease states involving this protein. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 9 | Mol. Cell. Neurosci. 2005 Apr 28: 613-24 |
| PMID | 15797709 |
| Title | Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site. |
| Abstract | Disrupted in schizophrenia 1 (DISC1) has been identified as a putative risk factor for schizophrenia and affective disorders through study of a Scottish family with a balanced (1;11) (q42.1;q14.3) translocation, which results in the disruption of the DISC1 locus and cosegregates with major psychiatric disease. Several other reports of genetic linkage and association between DISC1 and schizophrenia in a range of patient populations have added credibility to the DISC1-schizophrenia theory, but the function of the DISC1 protein is still poorly understood. Recent studies have suggested that DISC1 plays a role in neuronal outgrowth, possibly through reported interactions with the molecules Nudel and FEZ1. Here we have analyzed the DISC1 protein sequence to identify previously unknown regions that are important for the correct targeting of the protein and conducted imaging studies to identify DISC1 subcellular location. We have identified a central COILed-COIL region and show it is critical for the subcellular targeting of DISC1. This domain is independent from the C-terminal Nudel binding domain highlighting the multidomain nature/functionality of the DISC1 protein. Furthermore, we have been able to provide the first direct evidence that DISC1 is localized to mitochondria in cultured cortical neurons that are dependent on an intact cytoskeleton. Surprisingly, Nudel is seen to differentially associate with mitochondrial markers in comparison to DISC1. Disruption of the cytoskeleton results in colocalization of Nudel and mitochondrial markers-the first observation of such a direct relationship. Mitochondrial dysfunction has been implicated to play a role in schizophrenia so we speculate that mutations in DISC1 or Nudel may impair mitochondrial transport or function, initiating a cascade of events culminating in psychiatric illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 10 | Biochem. J. 2006 May 395: 587-98 |
| PMID | 16448387 |
| Title | Reinvestigation of the dysbindin subunit of BLOC-1 (biogenesis of lysosome-related organelles complex-1) as a dystrobrevin-binding protein. |
| Abstract | Dysbindin was identified as a dystrobrevin-binding protein potentially involved in the pathogenesis of muscular dystrophy. Subsequently, genetic studies have implicated variants of the human dysbindin-encoding gene, DTNBP1, in the pathogeneses of Hermansky-Pudlak syndrome and schizophrenia. The protein is a stable component of a multisubunit complex termed BLOC-1 (biogenesis of lysosome-related organelles complex-1). In the present study, the significance of the dystrobrevin-dysbindin interaction for BLOC-1 function was examined. Yeast two-hybrid analyses, and binding assays using recombinant proteins, demonstrated direct interaction involving COILed-COIL-forming regions in both dysbindin and the dystrobrevins. However, recombinant proteins bearing the COILed-COIL-forming regions of the dystrobrevins failed to bind endogenous BLOC-1 from HeLa cells or mouse brain or muscle, under conditions in which they bound the Dp71 isoform of dystrophin. Immunoprecipitation of endogenous dysbindin from brain or muscle resulted in robust co-immunoprecipitation of the pallidin subunit of BLOC-1 but no specific co-immunoprecipitation of dystrobrevin isoforms. Within BLOC-1, dysbindin is engaged in interactions with three other subunits, named pallidin, snapin and muted. We herein provide evidence that the same 69-residue region of dysbindin that is sufficient for dystrobrevin binding in vitro also contains the binding sites for pallidin and snapin, and at least part of the muted-binding interface. Functional, histological and immunohistochemical analyses failed to detect any sign of muscle pathology in BLOC-1-deficient, homozygous pallid mice. Taken together, these results suggest that dysbindin assembled into BLOC-1 is not a physiological binding partner of the dystrobrevins, likely due to engagement of its dystrobrevin-binding region in interactions with other subunits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 11 | Schizophr. Res. 2007 Sep 95: 151-7 |
| PMID | 17689931 |
| Title | Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study. |
| Abstract | To verify whether high-frequency rTMS applied above the area of the left prefrontal cortex in 15 stimulation sessions with maximum stimulation intensity is able to modify negative symptoms of schizophrenia in a double-blind, randomized controlled study. Twenty-two patients with schizophrenia stabilized on antipsychotic medication with prominent negative symptoms were included in the trial. They were divided into two groups: eleven were treated with effective rTMS and eleven with ineffective "sham" rTMS. The ineffectiveness of the sham rTMS was achieved through the stimulation COIL position. Stimulation was applied to the left dorsolateral prefrontal cortex. The stimulation frequency was 10 Hz. Stimulation intensity was 110% of the motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days. Each daily session consisted of 15 applications of 10-second duration and 30-second intervals between sequences. There were 1500 stimuli per session. During real rTMS treatment a statistically significant decrease of negative symptoms was found (approximately 29% reduction in the PANSS negative symptom subscale and 50% reduction in the SANS). No adverse events occurred during therapy except for a mild headaches. In sham rTMS treatment a decrease of negative symptoms was also identified, but to a lesser extent than in real rTMS (about 7% in negative subscale PANSS and 13% in SANS). The change in SANS achieved statistical significance. Mutual comparison revealed a greater decrease of negative symptoms in favor of real rTMS in contrast to sham rTMS. The augmentation of rTMS enabled patients to experience a significant decrease in the severity of the negative symptoms. Our results support the therapeutic potential of rTMS at higher frequency for negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 12 | Mol. Psychiatry 2007 Apr 12: 398-407 |
| PMID | 17389905 |
| Title | A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth. |
| Abstract | Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast two-hybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C(2)H(2)-type zinc-finger motif and COILed-COIL domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC(1)) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 13 | Biomacromolecules 2007 Dec 8: 3871-8 |
| PMID | 17979243 |
| Title | "Schizophrenic" micellization associated with coil-to-helix transitions based on polypeptide hybrid double hydrophilic rod-coil diblock copolymer. |
| Abstract | A polypeptide hybrid double hydrophilic diblock copolymer (DHBC), poly( N-isopropylacrylamide)- b-poly( l-glutamic acid) (PNIPAM- b-PLGA), was synthesized via the ring-opening polymerization of gamma-benzyl- l-glutamate N-carboxyanhydride (BLG-NCA) using monoamino-terminated PNIPAM as the macroinitiator, followed by deprotection of benzyl groups under alkaline conditions. Containing a thermoresponsive PNIPAM block and a pH-responsive PLGA block, the obtained polypeptide hybrid diblock copolymer molecularly dissolves in aqueous solution at alkaline pH and room temperature but supramolecularly self-assembles into PNIPAM-core micelles at alkaline pH and elevated temperatures and PLGA-core micelles at acidic pH and room temperature accompanied with COIL-to-helix transition of the PLGA sequence. The pH- and thermoresponsive "schizophrenic" micellization behavior of PNIPAM- b-PLGA diblock copolymer has been investigated by (1)H NMR, optical transmittance, fluorescence probe measurement, transmission electron microscopy (TEM), dynamic and static laser light scattering (LLS), and circular dichroism (CD) spectroscopy. Moreover, the micellization process was investigated employing stopped-flow light scattering technique. The pH-induced micelle growth of PNIPAM- b-PLGA in aqueous solution exhibits drastically different kinetics compared to that of conventional pH-responsive DHBCs, probably due to the stabilization effects exerted by the formed alpha-helix secondary structures within the PLGA core at low pH. Exhibiting "schizophrenic" micellization, the polypeptide sequence of PNIPAM- b-PLGA can either locate within micelle cores or stabilizing coronas. The incorporation of polypeptide block into DHBCs can endow them with structural versatility, tunable spatial arrangement of chain segments within self-assembled nanostructures, and broader applications in the field of biomedicines. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 14 | J. Cell Biol. 2008 Jun 181: 791-801 |
| PMID | 18504299 |
| Title | DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release. |
| Abstract | schizophrenia is one of the most debilitating neuropsychiatric disorders, affecting 0.5-1.0% of the population worldwide. Its pathology, attributed to defects in synaptic transmission, remains elusive. The dystrobrevin-binding protein 1 (DTNBP1) gene, which encodes a COILed-COIL protein, dysbindin, is a major susceptibility gene for schizophrenia. Our previous results have demonstrated that the sandy (sdy) mouse harbors a spontaneously occurring deletion in the DTNBP1 gene and expresses no dysbindin protein (Li, W., Q. Zhang, N. Oiso, E.K. Novak, R. Gautam, E.P. O'Brien, C.L. Tinsley, D.J. Blake, R.A. Spritz, N.G. Copeland, et al. 2003. Nat. Genet. 35:84-89). Here, using amperometry, whole-cell patch clamping, and electron microscopy techniques, we discovered specific defects in neurosecretion and vesicular morphology in neuroendocrine cells and hippocampal synapses at the single vesicle level in sdy mice. These defects include larger vesicle size, slower quantal vesicle release, lower release probability, and smaller total population of the readily releasable vesicle pool. These findings suggest that dysbindin functions to regulate exocytosis and vesicle biogenesis in endocrine cells and neurons. Our work also suggests a possible mechanism in the pathogenesis of schizophrenia at the synaptic level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 15 | Conf Proc IEEE Eng Med Biol Soc 2008 -1 2008: 4270-3 |
| PMID | 19163656 |
| Title | Effect of the different winding methods of coil on electromagnetic field during transcranial magnetic stimulation. |
| Abstract | Transcranial magnetic stimulation (TMS) is a powerful, non-invasive tool for investigating functions in the brain. The target inside the head is stimulated with eddy currents induced in the tissues by the time-varying magnetic field. TMS has been used in several applications in medical and clinical research which include brain mapping, treatment of mood disorder and schizophrenia, treatment of epilepsy, treatment of chronic pain and so on. The stimulation effect can be affected by the stimulation intensity. For COILs with the same shape, different winding methods make the COIL have different stimulation intensity. In this paper, three different methods for winding circular COILs are discussed. The electromagnetic fields induced by the three different circular COILs were analyzed. The results show that the circular COIL with the pancake COIL winding has the strongest stimulation intensity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 16 | Biol. Psychiatry 2008 Nov 64: 815-9 |
| PMID | 18632089 |
| Title | Connectivity between posterior parietal cortex and ipsilateral motor cortex is altered in schizophrenia. |
| Abstract | Recent advances have highlighted the hypothesis of schizophrenia as a disorder causing defective connectivity among distinct cortical regions. Neurophysiological evidence supporting this hypothesis, however, is still lacking. In the present study, we used a novel twin-COIL transcranial magnetic stimulation (tcTMS) approach to investigate ipsilateral parieto-motor connectivity in 20 schizophrenic patients (14 medicated, 6 unmedicated) and in 15 healthy age-matched volunteers. In healthy subjects, a conditioning TMS pulse applied over the ipsilateral posterior parietal cortex (PPC) at 90% of resting motor threshold (RMT) intensity was able to increase the excitability of the hand area of the right primary motor cortex, with peaks at interstimulus intervals (ISIs) of 4 and 15 msec. This paradigm of stimulation failed to reveal any facilitatory parieto-motor interaction in medicated and unmedicated schizophrenic patients. The between-group difference in paired-pulse facilitation was not ISI-specific. In following analyses, we found that the effects across ISIs induced by PPC conditioning at 90% RMT correlated with the Global Assessment Functioning score and with the negative subscale of the Positive and Negative Syndrome Scale, showing that patients with a better global functioning and lower negative symptoms had less impaired connectivity. Moreover the same parameter correlated with illness duration. Parieto-motor connectivity is impaired in schizophrenia. Cortico-cortical disconnection might be a core feature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 17 | Biol. Psychiatry 2008 Nov 64: 815-9 |
| PMID | 18632089 |
| Title | Connectivity between posterior parietal cortex and ipsilateral motor cortex is altered in schizophrenia. |
| Abstract | Recent advances have highlighted the hypothesis of schizophrenia as a disorder causing defective connectivity among distinct cortical regions. Neurophysiological evidence supporting this hypothesis, however, is still lacking. In the present study, we used a novel twin-COIL transcranial magnetic stimulation (tcTMS) approach to investigate ipsilateral parieto-motor connectivity in 20 schizophrenic patients (14 medicated, 6 unmedicated) and in 15 healthy age-matched volunteers. In healthy subjects, a conditioning TMS pulse applied over the ipsilateral posterior parietal cortex (PPC) at 90% of resting motor threshold (RMT) intensity was able to increase the excitability of the hand area of the right primary motor cortex, with peaks at interstimulus intervals (ISIs) of 4 and 15 msec. This paradigm of stimulation failed to reveal any facilitatory parieto-motor interaction in medicated and unmedicated schizophrenic patients. The between-group difference in paired-pulse facilitation was not ISI-specific. In following analyses, we found that the effects across ISIs induced by PPC conditioning at 90% RMT correlated with the Global Assessment Functioning score and with the negative subscale of the Positive and Negative Syndrome Scale, showing that patients with a better global functioning and lower negative symptoms had less impaired connectivity. Moreover the same parameter correlated with illness duration. Parieto-motor connectivity is impaired in schizophrenia. Cortico-cortical disconnection might be a core feature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 18 | Psychiatr. Genet. 2009 Jun 19: 162 |
| PMID | 19404162 |
| Title | No association between Rho-associated coiled-coil forming protein serine/threonine kinase1 gene and schizophrenia in the Japanese population. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 19 | Mol. Psychiatry 2009 Aug 14: 796-803 |
| PMID | 18332876 |
| Title | A genome-wide association study in 574 schizophrenia trios using DNA pooling. |
| Abstract | The cost of genome-wide association (GWA) studies can be prohibitively high when large samples are genotyped. We conducted a GWA study on schizophrenia (SZ) and to reduce the cost, we used DNA pooling. We used a parent-offspring trios design to avoid the potential problems of population stratification. We constructed pools from 605 unaffected controls, 574 SZ patients and a third pool from all the parents of the patients. We hybridized each pool eight times on Illumina HumanHap550 arrays. We estimated the allele frequencies of each pool from the averaged intensities of the arrays. The significance level of results in the trios sample was estimated on the basis of the allele frequencies in cases and non-transmitted pseudocontrols, taking into account the technical variability of the data. We selected the highest ranked SNPs for individual genotyping, after excluding poorly performing SNPs and those that showed a trend in the opposite direction in the control pool. We genotyped 63 SNPs in 574 trios and analysed the results with the transmission disequilibrium test. Forty of those were significant at P<0.05, with the best result at P=1.2 x 10(-6) for rs11064768. This SNP is within the gene CCDC60, a COILed-COIL domain gene. The third best SNP (P=0.00016) is rs893703, within RBP1, a candidate gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 20 | Biochemistry 2009 Aug 48: 7746-55 |
| PMID | 19583211 |
| Title | Oligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C. |
| Abstract | Genetic studies have established a role of disrupted-in-schizophrenia-1 (DISC1) in chronic mental diseases (CMD). Limited experimental data are available on the domain structure of the DISC1 protein although multiple interaction partners are known including a self-association domain within the middle part of DISC1 (residues 403-504). The DISC1 C-terminal domain is deleted in the original Scottish pedigree where DISC1 harbors two COILed-COIL domains and disease-associated polymorphisms at 607 and 704, as well as the important nuclear distribution element-like 1 (NDEL1) binding site at residues 802-839. Here, we performed mutagenesis studies of the C-terminal domain of the DISC1 protein (residues 640-854) and analyzed the expressed constructs by biochemical and biophysical methods. We identified novel DISC1 self-association motifs and the necessity of their concerted action for orderly assembly: the region 765-854 comprising a COILed-COIL domain is a dimerization domain and the region 668-747 an oligomerization domain; dimerization was found to be a prerequisite for orderly assembly of oligomers. Consistent with this, disease-associated polymorphism C704 displayed a slightly higher oligomerization propensity. The heterogeneity of DISC1 multimers in vitro was confirmed with a monoclonal antibody binding exclusively to HMW multimers. We also identified C-terminal DISC1 fragments in human brains, suggesting that C-terminal fragments could carry out DISC1-dependent functions. When the DISC1 C-terminal domain was transiently expressed in cells, it assembled into a range of soluble and insoluble multimers with distinct fractions selectively binding NDEL1, indicating functionality. Our results suggest that assembly of the C-terminal domain is controlled by distinct domains including the disease-associated polymorphism 704 and is functional in vivo. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 21 | Brain Stimul 2009 Jan 2: 14-21 |
| PMID | 20633399 |
| Title | Controversy: Repetitive transcranial magnetic stimulation or transcranial direct current stimulation shows efficacy in treating psychiatric diseases (depression, mania, schizophrenia, obsessive-complusive disorder, panic, posttraumatic stress disorder). |
| Abstract | Brain imaging studies performed over the past 20 years have generated new knowledge about the specific brain regions involved in the brain diseases that have been classically labeled as psychiatric. These include the mood and anxiety disorders, and the schizophrenias. As a natural next step, clinical researchers have investigated whether the minimally invasive brain stimulation technologies (transcranial magnetic stimulation [TMS] or transcranial direct current stimulation [tDCS]) might potentially treat these disorders. In this review, we critically review the research studies that have examined TMS or tDCS as putative treatments for depression, mania, obsessive-complusive disorder, posttraumatic stress disorder, panic disorder, or schizophrenia. (Separate controversy articles deal with using TMS or tDCS to treat pain or tinnitus. We will not review here the large number of studies using TMS or tDCS as research probes to understand disease mechanisms of psychiatric disorders.) Although there is an extensive body of randomized controlled trials showing antidepressant effects of daily prefrontal repetitive TMS, the magnitude or durability of this effect remains controversial. US Food and Drug Administration approval of TMS for depression was recently granted. There is much less data in all other diseases, and therapeutic effects in other psychiatric conditions, if any, are still controversial. Several issues and problems extend across all psychiatric TMS studies, including the optimal method for a sham control, appropriate COIL location, best device parameters (intensity, frequency, dosage, and dosing schedule) and refining what subjects should be doing during treatment (activating pathologic circuits or not). In general, TMS or tDCS as a treatment for most psychiatric disorders remains exciting but controversial, other than prefrontal TMS for depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 22 | Brain Stimul 2009 Jan 2: 14-21 |
| PMID | 20633399 |
| Title | Controversy: Repetitive transcranial magnetic stimulation or transcranial direct current stimulation shows efficacy in treating psychiatric diseases (depression, mania, schizophrenia, obsessive-complusive disorder, panic, posttraumatic stress disorder). |
| Abstract | Brain imaging studies performed over the past 20 years have generated new knowledge about the specific brain regions involved in the brain diseases that have been classically labeled as psychiatric. These include the mood and anxiety disorders, and the schizophrenias. As a natural next step, clinical researchers have investigated whether the minimally invasive brain stimulation technologies (transcranial magnetic stimulation [TMS] or transcranial direct current stimulation [tDCS]) might potentially treat these disorders. In this review, we critically review the research studies that have examined TMS or tDCS as putative treatments for depression, mania, obsessive-complusive disorder, posttraumatic stress disorder, panic disorder, or schizophrenia. (Separate controversy articles deal with using TMS or tDCS to treat pain or tinnitus. We will not review here the large number of studies using TMS or tDCS as research probes to understand disease mechanisms of psychiatric disorders.) Although there is an extensive body of randomized controlled trials showing antidepressant effects of daily prefrontal repetitive TMS, the magnitude or durability of this effect remains controversial. US Food and Drug Administration approval of TMS for depression was recently granted. There is much less data in all other diseases, and therapeutic effects in other psychiatric conditions, if any, are still controversial. Several issues and problems extend across all psychiatric TMS studies, including the optimal method for a sham control, appropriate COIL location, best device parameters (intensity, frequency, dosage, and dosing schedule) and refining what subjects should be doing during treatment (activating pathologic circuits or not). In general, TMS or tDCS as a treatment for most psychiatric disorders remains exciting but controversial, other than prefrontal TMS for depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 23 | J. Biol. Chem. 2010 Dec 285: 40554-61 |
| PMID | 20956536 |
| Title | CAMDI, a novel disrupted in schizophrenia 1 (DISC1)-binding protein, is required for radial migration. |
| Abstract | Centrosomes play a crucial role in the directed migration of developing neurons. However, the underlying mechanism is poorly understood. This study has identified a novel disrupted in schizophrenia 1 (DISC1)-interacting protein, named CAMDI after COILed-COIL protein associated with myosin II and DISC1, which translocates to the centrosome in a DISC1-dependent manner. Knockdown of CAMDI by shRNA revealed severely impaired radial migration with disoriented centrosomes. A yeast two-hybrid screen identified myosin II as a binding protein of CAMDI. CAMDI interacts preferentially with phosphomyosin II and induces an accumulation of phosphomyosin II at the centrosome in a DISC1-dependent manner. Interestingly, one single nucleotide polymorphism of the CAMDI gene (R828W) is identified, and its gene product was found to reduce the binding ability to phosphomyosin II. Furthermore, mice with overexpression of R828W in neurons exhibit an impaired radial migration. Our findings indicate that CAMDI is required for radial migration probably through DISC1 and myosin II-mediated centrosome positioning during neuronal development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 24 | J. Biol. Chem. 2010 Dec 285: 38630-40 |
| PMID | 20921223 |
| Title | Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression. |
| Abstract | Dysbindin-1 is a 50-kDa COILed-COIL-containing protein encoded by the gene DTNBP1 (dystrobrevin-binding protein 1), a candidate genetic factor for schizophrenia. Genetic variations in this gene confer a susceptibility to schizophrenia through a decreased expression of dysbindin-1. It was reported that dysbindin-1 regulates the expression of presynaptic proteins and the release of neurotransmitters. However, the precise functions of dysbindin-1 are largely unknown. Here, we show that dysbindin-1 is a novel nucleocytoplasmic shuttling protein and translocated to the nucleus upon treatment with leptomycin B, an inhibitor of exportin-1/CRM1-mediated nuclear export. Dysbindin-1 harbors a functional nuclear export signal necessary for its nuclear export, and the nucleocytoplasmic shuttling of dysbindin-1 affects its regulation of synapsin I expression. In brains of sandy mice, a dysbindin-1-null strain that displays abnormal behaviors related to schizophrenia, the protein and mRNA levels of synapsin I are decreased. These findings demonstrate that the nucleocytoplasmic shuttling of dysbindin-1 regulates synapsin I expression and thus may be involved in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 25 | Hum Brain Mapp 2010 Nov 31: 1643-52 |
| PMID | 20162598 |
| Title | Optimal transcranial magnetic stimulation coil placement for targeting the dorsolateral prefrontal cortex using novel magnetic resonance image-guided neuronavigation. |
| Abstract | The dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of several psychiatric illnesses including major depressive disorder and schizophrenia. In this regard, the DLPFC has been targeted in repetitive transcranial magnetic stimulation (rTMS) studies as a form of treatment to those patients who are resistant to medications. The '5-cm method' and the '10-20 method' for positioning the transcranial magnetic stimulation (TMS) COIL over DLPFC have been scrutinised due to poor targeting accuracies attributed to inter-subject variability. We evaluated the accuracy of such methods to localise the DLPFC on the scalp in 15 healthy subjects and compared them with our novel neuronavigational method, which first estimates the DLPFC position in the cortex based on a standard template and then determines the most appropriate position on the scalp in which to place the TMS COIL. Our neuronavigational method yielded a scalp position for the left DLPFC between electrodes F3 and F5 in standard space and was closest to electrode F5 in individual space. Further, we found that there was significantly less inter-subject variability using our neuronavigational method for localising the DLPFC on the scalp compared with the '5-cm method' and the '10-20 method'. Our findings also suggest that the '10-20 method' is superior to the '5-cm method' in reducing inter-subject variability and that electrode F5 should be the stimulation location of choice when MRI co-registration is not available. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 26 | Psychiatry Res 2010 Apr 176: 132-6 |
| PMID | 20202691 |
| Title | Cortical motor neurophysiology of patients with schizophrenia: a study using transcranial magnetic stimulation. |
| Abstract | Trancranial magnetic stimulation (TMS) provides a non-invasive means for exploring physiological alterations of central motor control in a variety of neuropsychiatric diseases. The present study aimed to assess the neurophysiological profile of muscle evoked responses to a standard TMS procedure in 51 medicated patients with schizophrenia and 51 age- and sex-matched healthy subjects. Motor evoked potentials (MEPs) from the abductor pollicis brevis muscle were elicited by stimulation of the contralateral motor cortex with a circular COIL. The hot spot was marked, and the resting motor threshold (RMTh), the stimulus intensity for maximum MEP (SI-max), the post-stimulus silent period of voluntary muscle activity, and MEP latency and amplitude were measured. The main findings were the significantly higher than normal values for RMTh and SI-max, which are both indices of neuronal excitability. In particular, patients who had ziprasidone in their therapeutic regimen demonstrated the highest SI-max for both hemispheres, and the highest RMTh for the left hemisphere, patients receiving olanzapine demonstrated the lowest RMTh for the left hemisphere, and those on quetiapine showed intermediate values. The silent period was longer in the patients than in the controls when a RMTh-related SI was used and did not differ between the two groups when a fixed SI was used. We concluded that the observed TMS changes could be interpreted as primary alterations of intracortical motor excitability followed by defects of cortical inhibition and should be attributed to schizophrenia, antipsychotic medication or the interaction between the two factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 27 | Dev. Biol. 2010 Apr 340: 41-53 |
| PMID | 20096683 |
| Title | A mutation in the pericentrin gene causes abnormal interneuron migration to the olfactory bulb in mice. |
| Abstract | Precise control of neuronal migration is essential for proper function of the brain. Taking a forward genetic screen, we isolated a mutant mouse with defects in interneuron migration. By genetic mapping, we identified a frame shift mutation in the pericentrin (Pcnt) gene. The Pcnt gene encodes a large centrosomal COILed-COIL protein that has been implicated in schizophrenia. Recently, frame shift and premature termination mutations in the pericentrin (PCNT) gene were identified in individuals with Seckel syndrome and microcephalic osteodysplastic primordial dwarfism (MOPD II), both of which are characterized by greatly reduced body and brain sizes. The mouse Pcnt mutant shares features with the human syndromes in its overall growth retardation and reduced brain size. We found that dorsal lateral ganglionic eminence (dLGE)-derived olfactory bulb interneurons are severely affected and distributed abnormally in the rostral forebrain in the mutant. Furthermore, mutant interneurons exhibit abnormal migration behavior and RNA interference knockdown of Pcnt impairs cell migration along the rostal migratory stream (RMS) into the olfactory bulb. These findings indicate that pericentrin is required for proper migration of olfactory bulb interneurons and provide a developmental basis for association of pericentrin function with interneuron defects in human schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 28 | World J. Biol. Psychiatry 2010 Aug 11: 719-28 |
| PMID | 20446881 |
| Title | Different apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase levels in cerebrospinal fluid of schizophrenia patients and healthy controls. |
| Abstract | To identify proteins differentially expressed in schizophrenia patients, we collected 50 microl cerebrospinal fluid from 17 first-episode schizophrenia patients and 10 healthy controls. Their proteins were separated by two-dimensional gel electrophoresis without using any depletion method and identified by mass spectrometry. Approximately 550 spots were detected, six of which had significantly different intensities in schizophrenia compared to control specimens. We were able to validate in individual samples the upregulation of apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase by Western blot analyses and detect the downregulation of transthyretin, TGF-beta receptor type-1 and COILed-COIL domain-containing protein 3 precursor. These findings may help to elucidate the disease mechanisms and confirm the hypothesis of disturbed cholesterol and phospholipid metabolism in schizophrenia, and thus reveal the final role players. Moreover, a grouped protein expression analysis of apolipoprotein E, apolipoprotein A-I, and prostaglandin-H2 D-isomerase in cerebrospinal fluid from patients might be a potential diagnostic tool for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 29 | J Med Assoc Thai 2010 May 93: 580-6 |
| PMID | 20524444 |
| Title | Transcranial magnetic stimulation for treatment resistant depression: six case reports and review. |
| Abstract | Depressive disorder is a common, recurrent, and chronic disorder that is a leading cause of functional impairment and disability An estimated 20-40% of patients do not benefit sufficiently from existing therapies. Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for psychiatric illness. Evidences support its use in depression, either alone or combined with antidepressants. During rTMS, a time-varying current is discharged in an insulated COIL attached to the scalp surface, generated a brief dynamic magnetic field that can freely, non-invasively penetrate the skull and induce the eddy current in the neural tissue. The rTMS works as a neuro-stimulator and neuro-modulator at the same time, which can modify the functionality of the brain circuits involved in the pathophysiology of mental illness especially in depressive disorder. The authors reported six cases of various types of depressive disorder, double depression, borderline personality disorder with depression, psychotic depression with nihilistic delusion, post-schizophrenic depression, and treatment resistant depression non-respond to electroconvulsive therapy (ECT). Four in six cases responded well with 10 daily sessions of rTMS. However, a patient with psychotic depression yielded no response. Five patients with moderate depression reached the remission criteria of Hamilton Depression Rating Scale-17 items (HAM-D-17). The means HAM-D-17 of rTMS responders were decreased from 22.4 (SD = 4.1) to 5.2 (SD = 2.9). A patient with psychotic depression did not show any benefit from rTMS and got subsequent modified ECT. This is the first cases report of using rTMS for the treatment of depression in Thailand. The rTMS gave promising results in various forms of depression. Due to its safety needing no anesthesia, suitable for out-patient care, rTMS might be a treatment alternative in the acute phase of moderate non-psychotic depression. The authors also reviewed the current evidence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 30 | Clin Neurophysiol 2011 Mar 122: 512-7 |
| PMID | 20864396 |
| Title | Impaired inter-hemispheric facilitatory connectivity in schizophrenia. |
| Abstract | To investigate the inter-hemispheric connections between the dorsal premotor cortex (dPM) and contralateral primary motor cortex (M1) in schizophrenia. Sixteen medicated, nine unmedicated schizophrenia patients and 20 healthy age-matched subjects were studied by twin-COIL Transcranial Magnetic Stimulation. To activate distinct facilitatory and inhibitory transcallosal pathways between dPM and the contralateral M1, the intensity of dPM stimulation was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of active motor threshold). Interstimulus intervals between conditioning stimulus and test stimulus were 6, 8 and 15 ms. schizophrenia patients had comparable efficacy of the inhibitory pathway. On the other hand, medicated patients showed less facilitation of contralateral M1 following dPM stimulation at 80% of active motor threshold, at interstimulus interval=8 ms. The individual amount of facilitation induced by dPM conditioning at 80% of active motor threshold at interstimulus interval=8 ms correlated negatively with negative symptoms. Inter-hemispheric facilitatory dPM-M1 connectivity is selectively altered in schizophrenia. This study produced evidence that dPM-M1 connectivity is dysfunctional and that correlates with negative symptoms. These results converge with previous studies which strongly hypothesize that inter- and intra-hemispheric connectivity disturbances may play a major role in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 31 | Hum. Mol. Genet. 2011 Oct 20: R175-81 |
| PMID | 21852244 |
| Title | Structure and evolutionary history of DISC1. |
| Abstract | Evolutionary and protein structural analyses can provide functional insights into genes implicated in human psychiatric diseases. Even eukaryotic organisms lacking nervous systems contain homologues of many key signalling molecules of animal neurons implying that human cognition derives, in part, from modifications of ancestral molecules and complexes. One protein whose evolutionary origin is obscure is DISC1 (disrupted in schizophrenia 1) whose gene locus has been associated with many psychiatric conditions including schizophrenia, clinical depression and bipolar disorder. This protein's rapid evolution and its unusual amino acid and ?-helix composition have hindered searches for DISC1 homologues in species other than vertebrates. Here, we review the evolution and structure of the DISC1 protein in the light of in-depth sequence analyses. These predict DISC1 orthologues in diverse eukaryotic organisms, including early-branching animals such as amphioxus, sea anemone, amoebas and Trichoplax, and in plants and algae. DISC1 thus is widespread among eukaryotes, although it remains absent from fungi, nematodes and Diptera, including fruit flies. These observations now permit studies of DISC1 function in simple non-vertebrate model organisms. Surprisingly, these analyses also identify between two and four sequence repeats in DISC1 orthologues. The first two of these repeats show significant sequence similarity to the UVR family of globular domains. These UVR-like repeats are predicted to contain, not COILed COIL structures, but rather two closely associated antiparallel ?-helices. One common missense variant in DISC1 (L607F) lies within the second DISC1 UVR-like domain. These observations should assist in delineating the functional regions of the DISC1 protein. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 32 | Langmuir 2011 Jun 27: 7231-40 |
| PMID | 21563804 |
| Title | Temperature- and pH-responsive self-assembly of poly(propylene oxide)-b-poly(lysine) block copolymers in aqueous solution. |
| Abstract | A series of poly(propylene oxide)-b-poly(L-lysine) (PPO-PK) block copolymers were synthesized using Huisgen's 1,3-dipolar cycloaddition, and the solution self-assembly was studied using transmission electron microscopy, circular dichroism spectroscopy, and dynamic and static light scattering techniques. In contrast to previous studies of poly(lysine)-based block copolymers, PPO-PK exhibits a significant shift in the pH associated with the helix-COIL transition of the poly(lysine) block, potentially a result of decreased hydrophobicity in the core PPO block. Given the proximity of the lower critical solution temperature of the PPO block, these materials exhibit both pH and temperature-responsive (i.e., "schizophrenic") self-assembly, the latter of which was interpreted in terms of changes in the second osmotic virial coefficient. Finally, the vesicle morphology obtained from these polymers was studied for the propensity in drug encapsulation and passive release. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 33 | Ann Gen Psychiatry 2011 -1 10: 3 |
| PMID | 21303566 |
| Title | Deep transcranial magnetic stimulation for the treatment of auditory hallucinations: a preliminary open-label study. |
| Abstract | schizophrenia is a chronic and disabling disease that presents with delusions and hallucinations. Auditory hallucinations are usually expressed as voices speaking to or about the patient. Previous studies have examined the effect of repetitive transcranial magnetic stimulation (TMS) over the temporoparietal cortex on auditory hallucinations in schizophrenic patients. Our aim was to explore the potential effect of deep TMS, using the H COIL over the same brain region on auditory hallucinations. Eight schizophrenic patients with refractory auditory hallucinations were recruited, mainly from Beer Ya'akov Mental Health Institution (Tel Aviv university, Israel) ambulatory clinics, as well as from other hospitals outpatient populations. Low-frequency deep TMS was applied for 10 min (600 pulses per session) to the left temporoparietal cortex for either 10 or 20 sessions. Deep TMS was applied using Brainsway's H1 COIL apparatus. Patients were evaluated using the Auditory Hallucinations Rating Scale (AHRS) as well as the Scale for the Assessment of Positive Symptoms scores (SAPS), Clinical Global Impressions (CGI) scale, and the Scale for Assessment of Negative Symptoms (SANS). This preliminary study demonstrated a significant improvement in AHRS score (an average reduction of 31.7% ± 32.2%) and to a lesser extent improvement in SAPS results (an average reduction of 16.5% ± 20.3%). In this study, we have demonstrated the potential of deep TMS treatment over the temporoparietal cortex as an add-on treatment for chronic auditory hallucinations in schizophrenic patients. Larger samples in a double-blind sham-controlled design are now being preformed to evaluate the effectiveness of deep TMS treatment for auditory hallucinations. This trial is registered with clinicaltrials.gov (identifier: NCT00564096). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 34 | Ann Gen Psychiatry 2011 -1 10: 3 |
| PMID | 21303566 |
| Title | Deep transcranial magnetic stimulation for the treatment of auditory hallucinations: a preliminary open-label study. |
| Abstract | schizophrenia is a chronic and disabling disease that presents with delusions and hallucinations. Auditory hallucinations are usually expressed as voices speaking to or about the patient. Previous studies have examined the effect of repetitive transcranial magnetic stimulation (TMS) over the temporoparietal cortex on auditory hallucinations in schizophrenic patients. Our aim was to explore the potential effect of deep TMS, using the H COIL over the same brain region on auditory hallucinations. Eight schizophrenic patients with refractory auditory hallucinations were recruited, mainly from Beer Ya'akov Mental Health Institution (Tel Aviv university, Israel) ambulatory clinics, as well as from other hospitals outpatient populations. Low-frequency deep TMS was applied for 10 min (600 pulses per session) to the left temporoparietal cortex for either 10 or 20 sessions. Deep TMS was applied using Brainsway's H1 COIL apparatus. Patients were evaluated using the Auditory Hallucinations Rating Scale (AHRS) as well as the Scale for the Assessment of Positive Symptoms scores (SAPS), Clinical Global Impressions (CGI) scale, and the Scale for Assessment of Negative Symptoms (SANS). This preliminary study demonstrated a significant improvement in AHRS score (an average reduction of 31.7% ± 32.2%) and to a lesser extent improvement in SAPS results (an average reduction of 16.5% ± 20.3%). In this study, we have demonstrated the potential of deep TMS treatment over the temporoparietal cortex as an add-on treatment for chronic auditory hallucinations in schizophrenic patients. Larger samples in a double-blind sham-controlled design are now being preformed to evaluate the effectiveness of deep TMS treatment for auditory hallucinations. This trial is registered with clinicaltrials.gov (identifier: NCT00564096). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 35 | Neuro Endocrinol. Lett. 2012 -1 33: 90-7 |
| PMID | 22467118 |
| Title | Does repetitive transcranial magnetic stimulation have a positive effect on working memory and neuronal activation in treatment of negative symptoms of schizophrenia? |
| Abstract | The objective of the study was to find out whether, under the conditions of a double-blind, placebo COIL controlled study, high-frequency repetitive transcranial magnetic stimulation (TMS) over the left prefrontal cortex will show positive effects on working memory with simultaneous assessment of respective changes in neuronal activation. Stimulation treatment led to a reduction of seriousness of negative schizophrenia symptoms in both comparative groups. However, mutual comparison of real (n=19) and sham (n=11) rTMS, respectively, has shown that the effect of real rTMS was statistically significantly higher compared with placebo stimulation. During stimulation treatment an improvement in working memory performance was also found. No statistically significant difference between the real and placebo sham rTMS, respectively, was established. The rate of neuronal activation did not change at all during rTMS treatment. From clinical point of view rTMS seems to be a well-tolerated neurostimulation method for treatment of negative schizophrenia symptoms with favourable of impact on cognitive functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 36 | J. Biol. Chem. 2012 Sep 287: 32381-93 |
| PMID | 22843697 |
| Title | The mitosis and neurodevelopment proteins NDE1 and NDEL1 form dimers, tetramers, and polymers with a folded back structure in solution. |
| Abstract | Paralogs NDE1 (nuclear distribution element 1) and NDEL1 (NDE-like 1) are essential for mitosis and neurodevelopment. Both proteins are predicted to have similar structures, based upon high sequence similarity, and they co-complex in mammalian cells. X-ray diffraction studies and homology modeling suggest that their N-terminal regions (residues 8-167) adopt continuous, extended ?-helical COILed-COIL structures, but no experimentally derived information on the structure of their C-terminal regions or the architecture of the full-length proteins is available. In the case of NDE1, no biophysical data exists. Here we characterize the structural architecture of both full-length proteins utilizing negative stain electron microscopy along with our established paradigm of chemical cross-linking followed by tryptic digestion, mass spectrometry, and database searching, which we enhance using isotope labeling for mixed NDE1-NDEL1. We determined that full-length NDE1 forms needle-like dimers and tetramers in solution, similar to crystal structures of NDEL1, as well as chain-like end-to-end polymers. The C-terminal domain of each protein, required for interaction with key protein partners dynein and DISC1 (disrupted-in-schizophrenia 1), includes a predicted disordered region that allows a bent back structure. This facilitates interaction of the C-terminal region with the N-terminal COILed-COIL domain and is in agreement with previous results showing N- and C-terminal regions of NDEL1 and NDE1 cooperating in dynein interaction. It sheds light on recently identified mutations in the NDE1 gene that cause truncation of the encoded protein. Additionally, analysis of mixed NDE1-NDEL1 complexes demonstrates that NDE1 and NDEL1 can interact directly. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 37 | Ann Gen Psychiatry 2012 -1 11: 13 |
| PMID | 22559192 |
| Title | Deep transcranial magnetic stimulation add-on for the treatment of auditory hallucinations: a double-blind study. |
| Abstract | About 25% of schizophrenia patients with auditory hallucinations are refractory to pharmacotherapy and electroconvulsive therapy. We conducted a deep transcranial magnetic stimulation (TMS) pilot study in order to evaluate the potential clinical benefit of repeated left temporoparietal cortex stimulation in these patients. The results were encouraging, but a sham-controlled study was needed to rule out a placebo effect. A total of 18 schizophrenic patients with refractory auditory hallucinations were recruited, from Beer Yaakov MHC and other hospitals outpatient populations. Patients received 10 daily treatment sessions with low-frequency (1 Hz for 10 min) deep TMS applied over the left temporoparietal cortex, using the H1 COIL at the intensity of 110% of the motor threshold. Procedure was either real or sham according to patient randomization. Patients were evaluated via the Auditory Hallucinations Rating Scale, Scale for the Assessment of Positive Symptoms-Negative Symptoms, Clinical Global Impressions, and Quality of Life Questionnaire. In all, 10 patients completed the treatment (10 TMS sessions). Auditory hallucination scores of both groups improved; however, there was no statistical difference in any of the scales between the active and the sham treated groups. Low-frequency deep TMS to the left temporoparietal cortex using the protocol mentioned above has no statistically significant effect on auditory hallucinations or the other clinical scales measured in schizophrenic patients. Clinicaltrials.gov identifier: NCT00564096. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 38 | Ann Gen Psychiatry 2012 -1 11: 13 |
| PMID | 22559192 |
| Title | Deep transcranial magnetic stimulation add-on for the treatment of auditory hallucinations: a double-blind study. |
| Abstract | About 25% of schizophrenia patients with auditory hallucinations are refractory to pharmacotherapy and electroconvulsive therapy. We conducted a deep transcranial magnetic stimulation (TMS) pilot study in order to evaluate the potential clinical benefit of repeated left temporoparietal cortex stimulation in these patients. The results were encouraging, but a sham-controlled study was needed to rule out a placebo effect. A total of 18 schizophrenic patients with refractory auditory hallucinations were recruited, from Beer Yaakov MHC and other hospitals outpatient populations. Patients received 10 daily treatment sessions with low-frequency (1 Hz for 10 min) deep TMS applied over the left temporoparietal cortex, using the H1 COIL at the intensity of 110% of the motor threshold. Procedure was either real or sham according to patient randomization. Patients were evaluated via the Auditory Hallucinations Rating Scale, Scale for the Assessment of Positive Symptoms-Negative Symptoms, Clinical Global Impressions, and Quality of Life Questionnaire. In all, 10 patients completed the treatment (10 TMS sessions). Auditory hallucination scores of both groups improved; however, there was no statistical difference in any of the scales between the active and the sham treated groups. Low-frequency deep TMS to the left temporoparietal cortex using the protocol mentioned above has no statistically significant effect on auditory hallucinations or the other clinical scales measured in schizophrenic patients. Clinicaltrials.gov identifier: NCT00564096. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 39 | Arch. Gen. Psychiatry 2012 Jul 69: 662-71 |
| PMID | 22393203 |
| Title | Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging. |
| Abstract | schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method. To test the hypothesis that direct physiological stimulation of the cortex will produce an abnormal thalamic response in individuals with schizophrenia. We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically connected regions (thalamus, medial superior frontal cortex, insula) using concurrent functional magnetic resonance imaging. The mean hemodynamic response from these regions was fit with the sum of 2 gamma functions, and response parameters were compared across groups. Academic research laboratory. Patients with schizophrenia and sex- and age-matched psychiatrically healthy subjects were recruited from the community. Peak amplitude of the thalamic hemodynamic response to spTMS of the precentral gyrus. The spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared with healthy subjects, patients with schizophrenia showed a reduced response to spTMS in the thalamus (P=1.86 × 10(-9)) and medial superior frontal cortex (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS COIL discharge. Functional connectivity analyses revealed weaker thalamus-medial superior frontal cortex and thalamus-insula connectivity in patients with schizophrenia compared with control subjects. Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 40 | Neurochem. Int. 2013 May 62: 870-2 |
| PMID | 23439384 |
| Title | Expression and differential response to haloperidol treatment of Cyclon/CCDC86 mRNA in schizophrenia patients. |
| Abstract | A gene known as Cyclon (cytokine-induced protein with COILed-COIL domain) or CCDC86 (COILed-COIL domain-containing protein 86) is known for its expression in leukocytes in mice, where it regulates the immune response. We investigated whether Cyclon/CCDC68 is expressed in leukocytes of schizophrenia patients and whether it might be used as a biological marker for the disease endophenotype segregation. We examined the level of mRNA of Cyclon/CCDC68 in white blood cells obtained from schizophrenia patients in relapse and remission as well as in healthy controls. The mRNA of Cyclon/CCDC68 was expressed by white blood cells of both schizophrenia patients and healthy controls. There was a dichotomous change in the levels of Cyclon/CCDC68 of relapsed patients before and after treatment. High Cyclon/CCDC68 levels were associated with a recent disease and presence of psychotic symptoms, while low levels were associated with a long duration of the disease and an absence of psychotic symptoms. These data indicate that Cyclon/CCDC68 levels correlate with the clinical presentation of relapsed schizophrenia. Cyclon/CCDC68 might be involved in the immune system disturbances observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 41 | Psychiatry Res 2013 Dec 214: 365-73 |
| PMID | 24045051 |
| Title | Altered phospholipid metabolism in schizophrenia: a phosphorus 31 nuclear magnetic resonance spectroscopy study. |
| Abstract | Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naïve and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 42 | Psychiatry Res 2013 Dec 214: 365-73 |
| PMID | 24045051 |
| Title | Altered phospholipid metabolism in schizophrenia: a phosphorus 31 nuclear magnetic resonance spectroscopy study. |
| Abstract | Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naïve and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 43 | Eur. Psychiatry 2013 Jan 28: 30-9 |
| PMID | 22559998 |
| Title | Deep transcranial magnetic stimulation as a treatment for psychiatric disorders: a comprehensive review. |
| Abstract | Deep transcranial magnetic stimulation (TMS) is a technique of neuromodulation and neurostimulation based on the principle of electromagnetic induction of an electric field in the brain. The COIL (H-COIL) used in deep TMS is able to modulate cortical excitability up to a maximum depth of 6 cm and is therefore able not only to modulate the activity of the cerebral cortex but also the activity of deeper neural circuits. Deep TMS is largely used for the treatment of drug-resistant major depressive disorder (MDD) and is being tested to treat a very wide range of neurological, psychiatric and medical conditions. The aim of this review is to illustrate the biophysical principles of deep TMS, to explain the pathophysiological basis for its utilization in each psychiatric disorder (major depression, autism, bipolar depression, auditory hallucinations, negative symptoms of schizophrenia), to summarize the results presented thus far in the international scientific literature regarding the use of deep TMS in psychiatry, its side effects and its effects on cognitive functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 44 | Biomacromolecules 2013 Dec 14: 4320-30 |
| PMID | 24219355 |
| Title | Synthesis and pH-responsive "schizophrenic" aggregation of a linear-dendron-like polyampholyte based on oppositely charged polypeptides. |
| Abstract | A novel linear-dendron-like polyampholyte, poly(L-lysine)-b-D2-poly(L-glutamic acid) [PLL-b-D2-(PLGA)4], where D2 is the second generation of poly(amido amine), was prepared by hydrolyzing poly(?-benzyloxycarbonyl-L-lysine)-b-D2-poly(?-benzyl-L-glutamate) copolymer which was synthesized via a combination of ring-opening polymerization and click chemistry. The pH-responsive self-assembly behaviors of PLL-b-D2-(PLGA)4 were investigated in detail. It is found that PLL-b-D2-(PLGA)4 can self-assemble into PLGA-core aggregates at acidic pH and PLL-core aggregates at alkaline pH, which was accompanied with the COIL-to-helix conformational transition of PLGA and PLL segments, respectively. The self-assembled aggregates with various morphologies, such as large compound micelles, worm-like micelles, large compound vesicles, simple vesicles, and rigid tubular structures have been obtained in "schizophrenic" aggregation process with simply increasing the solution pH. The hierarchical assembled fractal structures of PLL-b-D2-(PLGA)4 were observed during the solvent evaporation at high pH value. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 45 | Schizophr. Res. 2013 Sep 149: 167-73 |
| PMID | 23810122 |
| Title | A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: a double-blind trial. |
| Abstract | The aim of the study was to assess the effect of rTMS not only on the general severity of negative schizophrenia symptoms, but also particularly on their individual domains, such as affective flattening or blunting, alogia, avolition or apathy, anhedonia, and impaired attention. Forty schizophrenic male patients on stable antipsychotic medication with prominent negative symptoms were included in the study. They were divided into two groups: 23 were treated with active and 17 with placebo rTMS. Both treatments were similar, but placebo rTMS was administered using a purpose-built sham COIL. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). The stimulation frequency was 10 Hz; stimulation intensity was 110% of the individual motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days (five working days "on" and two weekend days "off" design). Each daily session consisted of 20 applications of 10-second duration with 30-second intervals between sequences. The patients and raters were blind to condition of stimulation treatment. The active rTMS led to a statistically significantly higher reduction of the Scale for the Assessment of Negative Symptoms (SANS) total score and of all domains of negative symptoms of schizophrenia. After Bonferroni adjustments for multiple testing, the statistical significance disappeared in alogia only. High-frequency rTMS stimulation over the left DLPFC at a high stimulation intensity with a sufficient number of applied stimulating pulses may represent an efficient augmentation of antipsychotics in alleviating the negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 46 | Schizophr. Res. 2013 Sep 149: 167-73 |
| PMID | 23810122 |
| Title | A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: a double-blind trial. |
| Abstract | The aim of the study was to assess the effect of rTMS not only on the general severity of negative schizophrenia symptoms, but also particularly on their individual domains, such as affective flattening or blunting, alogia, avolition or apathy, anhedonia, and impaired attention. Forty schizophrenic male patients on stable antipsychotic medication with prominent negative symptoms were included in the study. They were divided into two groups: 23 were treated with active and 17 with placebo rTMS. Both treatments were similar, but placebo rTMS was administered using a purpose-built sham COIL. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). The stimulation frequency was 10 Hz; stimulation intensity was 110% of the individual motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days (five working days "on" and two weekend days "off" design). Each daily session consisted of 20 applications of 10-second duration with 30-second intervals between sequences. The patients and raters were blind to condition of stimulation treatment. The active rTMS led to a statistically significantly higher reduction of the Scale for the Assessment of Negative Symptoms (SANS) total score and of all domains of negative symptoms of schizophrenia. After Bonferroni adjustments for multiple testing, the statistical significance disappeared in alogia only. High-frequency rTMS stimulation over the left DLPFC at a high stimulation intensity with a sufficient number of applied stimulating pulses may represent an efficient augmentation of antipsychotics in alleviating the negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 47 | J. Neurosci. Methods 2014 Jun 230: 37-50 |
| PMID | 24785589 |
| Title | Exploration of scanning effects in multi-site structural MRI studies. |
| Abstract | Pooling of multi-site MRI data is often necessary when a large cohort is desired. However, different scanning platforms can introduce systematic differences which confound true effects of interest. One may reduce multi-site bias by calibrating pivotal scanning parameters, or include them as covariates to improve the data integrity. In the present study we use a source-based morphometry (SBM) model to explore scanning effects in multi-site sMRI studies and develop a data-driven correction. Specifically, independent components are extracted from the data and investigated for associations with scanning parameters to assess the influence. The identified scanning-related components can be eliminated from the original data for correction. A small set of SBM components captured most of the variance associated with the scanning differences. In a dataset of 1460 healthy subjects, pronounced and independent scanning effects were observed in brainstem and thalamus, associated with magnetic field strength-inversion time and RF-receiving COIL. A second study with 110 schizophrenia patients and 124 healthy controls demonstrated that scanning effects can be effectively corrected with the SBM approach. Both SBM and GLM correction appeared to effectively eliminate the scanning effects. Meanwhile, the SBM-corrected data yielded a more significant patient versus control group difference and less questionable findings. It is important to calibrate scanning settings and completely examine individual parameters for the control of confounding effects in multi-site sMRI studies. Both GLM and SBM correction can reduce scanning effects, though SBM's data-driven nature provides additional flexibility and is better able to handle collinear effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 48 | J Psychiatr Res 2014 Sep 56: 43-9 |
| PMID | 24841112 |
| Title | Working memory dysfunction in delusional disorders: an fMRI investigation. |
| Abstract | Delusional disorder (DD) is a rare and understudied psychiatric disorder. There is limited number of studies concerning cognitive characteristics in DD. Using an established working memory paradigm with variable levels of memory load, we investigated alterations in functional magnetic resonance imaging (fMRI) of brain regions in patients with DD. This case control study included 9 patients with DD and 9 healthy control subjects matched for age, sex, and education level. Diagnosis of DD was confirmed using the Structured Clinical Interview for DSM-IV Axis I. The severity of the symptoms was evaluated using the Positive and Negative Syndrome Scale. All patients were asked to perform 0-back and 2-back tasks during fMRI experiments. Functional imaging was performed using the 3.0 T Philips whole-body scanner using an 8-channel head COIL. Participants with DD had less neural activation of the left dorsolateral prefrontal cortex in fMRI scans obtained during performance tasks. On the other hand, neural activation of the left and right superior temporal gyrus, left middle and inferior temporal gyrus, right and left posterior cingulate gyrus, right amygdala, left and right fusiform gyrus was more prominent in patients with DD in comparison with the control group. Patients with DD had dysfunction in the prefrontal, temporal and limbic regions of the brain in particular, during performance tasks of working memory. Our findings were in line with the findings of the early reports on deficient functioning in temporal or limbic regions of the brain. Further, patients with DD displayed prefrontal dysfunction as seen in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 49 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Mar 49: 30-5 |
| PMID | 24211840 |
| Title | Repetitive transcranial magnetic stimulation reduces cigarette consumption in schizophrenia patients. |
| Abstract | High-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) seemed to decrease tobacco consumption and craving in nicotine-dependent people without psychiatric disorder or otherwise healthy people. Even if the prevalence of cigarette smoking in schizophrenia patients is high and estimated to be between 45% and 88%, this technique has not been systematically studied in this indication in schizophrenia yet. The aim of this study was to test the ability of high-frequency (10Hz) rTMS over the left DLPFC to decrease cigarette consumption in schizophrenia patients. The study included 35 male schizophrenia patients on stable antipsychotic medication. The patients were divided into two groups: the first (18 patients) were actively stimulated and the second (17 patients) underwent sham (placebo) stimulation. The sham rTMS was administered using a purpose-built sham COIL that was identical in appearance to the real COIL and made the same noise but did not deliver a substantial stimulus. The rTMS was administered at the stimulation parameters: location (left dorsolateral prefrontal cortex: DLPFC), intensity of magnetic stimulation in % of motor threshold (110%), stimulation frequency (10Hz), number of trains (20), single train duration (10s), inter-train interval (30s), and total number of stimulation sessions (21). In each stimulation session, 2000TMSpulses were given, with a total of 42,000pulses per treatment course. Patients noted the number of cigarettes smoked in the 7days before treatment, during the whole stimulation treatment (21days), and again for a 7-day period after treatment. Cigarette consumption was statistically significantly lower in the actively stimulated patients than in the sham rTMS group as early as the first week of stimulation. No statistically relevant correlations were found in the changes of ongoing negative or depressive schizophrenia symptoms and the number of cigarettes smoked. High-frequency rTMS over the left DLPFC has the ability to decrease the number of cigarettes smoked in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 50 | Neuroscience 2015 Dec 310: 723-30 |
| PMID | 26475744 |
| Title | The CCDC55 couples cannabinoid receptor CNR1 to a putative DISC1 schizophrenia pathway. |
| Abstract | Our previous study suggested that the COILed COIL domain-containing 55 gene (CCDC55), also named as NSRP1 (nuclear speckle splicing regulatory protein 1 (NSRP1)), was encompassed in a haplotype block spanning over the serotonin transporter (5-HTT) gene in patients with schizophrenia (SCZ). However, the neurobiological function of CCDC55 gene remains unknown. This study aims to uncover the potential role of CCDC55 in SCZ-associated molecular pathways. Using molecular cloning, sequencing and immune blotting to identify basic properties, yeast two-hybrid screening and glutathione S-transferase (GST) pull-down assay to test protein-protein interaction, and confocal laser scanning microscopy (CSLM) to show intracellular interaction of proteins. (i) CCDC55 is expressed as a nuclear protein in human neuronal cells; (ii) Protein-protein interaction analyses showed CCDC55 physically interacted with Ran binding protein 9 (RanBP9) and disrupted in schizophrenia 1 (DISC1); (iii) CCDC55 and RanBP9 co-localized in the nucleus of human neuronal cells; (iv) CCDC55 also interacted with the cannabinoid receptor 1 (CNR1), and with the brain cannabinoid receptor-interacting protein 1a (CNRIP1a); (v) CNR1 activation in differentiated human neuronal cells resulted in an altered RanBP9 localization. CCDC55 may be involved in a functional bridging between the CNR1 activation and the DISC1/RanBP9-associated pathways. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 51 | Neuropsychiatr Dis Treat 2015 -1 11: 1625-38 |
| PMID | 26170675 |
| Title | The reduction of volume and fiber bundle connections in the hippocampus of EGR3 transgenic schizophrenia rats. |
| Abstract | There is a growing consensus that schizophrenia is ultimately caused by abnormal communication between spatially disparate brain structures. White matter fasciculi represent the primary infrastructure for long distance communication in the brain. In this study, we aimed to investigate the white matter connection in schizophrenia susceptible brain regions of early growth response factor 3 (EGR3) expressing rats. A rat model of schizophrenia was created by the transfection of the EGR3 gene into rat hippocampus. All animals were placed in a fixation system using a commercial rat-dedicated COIL. schizophrenia susceptible brain regions were scanned using in vivo diffusion tensor magnetic resonance imaging. The volume, quantity, average length of fiber bundles, fractional anisotropy, apparent diffusion coefficient, the relative heterosexual fraction, and volume ratio were collected in the whole brain and schizophrenia related brain areas (the hippocampus, thalamus, and prefrontal lobe). MedINRIA software was used for data processing of diffusion tensor and fiber bundles tracking. The fibronectin in relevant brain regions was also analyzed. There was a significant decrease in the volume of the fiber beam through the left hippocampus dentate in the schizophrenia model group in comparison to the control group and the risperidone treatment group (P<0.05). A significant reduction in the volume and number of the fiber bundles was also observed in left prefrontal-left hippocampus, left hippocampus-left thalamus, left prefrontal-left hippocampus-left thalamus areas in the model group (all P<0.05). The volume of hippocampus and the number of fiber bundles were reduced in EGR3 transgenic schizophrenia rats, and are the most sensitive indicators in schizophrenia. The diffusion tensor imaging technique plays an important role in the evaluation of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 52 | Brain Behav 2015 Oct 5: e00399 |
| PMID | 26516617 |
| Title | Use of T1-weighted/T2-weighted magnetic resonance ratio images to elucidate changes in the schizophrenic brain. |
| Abstract | One leading hypothesis suggests that schizophrenia (SZ) is a neurodevelopmental disorder caused by genetic defects in association with environmental risk factors that affect synapse and myelin formation. Recent magnetic resonance imaging (MRI) studies of SZ brain showed both gray matter (GM) reduction and white matter (WM) fractional anisotropy reduction. In this study, we used T1-weighted (T1w)/T2-weighted (T2w) MRI ratio images, which increase myelin-related signal contrast and reduce receiver-COIL bias. We measured T1w/T2w ratio image signal intensity in 29 patients with SZ and 33 healthy controls (HCs), and then compared them against bias-corrected T1w images. Mean T1w/T2w ratio signal intensity values across all SZ GM and WM voxels were significantly lower than those for the HC values (analysis of covariance with age, gender, handedness, and premorbid intelligence quotient as nuisance covariates). SZ mean WM T1w/T2w ratio values were related to Global Assessment of Functioning (GAF) scores and were inversely related to the positive psychotic symptoms of the Positive and Negative Syndrome Scale. Voxel-based analysis revealed significantly lower T1w/T2w ratio image signal intensity values in the right ventral putamen in SZ GM. T1w image intensities did not differ between the SZ and HC groups. T1-weighted/T2-weighted ratio imaging increased the detectability of SZ pathological changes. Reduced SZ brain signal intensity is likely due to diminished myelin content; therefore, mapping myelin-related SZ brain changes using T1w/T2w ratio images may be useful for studies of SZ brain abnormalities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 53 | Brain Behav 2015 Oct 5: e00399 |
| PMID | 26516617 |
| Title | Use of T1-weighted/T2-weighted magnetic resonance ratio images to elucidate changes in the schizophrenic brain. |
| Abstract | One leading hypothesis suggests that schizophrenia (SZ) is a neurodevelopmental disorder caused by genetic defects in association with environmental risk factors that affect synapse and myelin formation. Recent magnetic resonance imaging (MRI) studies of SZ brain showed both gray matter (GM) reduction and white matter (WM) fractional anisotropy reduction. In this study, we used T1-weighted (T1w)/T2-weighted (T2w) MRI ratio images, which increase myelin-related signal contrast and reduce receiver-COIL bias. We measured T1w/T2w ratio image signal intensity in 29 patients with SZ and 33 healthy controls (HCs), and then compared them against bias-corrected T1w images. Mean T1w/T2w ratio signal intensity values across all SZ GM and WM voxels were significantly lower than those for the HC values (analysis of covariance with age, gender, handedness, and premorbid intelligence quotient as nuisance covariates). SZ mean WM T1w/T2w ratio values were related to Global Assessment of Functioning (GAF) scores and were inversely related to the positive psychotic symptoms of the Positive and Negative Syndrome Scale. Voxel-based analysis revealed significantly lower T1w/T2w ratio image signal intensity values in the right ventral putamen in SZ GM. T1w image intensities did not differ between the SZ and HC groups. T1-weighted/T2-weighted ratio imaging increased the detectability of SZ pathological changes. Reduced SZ brain signal intensity is likely due to diminished myelin content; therefore, mapping myelin-related SZ brain changes using T1w/T2w ratio images may be useful for studies of SZ brain abnormalities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 54 | Magn Reson Med 2016 Feb 75: 498-502 |
| PMID | 25762462 |
| Title | Reproducibility of phase rotation stimulated echo acquisition mode at 3T in schizophrenia: Emphasis on glutamine. |
| Abstract | To determine the reproducibility and reliability of glutamine (Gln), measured with a very short echo time phase rotation stimulated echo acquisition mode (VTE-PR STEAM) sequence at 3T, in subjects with schizophrenia. Seven subjects with schizophrenia were scanned twice with VTE-PR STEAM in a Siemens 3T TIM Trio scanner with a 32-channel head COIL. Spectroscopic data were collected from two voxels in gray matter, one in the dorsal anterior cingulate and the other in the medial occipital cortex. Reproducibility was assessed using coefficients of variation (CVs) and reliability with standard error of measurement and intraclass correlations (ICCs). Phantoms containing increasing concentrations of Gln in a physiologic solution of other neurometabolites with overlapping resonances were scanned to assess the validity of spectral Gln measurement. Very good reliability and reproducibility for Gln in both regions of interest were supported by CVs of ?10.0% and ICCs of ?0.6, respectively. Phantom studies documented a robust correspondence between known Gln concentrations and VTE-PR STEAM measurements of this metabolite (R(2) ?=?0.988). The VTE-PR STEAM approach at 3T permits the longitudinal assessment of Gln and other (1) H MR spectroscopy neurometabolites in a clinically plausible setting. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 55 | Sci Rep 2016 -1 6: 18748 |
| PMID | 26728762 |
| Title | Missense mutation in DISC1 C-terminal coiled-coil has GSK3? signaling and sex-dependent behavioral effects in mice. |
| Abstract | Disrupted-in-schizophrenia 1 (DISC1) is a risk factor for schizophrenia and affective disorders. The full-length DISC1 protein consists of an N-terminal 'head' domain and a C-terminal tail domain that contains several predicted COILed-COILs, structural motifs involved in protein-protein interactions. To probe the in vivo effects of missense mutation of DISC1's C-terminal tail, we tested mice carrying mutation D453G within a predicted ?-helical COILed-COIL region. We report that, relative to wild-type littermates, female DISC1(D453G) mice exhibited novelty-induced hyperlocomotion, an anxiogenic profile in the elevated plus-maze and open field tests, and reduced social exploration of unfamiliar mice. Male DISC1(D453G) mice displayed a deficit in passive avoidance, while neither males nor females exhibited any impairment in startle reactivity or prepulse inhibition. Whole brain homogenates showed normal levels of DISC1 protein, but decreased binding of DISC1 to GSK3?, decreased phospho-inhibition of GSK3? at serine 9, and decreased levels of ?-catenin in DISC1(D453G) mice of either sex. Interrupted GSK3? signaling may thus be part of the mechanism underlying the behavioral phenotype associated with D453G, in common with the previously described N-terminal domain mutations Q31L and L100P in mice, and the schizophrenia risk-conferring variant R264Q in humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 56 | J Psychiatr Res 2016 Apr 75: 107-15 |
| PMID | 26828370 |
| Title | Cognitive functioning and deep transcranial magnetic stimulation (DTMS) in major psychiatric disorders: A systematic review. |
| Abstract | Deep transcranial magnetic stimulation (DTMS) is a non-invasive brain stimulation method mostly utilised in the treatment of major depression. The aim of the current study was to systematically review the literature on the cognitive effects of DTMS applied with the H-COIL system in major psychiatric disorders. Following a literature search in PsycInfo and PubMed (any time to December 2015), 13 out of 32 studies on DTMS and cognitive functioning were included in the current review. Three studies included 38 healthy participants, eight studies included 158 unipolar or bipolar depression patients and two studies included 45 schizophrenia patients. Low-frequency DTMS (1-3 sessions) had little effect on cognitive functioning in healthy participants. The most consistent cognitive and clinical improvements were reported in the short-term (after 20 daily sessions of high-frequency DTMS with H1-COIL) in studies with major depression patients. There was also a trend towards a short-term cognitive and clinical improvement in studies with schizophrenia patients. High-frequency DTMS might improve cognitive functioning and alleviate clinical symptoms in the short-term, particularly in major depression. However, this conclusion is based on data from mostly uncontrolled, open-label studies with patients receiving concurrent antidepressants or antipsychotics. Randomised, sham-controlled trials are needed to investigate the magnitude of the cognitive outcomes of DTMS in the short-term and beyond the daily stimulation phase in major psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 57 | Neuroimage 2016 Jan 124: 602-11 |
| PMID | 26375209 |
| Title | A nested phosphorus and proton coil array for brain magnetic resonance imaging and spectroscopy. |
| Abstract | A dual-nuclei radiofrequency COIL array was constructed for phosphorus and proton magnetic resonance imaging and spectroscopy of the human brain at 7T. An eight-channel transceive degenerate birdcage phosphorus module was implemented to provide whole-brain coverage and significant sensitivity improvement over a standard dual-tuned loop COIL. A nested eight-channel proton module provided adequate sensitivity for anatomical localization without substantially sacrificing performance on the phosphorus module. The developed array enabled phosphorus spectroscopy, a saturation transfer technique to calculate the global creatine kinase forward reaction rate, and single-metabolite whole-brain imaging with 1.4cm nominal isotropic resolution in 15min (2.3cm actual resolution), while additionally enabling 1mm isotropic proton imaging. This study demonstrates that a multi-channel array can be utilized for phosphorus and proton applications with improved coverage and/or sensitivity over traditional single-channel COILs. The efficient multi-channel COIL array, time-efficient pulse sequences, and the enhanced signal strength available at ultra-high fields can be combined to allow volumetric assessment of the brain and could provide new insights into the underlying energy metabolism impairment in several neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, as well as mental disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 58 | Schizophr Bull 2016 Mar 42: 301-8 |
| PMID | 26089351 |
| Title | Placebo Response in Repetitive Transcranial Magnetic Stimulation Trials of Treatment of Auditory Hallucinations in Schizophrenia: A Meta-Analysis. |
| Abstract | Several meta-analyses have assessed the response of patients with schizophrenia with auditory verbal hallucinations (AVH) to treatment with repetitive transcranial magnetic stimulation (rTMS); however, the placebo response has never been explored. Typically observed in a therapeutic trial, the placebo effect may have a major influence on the effectiveness of rTMS. The purpose of this meta-analysis is to evaluate the magnitude of the placebo effect observed in controlled studies of rTMS treatment of AVH, and to determine factors that can impact the magnitude of this placebo effect, such as study design considerations and the type of sham used.The study included twenty-one articles concerning 303 patients treated by sham rTMS. A meta-analytic method was applied to obtain a combined, weighted effect size, Hedges's g. The mean weighted effect size of the placebo effect across these 21 studies was 0.29 (P < .001). Comparison of the parallel and crossover studies revealed distinct results for each study design; placebo has a significant effect size in the 13 parallel studies (g = 0.44, P < 10(-4)), but not in the 8 crossover studies (g = 0.06, P = .52). In meta-analysis of the 13 parallel studies, the 45° position COIL showed the highest effect size. Our results demonstrate that placebo effect should be considered a major source of bias in the assessment of rTMS efficacy. These results fundamentally inform the design of further controlled studies, particularly with respect to studies of rTMS treatment in psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |