Publications by authors named "Kai-Chun Yang"

29 Publications

  • Page 1 of 1

Sub-regional hippocampal volumes in first-episode drug-naïve major depression disorder.

Neurosci Lett 2021 Oct 18;763:136178. Epub 2021 Aug 18.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei 112201, Taiwan; Center for Quality Management, Taipei Veterans General Hospital, Taipei 112201, Taiwan. Electronic address:

Hippocampal volume reduction was reported to underlie depressive symptomatology, however, the evidence to date remains inconsistent. For the complex intrinsic organization of hippocampus, the hippocampal volumes can be further divided into subfields or axial parts. The current study aimed to explore the alterations of hippocampal sub-regional volumes in first episode drug-naïve major depressive disorder (MDD) by two segmentation methods. Thirty-five first-episode drug-naïve MDD and 35 age- and gender-matched healthy controls (HC) were recruited. Volumes of three sub-regions of hippocampus along the longitudinal axis (head, body and tail) were analyzed manually and eight transverse subfields were automatically determined using FreeSurfer. An asymmetric index (AI) of volumes was defined as (∣Left - Right∣/∣Left + Right∣) * 100. There were significant reductions in the volumes of bilateral hippocampal head in MDD compared to HC. The volumes of eight subfields were not different between groups. MDD patients had higher AI values in the subfield of cornu ammonis 4/dentate gyrus than HC. The change in hippocampal sub-regional volumes might be an imaging biomarker in the first-episode, drug-naïve patients with MDD. Current findings may contribute to developing new diagnostic and therapeutic strategies for major depression.
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http://dx.doi.org/10.1016/j.neulet.2021.136178DOI Listing
October 2021

Evidence-Based Expert Consensus Regarding Long-Acting Injectable Antipsychotics for Schizophrenia from the Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN).

CNS Drugs 2021 Aug 27;35(8):893-905. Epub 2021 Jul 27.

Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec 2, Shih-Pai Rd., Beitou, 11217, Taipei, Taiwan.

Objective: Schizophrenia is a chronic, debilitating psychiatric disorder with a high risk of relapse. Nonadherence to medication is a significant contributor to poor outcomes. Although long-acting injectable (LAI) antipsychotics prevent the relapse of schizophrenia, several factors present obstacles to the use of LAI antipsychotics, and clinical guidelines for LAI antipsychotics remain limited. To provide clinical recommendations, the Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN) developed consensus statements for the effectiveness, target populations, initiation timing, and particular clinical situations for the use of LAI antipsychotics in patients with schizophrenia.

Methods: After a systematic literature review, a working group drafted consensus statements for the selected clinical topics and determined the levels of evidence-based recommendation based on the latest World Federation of Societies of Biological Psychiatry grading system. A scientific committee evaluated the draft statements and decided the final recommendations regarding the grades by anonymous voting after incorporating clinical experience and practice into the evidence from research.

Results: The TSBPN proposed ten consensus statements for the application of LAI antipsychotics. The current evidence supported that LAI antipsychotics could be a treatment option for all schizophrenia patients, including first-episode patients. LAI antipsychotics could be initiated both during an acute psychotic episode and when patients are stable. The consensus also gave recommendations for particular clinical situations with insufficient scientific data, such as for use in elderly or adolescent patients, patients with treatment-resistant schizophrenia, and breakthrough psychosis, and strategies to assist patients/caregivers with decision making.

Conclusions: The consensus statements developed by the TSBPN provide evidence-based clinical recommendations and could give clinicians more confidence when prescribing LAI antipsychotics to treat schizophrenia, thereby improving treatment outcomes.
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http://dx.doi.org/10.1007/s40263-021-00838-5DOI Listing
August 2021

Interleukin-1 family and serotonin transporter in first-episode, drug-naive major depressive disorder: A pilot study.

J Psychiatr Res 2021 03 19;135:174-180. Epub 2021 Jan 19.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; Center for Quality Management, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address:

Abnormalities of neuroinflammatory process and serotonergic system have been reported in major depressive disorder (MDD). However, most previous studies were performed in recurrent MDD and only a few studies explored the interaction of the two systems. This study examined both systems concurrently and their clinical relevance in first-episode drug-naive MDD. Thirty-four MDD patients and 34 age and gender matched healthy controls (HC) were recruited. Plasma concentrations of the cytokines of interleukin-1 (IL-1) family, including IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type 2 (IL-1R2) were measured using enzyme-linked immune-sorbent assays. The serotonin transporter (SERT) availability in midbrain, thalamus, caudate, and putamen was examined by single-photon emission computed tomography with I-ADAM. There were significantly lower concentrations of pro-inflammatory IL-1β and its inhibitor, IL-1R2 in MDD than HC. The SERT availability was at the same level between groups. A negative association between IL-1Ra concentration and the SERT availability in midbrain was observed in MDD but not in HC. Both IL-1β concentration and the SERT availability in caudate negatively correlated with depression severity and the effect of IL-1β was not moderated or mediated by the SERT. In conclusion, this study demonstrated the involvement of IL-1 family in the early stage of MDD, especially for IL-1β. SERT was not the main central target of altered IL-1β and these two systems might contribute to MDD by different mechanisms. The pathophysiology might be varied between early and recurrent MDD and tuning treatment strategies at different clinical stages might be needed.
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http://dx.doi.org/10.1016/j.jpsychires.2021.01.018DOI Listing
March 2021

Interaction of dopamine transporter and metabolite ratios underpinning the cognitive dysfunction in patients with carbon monoxide poisoning: A combined SPECT and MRS study.

Neurotoxicology 2021 01 7;82:26-34. Epub 2020 Nov 7.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; Center for Quality Management, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address:

Cognitive dysfunction has been reported in patients with carbon monoxide (CO) poisoning. However, the underpinning mechanism remained unclear. This study examined dopamine transporter (DAT) and metabolite ratios concurrently and their relationships with cognitive dysfunction in CO poisoning. Eighteen suicide attempters with charcoal burning which results in CO poisoning and 18 age- and gender- matched normal controls were recruited. A battery of cognitive assessments including attention, memory, and executive function was administered. Each participant received one single photon emission computed tomography with Tc-TRODAT for measuring striatal DAT availability and proton magnetic resonance spectroscopy to determine N-acetyl aspartate/creatine (NAA/Cr), choline-containing compounds/creatine (Cho/Cr) and myo-inositol/creatine (mI/Cr) in the left parietal white matter and mid-occipital gray matter (OGM). CO poisoning patients had significant impairments in memory and executive function. Compared to normal, CO poisoning patients had lower striatal DAT availability, lower NAA/Cr levels in both regions and higher Cho/Cr levels in both regions. In CO poisoning patients, the altered left striatal DAT availability and Cho/Cr level in OGM were significantly associated with executive dysfunction in the expected directions. Moreover, there was a significant interaction between these two imaging indices on their relationships with executive dysfunction and combination of them could adequately predict executive dysfunction in more CO poisoning cases than either alone. The current results suggested that both alterations in DAT availability and metabolite ratios might play crucial roles in executive dysfunction in CO poisoning. This research also highlights the importance of multimodal imaging approaches for studying neurotoxicity effects.
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http://dx.doi.org/10.1016/j.neuro.2020.11.002DOI Listing
January 2021

Massive upper gastrointestinal bleeding caused by an intercostal arterio-esophageal fistula: A rare case report.

Radiol Case Rep 2020 Oct 26;15(10):2026-2030. Epub 2020 Aug 26.

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, Taiwan.

Arterio-esophageal fistula (AEF) is a rare life-threatening cause of upper gastrointestinal bleeding. Realizing the risk factors and clinical presentations of AEF will enable us to provide timely diagnosis, efficient treatment, and better outcome. We present a 43-year-old Taiwanese man who had histories of destructive lung, innominate artery-trachea fistula, and received bilobectomy. He was admitted to our hospital with fresh blood drainage from nasogastric tube. He was diagnosed as right fifth intercostal artery esophageal fistula by computed tomography angiography and transcatheter arterial embolization was performed. The bleeding stopped and the patient was discharged uneventfully. The risk factors of AEF include esophageal foreign body, vascular surgery, thoracic arterial malformations, and concurrent chemoradiotherapy in T4-esophageal cancer. Computed tomography angiography may be the most sensitive diagnostic test. Transcatheter arterial embolization or endovascular stent grafting may be considered as the first-line treatment of AEF in the future.
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http://dx.doi.org/10.1016/j.radcr.2020.07.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475065PMC
October 2020

Recyclable three-dimensional Ag nanorod arrays decorated with O-g-CN for highly sensitive SERS sensing of organic pollutants.

J Hazard Mater 2019 11 25;379:120823. Epub 2019 Jun 25.

Department of Materials Science and Nanoengineering, Rice University, TX, 77005, USA.

A three-dimensional (3D) substrate was developed by assembling a monolayer of graphitic carbon nitride (O-g-CN) on Ag nanorod arrays (Ag NRs) for sensitive and recyclable surface enhanced Raman scattering (SERS) detection. The prepared Ag NRs/O-g-CN substrate not only generated a significant Raman enhancement effect as a result of the strong π-π stacking interaction between O-g-CN and the analytes but also possessed excellent self-cleaning property via visible-light irradiation that was attributed to its outstanding catalytic performance. Highly sensitive SERS detection could be achieved with a LOD of 8.2 × 10 M for R6 G, and the substrate could be used repeatedly for at least four cycles with tolerable intensity attenuation. In addition, the 3D substrate exhibited long-term stability originating from the electron-donor effect of O-g-CN and high reproducibility due to the uniform decoration of O-g-CN on the Ag NRs through the strong interaction. Furthermore, using Ag NRs/O-g-CN, the recyclable detection of antibiotics in a water sample was demonstrated with high sensitivity, which indicates that the 3D Ag NRs/O-g-CN substrate is a promising candidate for eliminating the challenges of single-use SERS substrates and building a portable SERS platform to sense organic molecular species.
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http://dx.doi.org/10.1016/j.jhazmat.2019.120823DOI Listing
November 2019

Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain.

Neuropsychopharmacology 2019 09 19;44(10):1706-1713. Epub 2019 Jun 19.

Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.

Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of vortioxetine by comparing its effect to the SSRI citalopram on the binding of [C]AZ10419369 to the 5-HT receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of vortioxetine was determined by [C]MADAM PET measurements before and after administration of vortioxetine (0.1-3.0 mg/kg) and data were used to confirm clinically relevant dosing in subsequent PET measurements with [C]AZ10419369. The 5-HT receptor binding was significantly decreased after 0.3 mg/kg of citalopram in the dorsal raphe nucleus (5%), as well as after 0.3 mg/kg of vortioxetine in six brain regions (~25%) or 1.0 mg/kg of vortioxetine in all 12 examined regions (~48%). Moreover, there was no effect of 1.0 mg/kg of vortioxetine on the binding of [C]Cimbi-36 to the 5-HT receptor, which has comparable sensitivity to 5-HT release as [C]AZ10419369 binding. In conclusion, at clinically relevant doses, vortioxetine induced larger reductions in [C]AZ10419369 binding than citalopram. These observations suggest that vortioxetine binds to the 5-HT receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.
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http://dx.doi.org/10.1038/s41386-019-0442-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784989PMC
September 2019

Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies.

Front Psychiatry 2018 24;9:767. Epub 2019 Jan 24.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.

Excessive glutamate release has been linked to stress and many neurodegenerative diseases. Evidence indicates abnormalities of glutamatergic neurotransmission or glutamatergic dysfunction as playing an important role in the development of many major psychiatric disorders (e.g., schizophrenia, bipolar disorder, and major depressive disorder). Recently, ketamine, an -methyl-d-aspartate antagonist, has been demonstrated to have promisingly rapid antidepressant efficacy for treatment-resistant depression. Many compounds that target the glutamate system have also become available that possess potential in the treatment of major psychiatric disorders. In this review, we update evidence from recent human studies that directly or indirectly measured glutamatergic neurotransmission and function in major psychiatric disorders using modalities such as magnetic resonance spectroscopy, positron emission tomography/single-photon emission computed tomography, and paired-pulse transcranial magnetic stimulation. The newer generation of antidepressants that target the glutamatergic system developed in human clinical studies is also reviewed.
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http://dx.doi.org/10.3389/fpsyt.2018.00767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353824PMC
January 2019

Novel Adult-Onset Systolic Cardiomyopathy Due to MYH7 E848G Mutation in Patient-Derived Induced Pluripotent Stem Cells.

JACC Basic Transl Sci 2018 Dec 31;3(6):728-740. Epub 2018 Dec 31.

Department of Medicine/Cardiology, University of Washington, Seattle, Washington.

A novel myosin heavy chain 7 mutation (E848G) identified in a familial cardiomyopathy was studied in patient-specific induced pluripotent stem cell-derived cardiomyocytes. The cardiomyopathic human induced pluripotent stem cell-derived cardiomyocytes exhibited reduced contractile function as single cells and engineered heart tissues, and genome-edited isogenic cells confirmed the pathogenic nature of the E848G mutation. Reduced contractility may result from impaired interaction between myosin heavy chain 7 and cardiac myosin binding protein C.
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http://dx.doi.org/10.1016/j.jacbts.2018.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314962PMC
December 2018

Serotonin concentration enhancers at clinically relevant doses reduce [C]AZ10419369 binding to the 5-HT receptors in the nonhuman primate brain.

Transl Psychiatry 2018 07 16;8(1):132. Epub 2018 Jul 16.

Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

The serotonin (5-HT) system plays an important role in the pathophysiology and treatment of several major psychiatric disorders. Currently, no suitable positron emission tomography (PET) imaging paradigm is available to assess 5-HT release in the living human brain. [C]AZ10419369 binds to 5-HT receptors and is one of the most 5-HT-sensitive radioligands available. This study applied 5-HT concentration enhancers which can be safely studied in humans, and examined their effect on [C]AZ10419369 binding at clinically relevant doses, including amphetamine (1 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA; 1 mg/kg) or 5-hydroxy-L-tryptophan (5-HTP; 5 mg/kg). Twenty-six PET measurements (14 for amphetamine, 6 for MDMA and 6 for 5-HTP) using a bolus and constant infusion protocol were performed in four cynomolgus monkeys before or after drug administration. Binding potential (BP) values were determined with the equilibrium method (integral interval: 63-123 min) using cerebellum as the reference region. BP values were significantly decreased in several examined brain regions after administration of amphetamine (range: 19-31%), MDMA (16-25%) or 5-HTP (13-31%). Reductions in [C]AZ10419369 binding were greater in striatum than cortical regions after administration of 5-HTP, while no prominent regional differences were found for amphetamine and MDMA. In conclusion, [C]AZ10419369 binding is sensitive to changes in 5-HT concentration induced by amphetamine, MDMA or 5-HTP. The robust changes in BP, following pretreatment drugs administered at clinically relevant doses, indicate that the applied PET imaging paradigms hold promise to be successfully used in future human studies.
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http://dx.doi.org/10.1038/s41398-018-0178-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048172PMC
July 2018

Potential Effect of Prolonged Sevoflurane Anesthesia on the Kinetics of [C]Raclopride in Non-human Primates.

Mol Imaging Biol 2018 04;20(2):183-187

Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm, Sweden.

Purpose: Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BP) of [C]raclopride in NHP.

Procedures: Three cynomolgus monkeys underwent two to three PET measurements with [C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BP in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region.

Results: In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman's ρ = - 0.79, p = 0.03), but not with BP (ρ = - 0.25, p = 0.55).

Conclusions: These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BP in consecutive PET measurements.
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http://dx.doi.org/10.1007/s11307-017-1120-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862918PMC
April 2018

Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain.

Int J Neuropsychopharmacol 2017 09;20(9):683-691

Karolinska Institutet and Stockholm County Council, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden; Rigshospitalet, Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark and University of Copenhagen, Faculty of Health and Medicine Sciences, Copenhagen, Denmark; AstraZeneca, PET Science Center at Karolinska Institutet, Personalized Health Care and Biomarkers, Stockholm, Sweden.

Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain.

Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region.

Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex.

Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain.
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http://dx.doi.org/10.1093/ijnp/pyx051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581490PMC
September 2017

Characterization of [C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

Eur J Nucl Med Mol Imaging 2017 Feb 5;44(2):308-320. Epub 2016 Nov 5.

Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Purpose: [C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [C]Lu AE92686 has high affinity for PDE10A (IC  = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.

Methods: A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.

Results: Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V ) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V values in target regions remained stable. Both pretreatment drugs significantly decreased [C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ) values, derived with the simplified reference tissue model (SRTM), were 13-17 in putamen and 3-5 in substantia nigra and correlated well to values from the Logan plot analysis.

Conclusions: The method proposed for quantification of [C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.
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http://dx.doi.org/10.1007/s00259-016-3544-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215309PMC
February 2017

Isolation and Mechanical Measurements of Myofibrils from Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Stem Cell Reports 2016 06 5;6(6):885-896. Epub 2016 May 5.

Bioengineering, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA.

Tension production and contractile properties are poorly characterized aspects of excitation-contraction coupling of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Previous approaches have been limited due to the small size and structural immaturity of early-stage hiPSC-CMs. We developed a substrate nanopatterning approach to produce hiPSC-CMs in culture with adult-like dimensions, T-tubule-like structures, and aligned myofibrils. We then isolated myofibrils from hiPSC-CMs and measured the tension and kinetics of activation and relaxation using a custom-built apparatus with fast solution switching. The contractile properties and ultrastructure of myofibrils more closely resembled human fetal myofibrils of similar gestational age than adult preparations. We also demonstrated the ability to study the development of contractile dysfunction of myofibrils from a patient-derived hiPSC-CM cell line carrying the familial cardiomyopathy MYH7 mutation (E848G). These methods can bring new insights to understanding cardiomyocyte maturation and developmental mechanical dysfunction of hiPSC-CMs with cardiomyopathic mutations.
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http://dx.doi.org/10.1016/j.stemcr.2016.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911495PMC
June 2016

Isolation and Mechanical Measurements of Myofibrils from Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Stem Cell Reports 2016 06 5;6(6):885-896. Epub 2016 May 5.

Bioengineering, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA.

Tension production and contractile properties are poorly characterized aspects of excitation-contraction coupling of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Previous approaches have been limited due to the small size and structural immaturity of early-stage hiPSC-CMs. We developed a substrate nanopatterning approach to produce hiPSC-CMs in culture with adult-like dimensions, T-tubule-like structures, and aligned myofibrils. We then isolated myofibrils from hiPSC-CMs and measured the tension and kinetics of activation and relaxation using a custom-built apparatus with fast solution switching. The contractile properties and ultrastructure of myofibrils more closely resembled human fetal myofibrils of similar gestational age than adult preparations. We also demonstrated the ability to study the development of contractile dysfunction of myofibrils from a patient-derived hiPSC-CM cell line carrying the familial cardiomyopathy MYH7 mutation (E848G). These methods can bring new insights to understanding cardiomyocyte maturation and developmental mechanical dysfunction of hiPSC-CMs with cardiomyopathic mutations.
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http://dx.doi.org/10.1016/j.stemcr.2016.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911495PMC
June 2016

Tumor necrosis factor receptor-associated factor 2 mediates mitochondrial autophagy.

Circ Heart Fail 2015 Jan 22;8(1):175-87. Epub 2014 Oct 22.

From the Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine (K.-C.Y., X.M., H.L., J.M., P.M.B., D.L.M., A.D.), Department of Cell Biology and Physiology (D.L.M., A.D.), Washington University School of Medicine, St. Louis, MO; and Department of Medicine, John Cochran VA Medical Center, St. Louis, MO (X.M., H.L., A.D.).

Background: Tumor necrosis factor (TNF) signaling protects against ischemia/reperfusion-induced cardiomyocyte death, in vitro, ex vivo, and in vivo. TNF-receptor-associated factor 2 (TRAF2), an E3 ubiquitin ligase, coordinates cytoprotective signaling downstream of both TNF receptors, via unclear mechanisms. Noting that TRAF2 is recruited to mitochondria, and that autophagic removal of ubiquitin-tagged damaged mitochondria is cytoprotective, we tested the hypothesis that TRAF2 mediates mitochondrial autophagy.

Methods And Results: TRAF2 localizes to the mitochondria in neonatal rat cardiac myocytes, and TNF treatment transcriptionally upregulates TRAF2 abundance in the mitochondrial subfraction. TRAF2 colocalizes with ubiquitin, p62 adaptor protein, and mitochondria within LC3-bound autophagosomes; and exogenous TRAF2 enhances autophagic removal of mitochondria. TRAF2 knockdown with adenoviral shRNA transduction induces accumulation of depolarized mitochondria in resting neonatal rat cardiac myocytes, as well as in those treated with TNF or uncoupling agent carbonyl cyanide m-chlorophenyl hydrazone, suggesting an essential role for TRAF2 in homeostatic and stress-induced mitochondrial autophagy. TRAF2 also colocalizes and interacts with PARKIN, a previously described E3 ubiquitin ligase and mitophagy effector, on depolarized mitochondria in neonatal rat cardiac myocytes. Exogenous expression of TRAF2, but not its E3 ligase-deficient mutants, is sufficient to partially restore mitophagy in the setting of PARKIN knockdown, suggesting redundancy in their ubiquitin ligase roles. TRAF2 abundance increases in the mitochondrial subfraction of ischemia/reperfusion-modeled hearts; and exogenous TRAF2, but not its E3 ligase-deficient mutants, reduces depolarized mitochondria and rescues cell death in neonatal rat cardiac myocytes subjected to hypoxia/reoxygenation.

Conclusions: Taken together, these data indicate an essential role for TRAF2 in concert with PARKIN as a mitophagy effector, which contributes to TRAF2-induced cytoprotective signaling.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.114.001635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303508PMC
January 2015

Association of thalamic serotonin transporter and interleukin-10 in bipolar I disorder: a SPECT study.

Bipolar Disord 2014 May 20;16(3):241-8. Epub 2013 Dec 20.

Department of Psychiatry, Taipei Veterans General Hospital and National Yang Ming University, Taipei, Taiwan.

Objectives: The serotonin hypothesis plays a critical role in the etiology of bipolar disorder (BD). Although many studies have demonstrated reciprocal relationships between serotonin metabolism and immune-inflammatory pathways that occur in depression, studies linking serotonergic function and cytokines are still limited concerning BD. The aim of this study was to investigate the interaction of brain serotonin transporter (SERT) and cytokines in BD.

Methods: Twenty patients with euthymic BD and 20 age- and sex-matched healthy controls (HC) were recruited. Single photon emission computed tomography with the radiotracer (123) I-ADAM was used for the SERT imaging. The specific uptake ratio, which represents SERT availability, was the primary measured outcome. Cytokines included the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and the anti-inflammatory cytokine interleukin-10 (IL-10). Cytokine concentration was measured using an enzyme-linked immunosorbent assay.

Results: SERT availability was significantly lower in the midbrain and caudate of patients with BD compared with HC, but not in the thalamus and putamen. IL-10 was significantly higher, whereas TNF-α was not different in euthymic patients with BD compared with HC. There was a significant association of SERT availability and IL-10 in the thalamus, but not in the midbrain, caudate, or putamen.

Conclusions: Our results demonstrate the interaction of SERT availability and IL-10 in euthymic BD. This result may further explain the role of SERT and cytokines in the etiology of BD.
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http://dx.doi.org/10.1111/bdi.12164DOI Listing
May 2014

Association of brain serotonin transporter availability and brain-derived neurotrophic factor in models of serotonin transporter genotypes in healthy subjects.

J Clin Psychopharmacol 2013 Jun;33(3):432-5

Department of Psychiatry, Taipei Veterans General Hospital & National Yang Ming University, Taipei, Taiwan.

The S-allele of functional polymorphisms of the serotonin transporter (SERT) gene has been demonstrated to have lower transcriptional activity compared with the L-allele, which shows low expression of SERT in the brain. However, this finding cannot be consistently replicated in vivo. The aim of this study was to determine the availability of SERT based on SERT genotype. We also examined the relationship between brain-derived neurotrophic factor (BDNF) and the availability of SERT. Sixty-two healthy subjects were recruited. Each subject underwent single-photon emission computed tomography with I-ADAM (I-labeled 2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine) for imaging SERT in the brain. The specific uptake ratio was measured, and venous blood was drawn when the subject underwent single-photon emission computed tomography to evaluate BDNF levels and SERT genotype. All subjects expressed SERT genotypes that were consistent with a biallelic model, and 26 subjects had SERT genotypes that were consistent with a triallelic model. No differences in specific uptake ratio were detected in the midbrain, putamen, caudate, and thalamus based on the SERT genotype using the biallelic and triallelic models. Interestingly, The Pearson correlation coefficient revealed a positive correlation between BDNF and SERT availability. In particular, this relationship was observed in homozygous S-allele expression and a genotype with low functional expression (SaSa/SaLg) in the biallelic and triallelic models of SERT genotypes, respectively. This finding might explain why the SS genotype of SERT did not increase the risk of major depressive disorder in Asian populations and implicate an important role of BDNF in the patients, who has the SS genotype of the SERT gene.
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http://dx.doi.org/10.1097/JCP.0b013e3182904a80DOI Listing
June 2013

Mechanical unloading activates FoxO3 to trigger Bnip3-dependent cardiomyocyte atrophy.

J Am Heart Assoc 2013 Apr 8;2(2):e000016. Epub 2013 Apr 8.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA.

Background: Mechanical assist device therapy has emerged recently as an important and rapidly expanding therapy in advanced heart failure, triggering in some patients a beneficial reverse remodeling response. However, mechanisms underlying this benefit are unclear.

Methods And Results: In a model of mechanical unloading of the left ventricle, we observed progressive myocyte atrophy, autophagy, and robust activation of the transcription factor FoxO3, an established regulator of catabolic processes in other cell types. Evidence for FoxO3 activation was similarly detected in unloaded failing human myocardium. To determine the role of FoxO3 activation in cardiac muscle in vivo, we engineered transgenic mice harboring a cardiomyocyte-specific constitutively active FoxO3 mutant (caFoxO3(flox);αMHC-Mer-Cre-Mer). Expression of caFoxO3 triggered dramatic and progressive loss of cardiac mass, robust increases in cardiomyocyte autophagy, declines in mitochondrial biomass and function, and early mortality. Whereas increases in cardiomyocyte apoptosis were not apparent, we detected robust increases in Bnip3 (Bcl2/adenovirus E1B 19-kDa interacting protein 3), an established downstream target of FoxO3. To test the role of Bnip3, we crossed the caFoxO3(flox);αMHC-Mer-Cre-Mer mice with Bnip3-null animals. Remarkably, the atrophy and autophagy phenotypes were significantly blunted, yet the early mortality triggered by FoxO3 activation persisted. Rather, declines in cardiac performance were attenuated by proteasome inhibitors. Consistent with involvement of FoxO3-driven activation of the ubiquitin-proteasome system, we detected time-dependent activation of the atrogenes program and sarcomere protein breakdown.

Conclusions: In aggregate, these data point to FoxO3, a protein activated by mechanical unloading, as a master regulator that governs both the autophagy-lysosomal and ubiquitin-proteasomal pathways to orchestrate cardiac muscle atrophy.
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http://dx.doi.org/10.1161/JAHA.113.000016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647287PMC
April 2013

Aggression in bipolar II disorder and its relation to the serotonin transporter.

J Affect Disord 2013 May 2;147(1-3):59-63. Epub 2012 Nov 2.

Department of Psychiatry Taipei Veterans General Hospital and National Yang Ming University, Taipei, Taiwan.

Background: Aggression is frequently observed in patients diagnosed with bipolar disorder (BD). Previous studies found a negative association between aggression and serotoninergic function in patients with BD, as well as in healthy subjects. The objective of this study was to determine whether there is an association between aggression and the availability of the serotonin transporter (SERT) in euthymic BD II patients.

Methods: Thirty-eight age-matched healthy controls (HCs) and 24 BD II patients were recruited. BD II patients were under stable treatment in the euthymic state. The Overt Aggression Scale (OAS) was used for the assessment of aggression. Single photon emission computed tomography with (123)I-ADAM was used for SERT imaging. A specific uptake ratio, which represents availability, was the primary measured outcome.

Results: The total OAS scores, as well as the scores on all of the sub-items, were significantly higher in BD II patients than in the HCs group. There was no significant difference in SERT availability between BD II and HCs subjects in different brain regions. The Pearson's correlation between the total OAS scores and the sub-item aggression and SERT availability was significant.

Limitation: The OAS was used for the assessment of the past week of the patients' condition and thus did not reflect their trait status.

Conclusions: The higher total scores of OAS in euthymic BD II patients than in HCs support the idea that aggression might be a trait marker for BD. Although SERT availability in euthymic BD II patients and in HCs did not differ significantly, the correlation of SERT availability and total OAS provides the possible explanation of aggression in BD II.
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http://dx.doi.org/10.1016/j.jad.2012.10.007DOI Listing
May 2013

Impaired cognition in bipolar I disorder: the roles of the serotonin transporter and brain-derived neurotrophic factor.

J Affect Disord 2012 Dec 11;143(1-3):131-7. Epub 2012 Aug 11.

Department of Psychiatry, Taipei Veterans General Hospital & National Yang Ming University, Taipei, Taiwan.

Background: Studies have proposed that cognitive deficits are present in a variety of mood states in bipolar disorder (BD). The goal of this study was to find the cognitive deficits in euthymic BD patients and to further explore possible underlying mechanisms of the deficits.

Methods: Thirty-three healthy controls (HCs) and twenty-three euthymic BD type I patients were recruited. Single photon emission computed tomography (SPECT) with (123)I-ADAM was used to image the serotonin transporter (SERT). Ten milliliters of venous blood was drawn for the measurement of brain derived neurotrophic factor (BDNF). Cognitive functions were tested included attention, memory, and executive function.

Results: We found that the SERT availability in both the midbrain and striatal regions was decreased in the BD patients compared with the HCs; however, the BDNF were not different between the two groups. There was no correlation between the SERT availability and the BDNF. Interestingly, there were statistically significant differences in sub-items of the facial memory test and the Wisconsin Card Sorting Test between the BD patients and the HCs, which showed that there was a cognitive deficit in the BD patients. However, the overall deficits in cognition were not significantly correlated with the SERT availability or the BDNF.

Limitation: The effect of medications on cognitive function and BDNF should be considered.

Conclusions: We replicated previous findings that showed cognitive deficits in euthymic BD patients. However, the underlying mechanism of cognitive deficits in euthymic BD patients cannot be entirely explained by SERT and BDNF.
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http://dx.doi.org/10.1016/j.jad.2012.05.043DOI Listing
December 2012

Impaired cognition in bipolar I disorder: the roles of the serotonin transporter and brain-derived neurotrophic factor.

J Affect Disord 2012 Dec 11;143(1-3):131-7. Epub 2012 Aug 11.

Department of Psychiatry, Taipei Veterans General Hospital & National Yang Ming University, Taipei, Taiwan.

Background: Studies have proposed that cognitive deficits are present in a variety of mood states in bipolar disorder (BD). The goal of this study was to find the cognitive deficits in euthymic BD patients and to further explore possible underlying mechanisms of the deficits.

Methods: Thirty-three healthy controls (HCs) and twenty-three euthymic BD type I patients were recruited. Single photon emission computed tomography (SPECT) with (123)I-ADAM was used to image the serotonin transporter (SERT). Ten milliliters of venous blood was drawn for the measurement of brain derived neurotrophic factor (BDNF). Cognitive functions were tested included attention, memory, and executive function.

Results: We found that the SERT availability in both the midbrain and striatal regions was decreased in the BD patients compared with the HCs; however, the BDNF were not different between the two groups. There was no correlation between the SERT availability and the BDNF. Interestingly, there were statistically significant differences in sub-items of the facial memory test and the Wisconsin Card Sorting Test between the BD patients and the HCs, which showed that there was a cognitive deficit in the BD patients. However, the overall deficits in cognition were not significantly correlated with the SERT availability or the BDNF.

Limitation: The effect of medications on cognitive function and BDNF should be considered.

Conclusions: We replicated previous findings that showed cognitive deficits in euthymic BD patients. However, the underlying mechanism of cognitive deficits in euthymic BD patients cannot be entirely explained by SERT and BDNF.
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http://dx.doi.org/10.1016/j.jad.2012.05.043DOI Listing
December 2012

Design of a high-efficiency grating coupler based on a silicon nitride overlay for silicon-on-insulator waveguides.

Appl Opt 2010 Nov;49(33):6455-62

Department of Electronic Engineering, Huafan University, Taipei, 22301, Taiwan.

A waveguide grating coupler based on a silicon nitride overlay at 1.55 μm for TE polarization is designed with no experimental demonstration. Its coupling efficiency for a fiber is 76%, the 1 dB bandwidth is 75 nm, and the coupling angle is 10°. The effects of different device parameters on the coupling performance for the grating coupler are discussed. The coupling efficiency of our grating coupler is almost equal, yet the 1 dB spectral bandwidth is around 25 nm broader, as compared with the grating coupler design based on a poly-silicon overlay. The coupling performance of our coupling device could still be further improved. The grating coupler presented in this paper is applicable to the optical coupling in nanophotonic integrated circuits.
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http://dx.doi.org/10.1364/AO.49.006455DOI Listing
November 2010

Predictors of carbon monoxide poisoning-induced delayed neuropsychological sequelae.

Gen Hosp Psychiatry 2010 May-Jun;32(3):310-4. Epub 2010 Jan 12.

Department of Psychiatry, Taipei Veterans General Hospital and National Yang Ming University, Taipei 112, Taiwan.

Objective: Carbon monoxide poisoning (COP) commonly results in delayed neuropsychological sequelae (DNS). The aim of the article is to demonstrate the clinical characteristics and potential predictors of COP-induced DNS later.

Method: Retrospective medical record review was performed for patients who had COP in the past year at a National Medical Center in Taiwan. Sixty patients with COP were registered during a one-year period. Fifty-six of them (93.3%) were COP because of suicide attempt. Patients with COP who have a complete medical record of carboxyhemoglobin (COHb) and Glasgow Coma Scale (GCS) and Mini-Mental Status Examination (MMSE) scores were recruited. Multiple regression analysis was performed to search for the predictive factors of DNS.

Results: Forty-three patients were recruited. Most had attempted suicide (93.0%) using CO, and thirteen developed DNS later. A longer duration of admission, more sessions of hyperbaric oxygen therapy, and positive findings in brain computed tomography (CT) scans were more often found in patients with DNS than those without DNS. The GCS and MMSE scores and positive findings in brain CT scans were associated with the development of DNS but COHb was not.

Conclusions: Our results identified several potential predictors of DNS. This finding may help clinicians understand and treat COP patients efficiently.
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http://dx.doi.org/10.1016/j.genhosppsych.2009.11.005DOI Listing
August 2010

Bubble technique for evaluating effective dose of diagnostic X-rays: a feasibility study.

J Radiat Res 2009 Sep 4;50(5):449-56. Epub 2009 Jul 4.

School of Medical Imaging and Radiological Science, Chung Shan Medical University, Taichung, Taiwan.

This study examined the feasibility of applying the bubble technique to evaluate effective dose for diagnostic X-rays. A BTI-GAMMA bubble detector from Bubble Technology Industries was used for gamma detection. A multi-slab acrylic (PMMA) phantom was fabricated to quantify the effective dose E based on an ICRP-60 report. Accordingly, the bubble detectors were evaluated through preliminary tests to ascertain both the reproducibility of specific X-ray doses and the linearity of multiple X-ray doses. Qualified bubble detectors were then inserted into a multi-slab acrylic phantom. The positions of the inserted bubbles closely corresponded with the position of represented organs or tissues. The effective dose E of X-ray was determined in 12 organ and tissue samples. The bubble detector was maintained at either 21.5 degrees C (for abdomen AP) or 22 degrees C (for chest PA) to optimize counting, and the assessed effective doses for males and females were 66.75 +/- 10.23 microSv and 66.47 +/- 9.89 microSv, respectively, for each chest PA X-ray exposure. The abdominal AP X-ray exposure doses were 1183.73 +/- 124.29 microSv and 976.70 +/- 120.13 microSv for males and females, respectively. Controlling and holding the bubble detector at an optimal ambient temperature during X-ray exposure was the most important issue in practical application, and the optimal temperature had to be adjusted slightly with incident X-ray to effectively suppress the largest bubbles to enable easy reading.
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http://dx.doi.org/10.1269/jrr.08084DOI Listing
September 2009

Medically unexplained symptoms and somatoform disorders: diagnostic challenges to psychiatrists.

J Chin Med Assoc 2009 May;72(5):251-6

Department of Psychiatry, Taipei Veterans General Hospital, Taiwan, R.O.C.

Background: Clinical limitations of the criteria of somatoform disorders (SDs) have been criticized. However, little objective evidence supports this notion. We aimed to examine the prevalence of SDs in a population with medically unexplained symptoms (MUS), which was expected to have higher probabilities meriting such diagnoses, and to evaluate factors that may influence the clinical judgment of psychiatrists.

Methods: Data of subjects with MUS (n = 101, 9.5%) as their chief consulting problems, of 1,068 consecutive ethnic Chinese adult medical inpatients referred for consultation-liaison psychiatry services, were reviewed. Psychiatric diagnoses including SDs and clinical variables were collected. Those with SDs were followed-up 1 year later, and structured interviews were applied.

Results: Patients with MUS had a high level of psychiatric comorbidity, especially depression (35.6%) and anxiety disorder (29.7%), rather than SDs (9.9%). Most diagnosed with SDs suffered from persistent MUS at the 1-year follow-up. Pain was the most common presentation of MUS. Most of the subjects diagnosed with SDs were female and younger, with multiple painful sites at presentation, no past psychiatric diagnosis and no comorbid organic diagnoses. The diagnosis of SDs was seldom given in those with simultaneous MUS and mood symptoms.

Conclusion: A significant proportion (9.5%) of patients in psychiatric consultation suffered from MUS, and most were comorbid with depression and anxiety. The identification of SDs was made in only 9.9%. Because MUS are associated with a high rate of mental comorbidities, psychiatric consultations while facing such clinical conditions are encouraged.
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http://dx.doi.org/10.1016/S1726-4901(09)70065-6DOI Listing
May 2009

White matter abnormalities in schizophrenia patients with tardive dyskinesia: a diffusion tensor image study.

Schizophr Res 2009 Apr 3;109(1-3):167-81. Epub 2009 Mar 3.

Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.

Objective: Tardive dyskinesia (TD) is a severe side effect of antipsychotics. While increasing evidence suggests that damaged brain microcircuitry of white matter (WM) is responsible for the clinical symptoms in schizophrenia, no reports of WM abnormality associated with TD were noted.

Method: Brain white matter abnormalities were investigated among 20 schizophrenia patients with TD (Schizophrenia with TD group), 20 age-, gender-, and handedness-matched schizophrenic patients without TD (Schizophrenia without TD group), and 20 matched healthy subjects with magnetic resonance imaging and diffusion tensor imaging analysis. Voxel-wise analysis was used to compare fractional anisotropy (FA) maps of the white matter following intersubject registration to Talairach space. Clinical ratings included the Positive and Negative Symptoms Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and the Simpson-Angus Scale (SAS).

Results: The study subjects were 75% female with average of 40.1+/-9. 8 years. The Schizophrenia with TD group had significantly higher PANSS total scores (p=0.024), PANSS negative score (p=0.001), SAS (p<0.001) and AIMS (p<0.001) scores; and demonstrated more widespread FA decreases than the Schizophrenia without TD group, especially over the inferior frontal gyrus, temporal sublobar extranuclear WM (around the basal ganglion), parietal precuneus gyrus WM (around somatosensory cortex), and medial frontal gyrus WM (around dorsolateral prefrontal cortex). The AIMS (p<0.01) and SAS (p<0.01) score positively correlated with decreased FA over these areas, and PANSS negative score positively correlated with FA decrease over medial frontal gyrus WM (p<0.01).

Conclusions: More widespread abnormality of white matter was noted among schizophrenia patients than those without, especially involved cortico-basal ganglion circuits with clinical symptom correlation of involuntary movements and negative symptoms. Further studies with larger sample size are required to validate the findings.
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http://dx.doi.org/10.1016/j.schres.2009.02.003DOI Listing
April 2009

Effectiveness of aripiprazole in treating obsessive compulsive symptoms.

Prog Neuropsychopharmacol Biol Psychiatry 2008 Feb 23;32(2):585-6. Epub 2007 Oct 23.

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http://dx.doi.org/10.1016/j.pnpbp.2007.10.009DOI Listing
February 2008
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