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Van Zandt M, Pittenger C. Sex Differences in Histamine Regulation of Striatal Dopamine. J Neurosci 2025; 45:e2182242025. [PMID: 40355265 PMCID: PMC12160404 DOI: 10.1523/jneurosci.2182-24.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 03/05/2025] [Accepted: 04/04/2025] [Indexed: 05/14/2025] Open
Abstract
Dopamine modulation of the basal ganglia differs in males and females and is implicated in numerous neuropsychiatric conditions, including some, like Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD), that have marked sex differences in prevalence. Genetic studies in TS and subsequent work in animals suggest that a loss of histamine may contribute to dysregulation of dopamine. Motivated by this, we characterized the modulation of striatal dopamine by histamine, using microdialysis, targeted pharmacology, and shRNA knockdown of histamine receptors. Intracerebroventricular (ICV) histamine reduced striatal dopamine in male mice, replicating previous work. In contrast, and unexpectedly, ICV histamine increased striatal dopamine in females. ICV or targeted infusion of agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, however, H2R had no discernible role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing only in proestrus, when estrogen levels are high, and estrus. These findings confirm the regulation of striatal dopamine by histamine but identify marked sex differences in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of sex differences in the striatal circuitry and in several neuropsychiatric conditions.
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Affiliation(s)
- Meghan Van Zandt
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06519
| | - Christopher Pittenger
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06519
- Yale Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06519
- Department of Psychology, Yale School of Arts and Sciences, New Haven, Connecticut 06519
- Center for Brain and Mind Health, Yale University School of Medicine, New Haven, Connecticut 06519
- Wu-Tsai Institute, Yale University, New Haven, Connecticut 06519
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Younger DS. Pediatric early-onset neuropsychiatric obsessive compulsive disorders. J Psychiatr Res 2025; 186:84-97. [PMID: 40222306 DOI: 10.1016/j.jpsychires.2025.03.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/06/2025] [Accepted: 03/25/2025] [Indexed: 04/15/2025]
Abstract
At the time of this writing, most pediatricians or child psychiatrists will probably have treated a child with early acute-onset obsessive compulsive disorder (OCD) behaviors due to the pediatric autoimmune neuropsychiatric disorder associated with Group A beta-hemolytic streptococcus, abbreviated PANDAS, described more than two decades ago; or Tourette syndrome, incorporating motor and vocal tics, described more than a century ago. One typically self-limited post-infectious OCD resulting from exposure to other putative microbial disease triggers defines PANS, abbreviating pediatric autoimmune neuropsychiatric syndrome. Tourette syndrome, PANDAS and PANS share overlapping neuroimaging features of hypometabolism of the medial temporal lobe and hippocampus on brain 18Fluorodeoxyglucose positron emission tomography fused to magnetic resonance imaging (PET/MRI) consistent with involvement of common central nervous system (CNS) pathways for the shared clinical expression of OCD. The field of pediatric neuropsychiatric disorders manifesting OCD behaviors is at a crossroads commensurate with recent advances in the neurobiology of the medial temporal area, with its wide-ranging connectivity and cortical cross-talk, and CNS immune responsiveness through resident microglia. This review advances the field of pediatric neuropsychiatric disorders and in particular PANS, by providing insights through clinical vignettes and descriptive clinical and neuroimaging correlations from the author's file. Neuroscience collaborations with child psychiatry and infectious disease practitioners are needed to design clinical trials with the necessary rigor to provide meaningful insights into the rational clinical management of PANS with the aim of developing evidence-based guidelines for the clinical management of early, abrupt-onset childhood OCD to avert potentially life-long neuropsychological struggles.
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Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, And the Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, USA.
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Hall MD, Gipson KS, Gipson SYMT, Colvin MK, Nguyen STT, Greenberg E. Disrupted Cortico-Striato-Thalamo-Cortical Circuitry and Sleep Disturbances in Obsessive-Compulsive Spectrum, Chronic Tic, and Attention-Deficit/Hyperactivity Disorders. Harv Rev Psychiatry 2025; 33:114-126. [PMID: 40344416 DOI: 10.1097/hrp.0000000000000429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
Abstract
ABSTRACT The bidirectional relationship between sleep and obsessive-compulsive spectrum disorders (OCSDs), chronic tic disorders (CTDs), and attention-deficit/hyperactivity disorder (ADHD) is not well understood. To better treat individuals with these co-occurring sleep and developmental neuropsychiatric conditions, it is necessary to determine the common neural underpinnings to then target with treatment. Research has implicated dysregulated cortico-striatal-thalamo-cortical (CSTC) neurocircuitry in the development of CTDs, OCSDs, and ADHD. We review current literature to assess the state of knowledge about the neurocircuitry of OCSDs, CTDs, and ADHD, and their related sleep disturbances. Our review consistently implicates CSTC-pathway disruptions in OCSDs, CTDs, and ADHD, as well as dopamine and GABA dysregulation, primary neurotransmitters in CSTC circuitry, in sleep disorders. In addition, we highlight reports of subjective poor sleep and insomnia in adults with OCSDs, CTDs, and ADHD, and sleep movement disorders in adults with CTDs. The limited sleep research on youth with these conditions has demonstrated some similar findings. Unfortunately, much of the current research to date has not employed polysomnographic methods for objective sleep-related assessments. Future research should further clarify the neural association between these neuropsychiatric conditions and sleep disturbances to better guide potential therapeutic targets. Determining the most effective treatments for subjective sleep-related complaints in patients with these conditions will be crucial, particularly for determining treatment course-whether to prioritize treatment of the underlying condition, the specific sleep symptoms, or both simultaneously.
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Affiliation(s)
- Margaret D Hall
- From Department of Psychology, Miami University (Ms. Hall); Division of Pediatric Pulmonology and Sleep Medicine (Dr. K. Gipson); Department of Psychiatry, Massachusetts General Hospital, Boston, MA (Drs. S. Gipson, Colvin, and Greenberg); Stritch School of Medicine, Loyola University of Chicago (Ms. Nguyen)
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Cadeddu R, Branca C, Braccagni G, Musci T, Piras IS, Anderson CJ, Capecchi MR, Huentelman MJ, Moos PJ, Bortolato M. Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D 3 dopamine receptors. Mol Psychiatry 2025:10.1038/s41380-025-02970-w. [PMID: 40155412 DOI: 10.1038/s41380-025-02970-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/05/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025]
Abstract
The gene CELSR3 (Cadherin EGF LAG Seven-pass-G-type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, Celsr3 mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of Celsr3 mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that Celsr3 mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of Celsr3 mutants. Single-nucleus transcriptomics also showed significant upregulation of the Drd3 gene, encoding the dopamine D3 receptor, in striosomal D1-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D3 receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D1-positive neurons. Activating and blocking D3 receptors amplified or decreased tic-like jerks and stereotypies in Celsr3-deficient mice, respectively. These findings suggest that modifications of D3 receptor distribution contribute to the tic-like responses associated with Celsr3 deficiency.
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Affiliation(s)
- Roberto Cadeddu
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Caterina Branca
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Giulia Braccagni
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Teresa Musci
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Ignazio S Piras
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Collin J Anderson
- Department of Neurology, School of Medicine, University of Utah, Salt Lake City, UT, USA
- School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia
- School of Biomedical Engineering, University of Sydney, Camperdown, NSW, Australia
| | - Mario R Capecchi
- Department of Human Genetics, College of Medicine, University of Utah, Salt Lake City, UT, USA
| | - Matthew J Huentelman
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Philip J Moos
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Marco Bortolato
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
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Van Zandt M, Pittenger C. Sexual dimorphism in histamine regulation of striatal dopamine. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.05.20.595049. [PMID: 38826392 PMCID: PMC11142073 DOI: 10.1101/2024.05.20.595049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Dopamine modulation of the basal ganglia differs in males and females and is implicated in numerous neuropsychiatric conditions, including some, like Tourette Syndrome (TS) and attention deficit hyperactivity disorder (ADHD), that have marked sex differences in prevalence. Genetic studies in TS and subsequent work in animals suggest that a loss of histamine may contribute to dysregulation of dopamine. Motivated by this, we characterized the modulation of striatal dopamine by histamine, using microdialysis, targeted pharmacology, and shRNA knockdown of histamine receptors. Intracerebroventricular (ICV) histamine reduced striatal dopamine in male mice, replicating previous work. In contrast, and unexpectedly, ICV histamine increased striatal dopamine in females. ICV or targeted infusion of agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, however, H2R had no discernible role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing only in estrus/proestrus, when estrogen levels are high. These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of sex differences in the striatal circuitry, and in several neuropsychiatric conditions.
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Affiliation(s)
- Meghan Van Zandt
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA, 06519
| | - Christopher Pittenger
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA, 06519
- Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA, 06519
- Department of Psychology, Yale School of Arts and Sciences, New Haven, USA, 06519
- Center for Brain and Mind Health, Yale University School of Medicine, New Haven, USA, 06519
- Wu-Tsai Institute, Yale University, New Haven, CT, USA, 06519
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Kowalski TF, Wang R, Tischfield MA. Genetic advances and translational phenotypes in rodent models for Tourette disorder. Curr Opin Neurobiol 2025; 90:102967. [PMID: 39793296 DOI: 10.1016/j.conb.2024.102967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 12/11/2024] [Accepted: 12/12/2024] [Indexed: 01/13/2025]
Abstract
Tourette disorder (TD) is a neurodevelopmental condition affecting approximately 0.3%-1% of children and adolescents. It is defined by motor and vocal tics but encompasses wide ranging phenotypes due to its complex genetic origins, involving hundreds of risk genes across various signaling pathways. Traditional animal models of TD have focused on circuit manipulation or neuron ablation strategies to investigate its underlying causes and associated brain changes. However, the recent identification of high-confidence risk genes has opened new possibilities for creating models that express the exact genetic variants associated with TD. This review discusses early attempts to model TD in rodents and highlights advancements in next-generation models with true construct validity through the expression of orthologous human mutations in high-confidence risk genes. Additionally, we examine the translational potential of integrating cognitive and sensorimotor approaches to evaluate TD-related phenotypes in rodents, including changes to reinforcement learning, habitual behavior, and incentive motivation.
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Affiliation(s)
- Tess F Kowalski
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Child Health Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Riley Wang
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA
| | - Max A Tischfield
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Child Health Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
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Mohamed ZA, Dong H, Xue Y, Bai M, Ouyang Y, Jia F. Prolonged screen time is associated with increased severity of tic symptoms in children with tic disorders. Ital J Pediatr 2025; 51:16. [PMID: 39865274 PMCID: PMC11770938 DOI: 10.1186/s13052-025-01851-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 01/12/2025] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND Recent studies have emphasized the association between prolonged screen exposure and neurodevelopmental disorders, though its correlation with tic disorders (TDs) remains ambiguous. We thus conducted this study to investigate the association between screen time (ST) and the severity of tic symptoms in children diagnosed with TDs. METHODS We conducted a retrospective case-control study with 342 cases of TDs and 270 controls, collecting data from March 2021 to December 2023. The main exposure variable was daily ST for each child, and tic severity, evaluated using the Yale Global Tic Severity Scale (YGTSS), was the outcome variable. Statistical analysis included descriptive statistics, Pearson's correlation analysis to examine the relationship between screen time and tic severity, and multivariate regression analysis to evaluate the predictive power of screen time for tic symptoms. RESULTS Our findings revealed that children with TDs had significantly longer ST compared to the control group, averaging 116.06 ± 147.9 min/day versus 43.23 ± 37.5 min/day, p < 0.001. We also noted a positive correlation between ST and TDs( r = 0.461, p < 0.01). Daily ST was a significant predictor of overall YGTSS scores (t = 9.58, p < 0.001), suggesting that increased ST is associated with heightened tic symptoms. However, age of first exposure to screens was not significantly correlated with tic severity (p > 0.05). Though we observed a negative correlation between ST and vitamin D levels, the results were not statistically significant (p > 0.05). CONCLUSION Children with TDs had longer ST compared to their control's counterparts, and prolonged ST was significantly associated with heightened tic severity, which highlights the critical need for careful monitoring and regulation of screen time in children with TDs.
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Affiliation(s)
- Zakaria Ahmed Mohamed
- Department of developmental and behavior pediatrics, Children's Medical Center, The First Hospital of Jilin University, Jilin University, Changchun, China
- The Child Health Clinical Research Center of Jilin Province, Changchun, China
| | - Hanyu Dong
- Department of developmental and behavior pediatrics, Children's Medical Center, The First Hospital of Jilin University, Jilin University, Changchun, China
- The Child Health Clinical Research Center of Jilin Province, Changchun, China
| | - Yang Xue
- Department of developmental and behavior pediatrics, Children's Medical Center, The First Hospital of Jilin University, Jilin University, Changchun, China
- The Child Health Clinical Research Center of Jilin Province, Changchun, China
| | - Miaoshui Bai
- Department of developmental and behavior pediatrics, Children's Medical Center, The First Hospital of Jilin University, Jilin University, Changchun, China
- The Child Health Clinical Research Center of Jilin Province, Changchun, China
| | - Yuling Ouyang
- Department of developmental and behavior pediatrics, Children's Medical Center, The First Hospital of Jilin University, Jilin University, Changchun, China
- The Child Health Clinical Research Center of Jilin Province, Changchun, China
| | - Feiyong Jia
- Department of developmental and behavior pediatrics, Children's Medical Center, The First Hospital of Jilin University, Jilin University, Changchun, China.
- The Child Health Clinical Research Center of Jilin Province, Changchun, China.
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Lu MQ, Shi ZG, Shang J, Gao L, Gao L, Gao WJ. ChangPu YuJin Tang improves Tourette disorder symptoms by modulating amino acid neurotransmitters in IDPN model rats. Metab Brain Dis 2024; 39:1543-1558. [PMID: 39312065 DOI: 10.1007/s11011-024-01411-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 08/09/2024] [Indexed: 11/05/2024]
Abstract
INTRODUCTION Changpu Yujin Tang(CPYJT), a Chinese herbal compound, is an effective therapeutic strategy for pediatric patients with Tourette disorder (TD). Therefore, this work aims to investigate the therapeutic mechanisms of CPYJT. METHODS Behavioral and cellular ultrastructural evaluation of the therapeutic effects of CPYJT in TD model rats. Colorimetric methods, reverse transcription‑quantitative PCR, and Western Blot were used to measure the altered levels of GLU, GABA, and the levels of VGLUT1, GLUD1, GABRA3, and GAD65 in the cortex, striatum, and thalamus of the TD model rats after 7, 14, 21, and 28 days of CPYJT administration. RESULTS CPYJT significantly reduced stereotypic behavior and motor behavior scores in TD model rats. CPYJT ameliorates myelin structural damage in TD model rat neuronal cells. CPYJT decreased GLU content, elevated GABA content, decreased GLUD1 and VGLUT1 levels, and elevated GAD65 and GABRA3 levels in TD model rats' cortex, striatum, and thalamus. CPYJT has different regulatory time points in the cortex, striatum, and thalamus for critical factors of amino acid-based neurotransmission. CONCLUSION CPYJT protects behavioral and structural damage of neuronal cells in multiple brain regions in TD model rats.
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Affiliation(s)
- Man-Qi Lu
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China
- Longhua Hospital Shanghai University of Traditional Chinese Medicine, shanghai, 200000, China
| | - Zheng-Gang Shi
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China.
| | - Jing Shang
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China
| | - Lü Gao
- Shanxi University Of Chinese Medicine Third Clinical Medical College Pediatric Teaching and Research Department, Taiyuan, 140100, Shanxi, China
| | - Lei Gao
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China
| | - Wei-Jiao Gao
- Clinical College of Chinese Medicine, Gansu University Of Chinese Medicine, Lanzhou, 730000, Gansu, P.R. China
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Vilela-Filho O, Souza JT, Ragazzo PC, Silva DJ, Oliveira PM, Goulart LC, Reis MD, Piedimonte F, Ribeiro TM. Bilateral Globus Pallidus Externus Deep Brain Stimulation for the Treatment of Refractory Tourette Syndrome: An Open Clinical Trial. Neuromodulation 2024; 27:742-758. [PMID: 37294231 DOI: 10.1016/j.neurom.2023.04.473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 06/10/2023]
Abstract
OBJECTIVES We have previously proposed that Tourette syndrome (TS) is the clinical expression of the hyperactivity of globus pallidus externus (GPe) and various cortical areas. This study was designed to test this hypothesis by verifying the efficacy and safety of bilateral GPe deep brain stimulation (DBS) for treating refractory TS. MATERIALS AND METHODS In this open clinical trial, 13 patients were operated on. Target coordinates (center of GPe) were obtained by direct visualization. Physiological mapping was performed with macrostimulation and microrecording. Primary and secondary outcome measures were, respectively, responder and improvement rates of TS and comorbidities, according to pre- and postoperative scores on the following assessment instruments: Yale Global Tic Severity Scale, Yale-Brown Obsessive Compulsive Scale, Beck Depression Inventory/Hamilton Depression Rating Scale, Beck Anxiety Inventory/Hamilton Anxiety Rating Scale, and Concentrated Attention test. RESULTS Intraoperative stimulation (100 Hz/5.0V) did not produce any adverse effects or impact on tics. Microrecording revealed bursting cells discharging synchronously with tics in the central part of the dorsal half of GPe. Patients were followed up for a mean of 61.46±48.50 months. Responder rates were 76.9%, 75%, 71.4%, 71.4%, and 85.7%, respectively, for TS, obsessive-compulsive disorder (OCD), depression, anxiety, and attention deficit hyperactivity disorder. Mean improvements among responders in TS, OCD, depression, and anxiety were 77.4%, 74.7%, 89%, and 84.8%, respectively. After starting stimulation, tic improvement was usually delayed, taking up to ten days to manifest. Afterward, it increased over time, usually reaching its maximum at approximately one year postoperatively. The best stimulation parameters were 2.3V to 3.0V, 90 to 120 μsec, and 100 to 150 Hz, and the most effective contacts were the two dorsal ones. Two complications were registered: reversible impairment of previous depression and transient unilateral bradykinesia. CONCLUSIONS Bilateral GPe-DBS proved to be low risk and quite effective for treating TS and comorbidities, ratifying the pathophysiological hypothesis that led to this study. Moreover, it compared favorably with DBS of other targets currently in use.
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Affiliation(s)
- Osvaldo Vilela-Filho
- Division of Neurosurgery, Department of Surgery, Medical School, Federal University of Goiás, Goiânia, Goiás, Brazil; Nervous System Unity, Clinics Hospital, Medical School, Federal University of Goiás, Goiânia, Goiás, Brazil; Department of Stereotactic and Functional Neurosurgery, Goiânia Neurological Institute, Goiânia, Goiás, Brazil.
| | - Joaquim T Souza
- Nervous System Unity, Clinics Hospital, Medical School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Paulo C Ragazzo
- Department of Neurology, Goiânia Neurological Institute, Goiânia, Goiás, Brazil
| | - Délson J Silva
- Nervous System Unity, Clinics Hospital, Medical School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Paulo M Oliveira
- Department of Psychiatry, Medical School, Federal University of Goiás, Goiânia, Goiás, Brazil; Department of Psychiatry, Goiânia Neurological Institute, Goiânia, Goiás, Brazil
| | - Lissa C Goulart
- Nervous System Unity, Clinics Hospital, Medical School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Manoel D Reis
- Department of Psychiatry, Goiânia Neurological Institute, Goiânia, Goiás, Brazil
| | - Fabian Piedimonte
- JJ Naon Institute of Morphology, Medical School, University of Buenos Aires, Buenos Aires, Argentina
| | - Telma M Ribeiro
- Department of Psychiatry, Goiânia Neurological Institute, Goiânia, Goiás, Brazil
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Branca C, Bortolato M. The role of neuroactive steroids in tic disorders. Neurosci Biobehav Rev 2024; 160:105637. [PMID: 38519023 PMCID: PMC11121756 DOI: 10.1016/j.neubiorev.2024.105637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 03/03/2024] [Accepted: 03/19/2024] [Indexed: 03/24/2024]
Abstract
Tics are sudden, repetitive movements or vocalizations. Tic disorders, such as Tourette syndrome (TS), are contributed by the interplay of genetic risk factors and environmental variables, leading to abnormalities in the functioning of the cortico-striatal-thalamo-cortical (CSTC) circuitry. Various neurotransmitter systems, such as gamma-aminobutyric acid (GABA) and dopamine, are implicated in the pathophysiology of these disorders. Building on the evidence that tic disorders are predominant in males and exacerbated by stress, emerging research is focusing on the involvement of neuroactive steroids, including dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone, in the ontogeny of tics and other phenotypes associated with TS. Emerging evidence indicates that DHEAS levels are significantly elevated in the plasma of TS-affected boys, and the clinical onset of this disorder coincides with the period of adrenarche, the developmental stage characterized by a surge in DHEAS synthesis. On the other hand, allopregnanolone has garnered particular attention for its potential to mediate the adverse effects of acute stress on the exacerbation of tic severity and frequency. Notably, both neurosteroids act as key modulators of GABA-A receptors, suggesting a pivotal role of these targets in the pathophysiology of various clinical manifestations of tic disorders. This review explores the potential mechanisms by which these and other neuroactive steroids may influence tic disorders and discusses the emerging therapeutic strategies that target neuroactive steroids for the management of tic disorders.
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Affiliation(s)
- Caterina Branca
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Marco Bortolato
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
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Kopelman JM, Chohan MO, Hsu AI, Yttri EA, Veenstra-VanderWeele J, Ahmari SE. Forebrain EAAT3 Overexpression Increases Susceptibility to Amphetamine-Induced Repetitive Behaviors. eNeuro 2024; 11:ENEURO.0090-24.2024. [PMID: 38514191 PMCID: PMC11012153 DOI: 10.1523/eneuro.0090-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 03/23/2024] Open
Abstract
Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the SLC1A1 gene with OCD. The most common of these OCD-associated polymorphisms increases the expression of the encoded protein, excitatory amino acid transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of Slc1a1 in forebrain neurons. The mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and Slc1a1-overexpressing (OE) mice, but Slc1a1-OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in Slc1a1-OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in Slc1a1-OE mice were driven by cFos expression specifically in D1 neurons, as Slc1a1-OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in Slc1a1-OE mice.
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Affiliation(s)
- Jared M Kopelman
- Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
- Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15260
| | - Muhammad O Chohan
- Department of Psychiatry, Columbia University, New York, New York 10032
- New York State Psychiatric Institute, New York, New York 10032
| | - Alex I Hsu
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15260
| | - Eric A Yttri
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15260
| | - Jeremy Veenstra-VanderWeele
- Department of Psychiatry, Columbia University, New York, New York 10032
- New York State Psychiatric Institute, New York, New York 10032
| | - Susanne E Ahmari
- Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
- Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15260
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12
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Prescott TJ, Montes González FM, Gurney K, Humphries MD, Redgrave P. Simulated Dopamine Modulation of a Neurorobotic Model of the Basal Ganglia. Biomimetics (Basel) 2024; 9:139. [PMID: 38534824 DOI: 10.3390/biomimetics9030139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 03/28/2024] Open
Abstract
The vertebrate basal ganglia play an important role in action selection-the resolution of conflicts between alternative motor programs. The effective operation of basal ganglia circuitry is also known to rely on appropriate levels of the neurotransmitter dopamine. We investigated reducing or increasing the tonic level of simulated dopamine in a prior model of the basal ganglia integrated into a robot control architecture engaged in a foraging task inspired by animal behaviour. The main findings were that progressive reductions in the levels of simulated dopamine caused slowed behaviour and, at low levels, an inability to initiate movement. These states were partially relieved by increased salience levels (stronger sensory/motivational input). Conversely, increased simulated dopamine caused distortion of the robot's motor acts through partially expressed motor activity relating to losing actions. This could also lead to an increased frequency of behaviour switching. Levels of simulated dopamine that were either significantly lower or higher than baseline could cause a loss of behavioural integration, sometimes leaving the robot in a 'behavioral trap'. That some analogous traits are observed in animals and humans affected by dopamine dysregulation suggests that robotic models could prove useful in understanding the role of dopamine neurotransmission in basal ganglia function and dysfunction.
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Affiliation(s)
- Tony J Prescott
- Department of Computer Science, University of Sheffield, Sheffield S10 2TN, UK
| | | | - Kevin Gurney
- Department of Psychology, University of Sheffield, Sheffield S10 2TN, UK
| | - Mark D Humphries
- School of Psychology, University of Nottingham, Nottingham NG7 2RD, UK
| | - Peter Redgrave
- Department of Psychology, University of Sheffield, Sheffield S10 2TN, UK
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13
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Zouki JJ, Ellis EG, Morrison-Ham J, Thomson P, Jesuthasan A, Al-Fatly B, Joutsa J, Silk TJ, Corp DT. Mapping a network for tics in Tourette syndrome using causal lesions and structural alterations. Brain Commun 2023; 5:fcad105. [PMID: 37215485 PMCID: PMC10198704 DOI: 10.1093/braincomms/fcad105] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/29/2023] [Accepted: 04/02/2023] [Indexed: 05/24/2023] Open
Abstract
Tics are sudden stereotyped movements or vocalizations. Cases of lesion-induced tics are invaluable, allowing for causal links between symptoms and brain structures. While a lesion network for tics has recently been identified, the degree to which this network translates to Tourette syndrome has not been fully elucidated. This is important given that patients with Tourette syndrome make up a large portion of tic cases; therefore, existing and future treatments should apply to these patients. The aim of this study was to first localize a causal network for tics from lesion-induced cases and then refine and validate this network in patients with Tourette syndrome. We independently performed 'lesion network mapping' using a large normative functional connectome (n = 1000) to isolate a brain network commonly connected to lesions causing tics (n = 19) identified through a systematic search. The specificity of this network to tics was assessed through comparison to lesions causing other movement disorders. Using structural brain coordinates from prior neuroimaging studies (n = 7), we then derived a neural network for Tourette syndrome. This was done using standard anatomical likelihood estimation meta-analysis and a novel method termed 'coordinate network mapping', which uses the same coordinates, yet maps their connectivity using the aforementioned functional connectome. Conjunction analysis was used to refine the network for lesion-induced tics to Tourette syndrome by identifying regions common to both lesion and structural networks. We then tested whether connectivity from this common network is abnormal in a separate resting-state functional connectivity MRI data set from idiopathic Tourette syndrome patients (n = 21) and healthy controls (n = 25). Results showed that lesions causing tics were distributed throughout the brain; however, consistent with a recent study, these were part of a common network with predominant basal ganglia connectivity. Using conjunction analysis, coordinate network mapping findings refined the lesion network to the posterior putamen, caudate nucleus, globus pallidus externus (positive connectivity) and precuneus (negative connectivity). Functional connectivity from this positive network to frontal and cingulate regions was abnormal in patients with idiopathic Tourette syndrome. These findings identify a network derived from lesion-induced and idiopathic data, providing insight into the pathophysiology of tics in Tourette syndrome. Connectivity to our cortical cluster in the precuneus offers an exciting opportunity for non-invasive brain stimulation protocols.
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Affiliation(s)
- Jade-Jocelyne Zouki
- Correspondence to: Jade-Jocelyne Zouki Cognitive Neuroscience Unit School of Psychology, Deakin University 221 Burwood Hwy, Burwood, VIC 3125, Australia E-mail:
| | - Elizabeth G Ellis
- Centre for Social and Early Emotional Development and School of Psychology, Deakin University, Geelong VIC 3220, Australia
| | - Jordan Morrison-Ham
- Centre for Social and Early Emotional Development and School of Psychology, Deakin University, Geelong VIC 3220, Australia
| | - Phoebe Thomson
- Department of Paediatrics, The University of Melbourne, Melbourne VIC 3010, Australia
- Developmental Imaging, Murdoch Children’s Research Institute, Melbourne VIC 3052, Australia
- Autism Center, Child Mind Institute, New York NY 10022, USA
| | - Aaron Jesuthasan
- Neurology Department, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Bassam Al-Fatly
- Department of Neurology with Experimental Neurology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Juho Joutsa
- Turku Brain and Mind Center, Clinical Neurosciences, University of Turku, Turku, FI-20014, Finland
- Turku PET Centre, Neurocenter, Turku University Hospital, Turku, FI-20520, Finland
| | | | - Daniel T Corp
- Correspondence may also be addressed to: Daniel T. Corp E-mail:
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14
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Marazziti D, Palermo S, Arone A, Massa L, Parra E, Simoncini M, Martucci L, Beatino MF, Pozza A. Obsessive-Compulsive Disorder, PANDAS, and Tourette Syndrome: Immuno-inflammatory Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1411:275-300. [PMID: 36949315 DOI: 10.1007/978-981-19-7376-5_13] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
In the last years, much focus has been given to the possible role of inflammatory and immunologic alterations in the pathophysiology of obsessive-compulsive disorder (OCD) and some related conditions, such as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and Tourette syndrome (TS). Although the matter is intriguing, the available data are still controversial and/or limited. Therefore, the aim of this chapter was at reviewing and commenting on the literature on possible dysfunctions of inflammatory and immune system processes in OCD, PANDAS, and TS.This narrative review was carried out through searching PubMed and Google Scholar for English language papers from January 1985 to December 31, 2021.The data gathered up to now would suggest that the mechanisms involved might be heterogeneous according to the age of the patients and the disorder examined. Indeed, PANDAS seem more related to infections triggering autoimmunity not necessarily following group A beta-hemolytic streptococcal (GABHS) infection, as supposed in the past. Autoimmunity seems also important in TS, if coupled with an individual vulnerability that can be genetic and/or environmental. The data in adult OCD, albeit scattered and sometimes obtained in small samples of patients, would indicate that immune system and inflammatory processes are involved in the pathophysiology of the disorder. However, it is still unclear to conclude whether they are primary or secondary phenomena.In conclusion, taken together, the current findings pave that way towards novel and promising domains to explore the pathophysiology of OCD and related disorders, as well towards the development of innovative therapeutic strategy beyond current pharmacological paradigms.
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Affiliation(s)
- Donatella Marazziti
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy.
- Saint Camillus International University of Health and Medical Sciences - UniCamillus, Rome, Italy.
| | - Stefania Palermo
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Alessandro Arone
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Lucia Massa
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Elisabetta Parra
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Marly Simoncini
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Lucia Martucci
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Maria Francesca Beatino
- Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Andrea Pozza
- Dipartimento di Scienze Mediche, Chirurgiche e Neuroscienze, University of Siena, Siena, Italy
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15
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Younger DS. Pediatric neuropsychiatric disorders with motor and nonmotor phenomena. HANDBOOK OF CLINICAL NEUROLOGY 2023; 196:367-387. [PMID: 37620079 DOI: 10.1016/b978-0-323-98817-9.00028-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
The concept of pediatric autoimmune neuropsychiatric disorders associated with group A beta-hemolytic streptococcus (PANDAS) has become seminal since first introduced more than two decades ago. At the time of this writing, most neurologists, pediatricians, psychiatrists, and general pediatricians will probably have heard of this association or treated an affected child with PANDAS. The concept of an acute-onset, and typically self-limited, postinfectious autoimmune neuropsychiatric disorder resembling PANDAS manifesting vocal and motor tics and obsessive-compulsive disorder has broadened to other putative microbes and related endogenous and exogenous disease triggers. These disorders with common features of hypometabolism in the medial temporal lobe and hippocampus in brain 18fluorodeoxyglucose positron emission tomography fused to magnetic resonance imaging (FDG PET-MRI), form a spectrum: with the neuropsychiatric disorder Tourette syndrome and PANDAS with its well-defined etiopathogenesis at one end, and pediatric abrupt-onset neuropsychiatric syndrome (PANS), alone or associated with specific bacterial and viral pathogens, at the other end. The designation of PANS in the absence of a specific trigger, as an exclusionary diagnosis, reflects the current problem in nosology.
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Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States; Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States.
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16
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Ramteke A, Lamture Y. Tics and Tourette Syndrome: A Literature Review of Etiological, Clinical, and Pathophysiological Aspects. Cureus 2022; 14:e28575. [PMID: 36185878 PMCID: PMC9520955 DOI: 10.7759/cureus.28575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 08/30/2022] [Indexed: 11/07/2022] Open
Abstract
Tourette syndrome (TS) is a condition characterized by tics produced because of neuropsychiatric malfunctioning occurring in childhood, which becomes less severe in adulthood, followed by a difference in the severity of tics between two persons. TS is a diverse variable in which symptoms vary in different patients. It is associated with comorbidities like obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and depression, and hampers the quality of life. Comorbid disorders must be investigated and treated as part of the clinical approach for all TS patients. Clinicians should be aware of the infrequent but serious neurological problems that can occur in these patients and recommend aggressively treating tics. Currently, there is more emphasis on symptom-based treatments by medicines, but as etiological knowledge improves, we will divert to disease-modifying medications in the future. Behavioral, pharmacological, and surgical methods can treat TS. Neuroleptics, other drugs, and behavioral therapies are the first-line options. Deep brain stimulation is evolving but has its pros and cons. The main focus of this review is on tics characteristics, how to manage and assess them, and limitations in the clinical spectrum.
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17
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A Pilot Study on Plasma and Urine Neurotransmitter Levels in Children with Tic Disorders. Brain Sci 2022; 12:brainsci12070880. [PMID: 35884687 PMCID: PMC9313232 DOI: 10.3390/brainsci12070880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
Background: Tic disorders (TDs), including Tourette syndrome, are childhood-onset neuropsychiatric disorders characterized by motor and/or vocal tics that commonly affect children’s physical and mental health. The pathogenesis of TDs may be related to abnormal neurotransmitters in the cortico-striatal-thalamo-cortical circuitry, especially dopaminergic, glutamatergic, and serotonergic neurotransmitters. The purpose of this study was to preliminarily investigate the differences in the three types of neurotransmitters in plasma and urine between children with TD and healthy children. Methods: We collected 94 samples of plasma and 69 samples of urine from 3–12-year-old Chinese Han children with TD before treatment. The plasma and urine of the same number of healthy Chinese Han children, matched for age and sex, participating in a physical examination, were collected. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the three types of neurotransmitters in the above samples. Results: The plasma levels of norepinephrine, glutamic acid, and γ-aminobutyric acid, and the urine levels of normetanephrine and 5-hydroxyindoleacetic acid were higher in the TD children than in healthy children. The area under the curve (AUC) values of the above neurotransmitters in plasma and urine analyzed by receiver operating characteristic curve analysis were all higher than 0.6, with significant differences. Among them, the combined AUC of dopamine, norepinephrine, normetanephrine, glutamic acid, and γ-aminobutyric acid in the 8–12-year-old subgroup was 0.930, and the sensitivity and specificity for TD were 0.821 and 0.974, respectively (p = 0.000). Conclusions: There are differences in plasma and urine neurotransmitters between TD children and healthy children, which lays a foundation for further research on the pathogenesis of TD.
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18
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Chen J, Xie Y, Lin Q, Qian Z, Feng J, Zhang J, Chen Y, Chen W, Wu Y, Guo Z. Investigating Acupoint Selection and Combinations of Acupuncture for Tic Disorders: An Association Rule Mining and Network Analysis Study. Front Neurol 2022; 13:894951. [PMID: 35756940 PMCID: PMC9226724 DOI: 10.3389/fneur.2022.894951] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 05/17/2022] [Indexed: 12/02/2022] Open
Abstract
Objective Tic disorders (TDs) are common mental disorders in children and adolescents, and the clinical application of acupuncture for treating TDs is becoming increasingly widespread. However, the criteria for selecting acupoint prescriptions and combinations have not been summarized. Therefore, data mining was used herein to determine the treatment principles and the most effective acupoint selection and compatibility criteria for the treatment of TDs. Methods Clinical studies and observations of the efficacy of acupuncture treatment for TDs were obtained from the PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP, and Chinese Biomedical (CBM) databases. The data on the acupoint prescriptions applied in these studies were collected, and network and association analyses were used to reveal the relationships between acupoints and to identify acupoint combinations. Additionally, the principles of acupuncture for TDs were determined through cluster analysis. Subgroup analysis of acupuncture prescriptions based on specific categorical diagnoses was performed to further assess the selection of acupoints. Results Eighty-six trials were identified, and 257 groups of effective prescriptions involving 121 acupoints were extracted. Bai-hui (DU20), Feng-chi (GB20), Tai-chong (LR3), He-gu (LI4), and San-yin-jiao (SP6) were the most regularly used acupoints for treating TDs. The Governor Vessel, gallbladder, and large intestine meridians were more commonly used than other meridians. Moreover, most acupoint sites focused on the head and neck. Network analysis revealed potentially effective acupoint prescriptions for their commonly used acupoints, namely, Bai-hui (DU20), Si-shen-cong (EX-HN1), Feng-chi (GB20), Nei-guan (PC6), Shen-men (HT7), He-gu (LI4), Zu-san-li (ST36), San-yin-jiao (SP6) and Tai-chong (LR3). Association rule mining indicated that potential point combinations that should be prioritized in TD treatment are Bai-hui (DU20), Neiguan (PC6) and Sanyinjiao (SP6). Cluster analysis revealed the treatment principle of “coordinating yin and yang, tonifying qi and blood, dispelling pathogenic wind and eliminating phlegm”. The core acupoint prescription of TS treatment comprised He-gu (LI4), Feng-chi (GB20), Tai-chong (LR3), Bai-hui (DU20), Yin-tang (EX-HN3), Si-shen-cong (EX-HN1), San-yin-jiao (SP6), and Nei-guan (PC6). The core group included He-gu (LI4) and Feng-chi (GB20). Proximal points were usually used in TS as an additional method of point selection. Conclusion Using data mining analysis of published studies, this study provides valuable information regarding the selection of the most effective acupoints and point combinations for clinical acupuncture practice for treating TDs.
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Affiliation(s)
- Jieting Chen
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China.,Sixth Clinical School of Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yufeng Xie
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Qingchan Lin
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China.,Sixth Clinical School of Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Ziliang Qian
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Jun Feng
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China.,Sixth Clinical School of Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Jianmei Zhang
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China.,Sixth Clinical School of Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yun Chen
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wenhan Chen
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yueting Wu
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China.,Sixth Clinical School of Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Ziyi Guo
- Macau University of Science and Technology, Taipa, Macao SAR, China
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19
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Li X, Liu X, Liu Y, Gao R, Wu X, Gao X. Highly sensitive detection of dopamine based on gold nanoflowers enhanced-Tb(III) fluorescence. Talanta 2022; 249:123700. [PMID: 35751922 DOI: 10.1016/j.talanta.2022.123700] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 06/11/2022] [Accepted: 06/15/2022] [Indexed: 12/20/2022]
Abstract
We developed a trace level detection method for dopamine (DA) based on the metal-enhanced fluorescence (MEF) effect of gold nanoflowers (AuNFs). AuNFs prepared were excellent enhancement fluorescence substrates due to their unique morphology with rich edges and sharp quoins. DA was the target analyte and also as a bridge reagent that could regulate the distance between AuNFs and Tb3+. The characteristic fluorescence of Tb3+ was enhanced significantly through the synergistic effect between the luminescence sensitized by DA and the MEF caused by AuNFs. Under the optimum experimental conditions, the fluorescence intensity of Tb3+ at 545 nm demonstrated very significant sensing ability against DA concentration and showed a good linear relationship in the range of 0.80-300 nM and the limit of detection was 0.21 nM (S/N = 3). The proposed method was also validated in serum samples and the dopamine hydrochloride injection samples with satisfactory results.
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Affiliation(s)
- XueQin Li
- School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China
| | - Xingcen Liu
- School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China
| | - Yujie Liu
- School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China
| | - Ran Gao
- School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China
| | - Xia Wu
- School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China.
| | - Xibao Gao
- School of Public Health, Shandong University, Jinan, 250012, PR China
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20
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Huang CH, Liao WL, Lee DY, Chou IC, Wang MY, Hsieh CL. Effects of Yi-Gan-san on the psychiatric behavior of children and adolescents with Tourette's Syndrome: A randomized, double-blind, controlled preliminary study. JOURNAL OF ETHNOPHARMACOLOGY 2022; 290:115098. [PMID: 35182665 DOI: 10.1016/j.jep.2022.115098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/25/2022] [Accepted: 02/07/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gilles de la Tourette's Syndrome (TS) is a childhood-onset disease with clinical features of motor and phonic tics. Yi-Gan-san (YGS) is a traditional Chinese medicine formula that can reduce aggressiveness and agitation and inhibit dopamine function. This study investigated the effects of YGS on the psychiatric behavior of children and adolescents with TS. METHODS A double-blind, randomized, controlled preliminary study was conducted. A total of 38 patients with TS were assigned to the control group (CG, 19 patients) who received the oral administration of YGS placebo (90% starch and 10% YGS; 2.5 g thrice daily) or to a treatment group (TG, 19 patients) who received YGS for 4 weeks. The primary outcome measure was the change in Yale Global Tic Severity Scale (YGTSS) overall and subscale scores. RESULTS The intensity score for phonic tics before oral administration of YGS, and after 2 weeks, 3 weeks and 4 weeks was not significantly different between CG and TG groups (2.94 ± 1.14 vs 2.79 ± 1.08, p = .686; 2.29 ± 1.21 vs 1.95 ± 1.08, p = .370; 2.41 ± 1.18 vs 2.05 ± 1.51, p = .435; and 2.29 ± 1.26 vs 1.84 ± 1.42, p = .323, respectively), while the intensity score for phonic tics after 1-week oral administration of YGS in the TG was 1.89 ± 1.10 lower than 3.06 ± 1.39 in the CG (p = .008). CONCLUSION Oral administration of YGS for 1 week only reduced the intensity of phonic tics compared with oral administration of YGS placebo, suggesting that YGS can reduce their intensity for a short period, and the compliance of oral administration of YGS for 4 weeks can be accepted in children and adolescents with Tourette's Syndrome. However, because this study was preliminary, the selection of an appropriate placebo and dosage and long-term observations are crucial areas for future studies.
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Affiliation(s)
- Cheng-Hao Huang
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung City, 40402, Taiwan; Department of Chinese Medicine, China Medical University Hospital, Taichung City, 40447, Taiwan.
| | - Wen-Ling Liao
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung City, 40402, Taiwan; Center for Personalized Medicine, China Medical University Hospital, Taichung City, 40447, Taiwan.
| | - Der-Yen Lee
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung City, 40402, Taiwan.
| | - I-Ching Chou
- School of Chinese Medicine, China Medical University, Taichung City, 40402, Taiwan; Division of Pediatric Neurology, China Medical University Children's Hospital, Taichung City, 40447, Taiwan.
| | - Ming-Yu Wang
- Department of Psychiatry, China Medical University Hsinchu Hospital, Hsinchu County, 302, Taiwan.
| | - Ching-Liang Hsieh
- Department of Chinese Medicine, China Medical University Hospital, Taichung City, 40447, Taiwan; Chinese Medicine Research Center, China Medical University, Taichung City, 40402, Taiwan; Graduate Institute of Acupuncture Science, China Medical University, Taichung City, 40402, Taiwan.
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21
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Wang N, Wu X, Yang Q, Wang D, Wu Z, Wei Y, Cui J, Hong L, Xiong L, Qin D. Qinglong Zhidong Decoction Alleviated Tourette Syndrome in Mice via Modulating the Level of Neurotransmitters and the Composition of Gut Microbiota. Front Pharmacol 2022; 13:819872. [PMID: 35392572 PMCID: PMC8981146 DOI: 10.3389/fphar.2022.819872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 03/07/2022] [Indexed: 02/05/2023] Open
Abstract
Qinglong Zhidong Decoction (QLZDD), a traditional Chinese medicine (TCM) prescription, has been effectively used to alleviate Tourette syndrome (TS) in children. However, the therapeutic mechanism of QLZDD on TS has not been evaluated. The present study aims to elucidate the therapeutic effect and the possible therapeutic mechanism of QLZDD on TS in mouse model. A 3,3-iminodipropionitrile (IDPN, 350 mg/kg)-induced-TS mouse model was established. The mice were randomly divided into the control group, the model group, the haloperidol group (14 mg/kg), the low-, middle-, or high-QLZDD-dose groups (6.83 g/kg, 13.65 g/kg, 27.3 g/kg). QLZDD was administrated orally once a day for 4 weeks. The tic-like behavior was recorded weekly. Then, neurotransmitters and neurotransmitter receptors were analyzed by ELISA, immunohistochemistry (IHC), and quantitative reverse transcription PCR in striatum. Further, the alteration to intestinal flora was monitored by 16s rRNA sequencing, and the role of gut microbiota in the alleviation of TS by QLZDD was investigated. QLZDD ameliorated the tic-like behavior, and decreased the level of excitatory neurotransmitters such as Glu and DA and increased the level of the inhibitory neurotransmitter GABA significantly. Moreover, QLZDD significantly blocked the mRNA expression and the protein expression of D1R and D2R in the striatum, while activated the levels of DAT and GABAR. Interestingly, QLZDD mediated the composition of gut microbiota by increasing the abundance of Lactobacillus and Bacteroides but decreasing the abundance of Alloprevotella and Akkermansia. Taken together, QLZDD ameliorated the tic-like behavior in TS mouse, its mechanism of action may be associated with restoring the balance of gut microbiota and neurotransmitters. The study indicated a promising role of QLZDD in alleviating TS and a therapeutic strategy for fighting TS in clinical settings.
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Affiliation(s)
- Na Wang
- Yunnan University of Chinese Medicine, Kunming, China
- Huanghe S & T University, Zhengzhou, China
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinchen Wu
- Yunnan University of Chinese Medicine, Kunming, China
| | - Qi Yang
- Yunnan University of Chinese Medicine, Kunming, China
| | - Dingyue Wang
- Yunnan University of Chinese Medicine, Kunming, China
| | - Zhao Wu
- Yunnan University of Chinese Medicine, Kunming, China
| | - Yuanyuan Wei
- Yunnan University of Chinese Medicine, Kunming, China
| | - Jieqiong Cui
- Yunnan University of Chinese Medicine, Kunming, China
| | - Li Hong
- Yunnan University of Chinese Medicine, Kunming, China
| | - Lei Xiong
- Yunnan University of Chinese Medicine, Kunming, China
| | - Dongdong Qin
- Yunnan University of Chinese Medicine, Kunming, China
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22
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Chohan MO, Kopelman JM, Yueh H, Fazlali Z, Greene N, Harris AZ, Balsam PD, Leonardo ED, Kramer ER, Veenstra-VanderWeele J, Ahmari SE. Developmental impact of glutamate transporter overexpression on dopaminergic neuron activity and stereotypic behavior. Mol Psychiatry 2022; 27:1515-1526. [PMID: 35058566 PMCID: PMC9106836 DOI: 10.1038/s41380-021-01424-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 10/30/2021] [Accepted: 12/16/2021] [Indexed: 11/09/2022]
Abstract
Obsessive-compulsive disorder (OCD) is a disabling condition that often begins in childhood. Genetic studies in OCD have pointed to SLC1A1, which encodes the neuronal glutamate transporter EAAT3, with evidence suggesting that increased expression contributes to risk. In mice, midbrain Slc1a1 expression supports repetitive behavior in response to dopaminergic agonists, aligning with neuroimaging and pharmacologic challenge studies that have implicated the dopaminergic system in OCD. These findings suggest that Slc1a1 may contribute to compulsive behavior through altered dopaminergic transmission; however, this theory has not been mechanistically tested. To examine the developmental impact of Slc1a1 overexpression on compulsive-like behaviors, we, therefore, generated a novel mouse model to perform targeted, reversible overexpression of Slc1a1 in dopaminergic neurons. Mice with life-long overexpression of Slc1a1 showed a significant increase in amphetamine (AMPH)-induced stereotypy and hyperlocomotion. Single-unit recordings demonstrated that Slc1a1 overexpression was associated with increased firing of dopaminergic neurons. Furthermore, dLight1.1 fiber photometry showed that these behavioral abnormalities were associated with increased dorsal striatum dopamine release. In contrast, no impact of overexpression was observed on anxiety-like behaviors or SKF-38393-induced grooming. Importantly, overexpression solely in adulthood failed to recapitulate these behavioral phenotypes, suggesting that overexpression during development is necessary to generate AMPH-induced phenotypes. However, doxycycline-induced reversal of Slc1a1/EAAT3 overexpression in adulthood normalized both the increased dopaminergic firing and AMPH-induced responses. These data indicate that the pathologic effects of Slc1a1/EAAT3 overexpression on dopaminergic neurotransmission and AMPH-induced stereotyped behavior are developmentally mediated, and support normalization of EAAT3 activity as a potential treatment target for basal ganglia-mediated repetitive behaviors.
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Affiliation(s)
- Muhammad O Chohan
- Department of Psychiatry, Columbia University, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
| | - Jared M Kopelman
- Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA, USA
- Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Hannah Yueh
- Department of Psychiatry, Columbia University, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
| | - Zeinab Fazlali
- Department of Psychiatry, Columbia University, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
| | - Natasha Greene
- New York State Psychiatric Institute, New York, NY, USA
- Department of Psychology, Barnard College of Columbia University, New York, NY, USA
| | - Alexander Z Harris
- Department of Psychiatry, Columbia University, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
| | - Peter D Balsam
- Department of Psychiatry, Columbia University, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
- Department of Psychology, Barnard College of Columbia University, New York, NY, USA
| | - E David Leonardo
- Department of Psychiatry, Columbia University, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
| | - Edgar R Kramer
- Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth, Devon, UK
| | - Jeremy Veenstra-VanderWeele
- Department of Psychiatry, Columbia University, New York, NY, USA.
- New York State Psychiatric Institute, New York, NY, USA.
| | - Susanne E Ahmari
- Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA, USA.
- Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA, USA.
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23
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Enhanced habit formation in Tourette patients explained by shortcut modulation in a hierarchical cortico-basal ganglia model. Brain Struct Funct 2022; 227:1031-1050. [PMID: 35113242 PMCID: PMC8930794 DOI: 10.1007/s00429-021-02446-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 12/15/2021] [Indexed: 12/28/2022]
Abstract
Devaluation protocols reveal that Tourette patients show an increased propensity to habitual behaviors as they continue to respond to devalued outcomes in a cognitive stimulus-response-outcome association task. We use a neuro-computational model of hierarchically organized cortico-basal ganglia-thalamo-cortical loops to shed more light on habit formation and its alteration in Tourette patients. In our model, habitual behavior emerges from cortico-thalamic shortcut connections, where enhanced habit formation can be linked to faster plasticity in the shortcut or to a stronger feedback from the shortcut to the basal ganglia. We explore two major hypotheses of Tourette pathophysiology-local striatal disinhibition and increased dopaminergic modulation of striatal medium spiny neurons-as causes for altered shortcut activation. Both model changes altered shortcut functioning and resulted in higher rates of responses towards devalued outcomes, similar to what is observed in Tourette patients. We recommend future experimental neuroscientific studies to locate shortcuts between cortico-basal ganglia-thalamo-cortical loops in the human brain and study their potential role in health and disease.
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24
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D3 Receptors and PET Imaging. Curr Top Behav Neurosci 2022; 60:251-275. [PMID: 35711027 DOI: 10.1007/7854_2022_374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
This chapter encapsulates a short introduction to positron emission tomography (PET) imaging and the information gained by using this technology to detect changes of the dopamine 3 receptor (D3R) at the molecular level in vivo. We will discuss available D3R radiotracers, emphasizing [11C]PHNO. The focus, however, will be on PET findings in conditions including substance abuse, obesity, traumatic brain injury, schizophrenia, Parkinson's disease, and aging. Finally, there is a discussion about progress in producing next-generation selective D3R radiotracers.
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25
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MacLean JA, Ferman D, Chu JK, Liker MA, Sanger TD. Transient Complete Resolution of Tourette Syndrome Symptoms Following Personalized Depth Electrode Placement. Brain Sci 2021; 11:1559. [PMID: 34942861 PMCID: PMC8699357 DOI: 10.3390/brainsci11121559] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/23/2021] [Accepted: 11/23/2021] [Indexed: 11/16/2022] Open
Abstract
Treatment refractory Tourette syndrome has been shown to be improved with deep brain stimulation, but with multiple possible stimulation locations and variable and incomplete benefit. This study presents a single case of complete amelioration of motor and verbal tics in a patient with Tourette syndrome during placement of 12 stereo-EEG electrodes to identify optimal targets for permanent stimulating electrodes. Subsequently, substantial improvement in motor and verbal tic frequency occurred with placement and programming of permanent electrodes in bilateral globus pallidus internus and nucleus accumbens, but without the complete resolution seen during depth electrode placement. We suggest that simultaneous stimulation at multiple patient-specific targets could provide effective control of Tourette symptomatology, but further study will be needed.
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Affiliation(s)
- Jennifer A. MacLean
- Department of Neurology, Children’s Health of Orange County, Orange, CA 92868, USA;
| | - Diana Ferman
- Department of Neurology, University of Southern California, Los Angeles, CA 90033, USA;
| | - Jason K. Chu
- Department of Neurosurgery, University of Southern California, Los Angeles, CA 90033, USA; (J.K.C.); (M.A.L.)
- Department of Neurosurgery, Children’s Hospital of Los Angeles, Los Angeles, CA 90027, USA
| | - Mark A. Liker
- Department of Neurosurgery, University of Southern California, Los Angeles, CA 90033, USA; (J.K.C.); (M.A.L.)
- Department of Neurosurgery, Children’s Hospital of Los Angeles, Los Angeles, CA 90027, USA
| | - Terence D. Sanger
- Department of Neurology, Children’s Health of Orange County, Orange, CA 92868, USA;
- Department of Electrical Engineering and Computer Science, University of California, Irvine, CA 92697, USA
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26
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Randomized Controlled Trial of Probiotic PS128 in Children with Tourette Syndrome. Nutrients 2021; 13:nu13113698. [PMID: 34835954 PMCID: PMC8619307 DOI: 10.3390/nu13113698] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 11/23/2022] Open
Abstract
Tourette syndrome results from a complex interaction between social–environmental factors, multiple genetic abnormalities, and neurotransmitter disturbances. This study is a double-blinded, randomized controlled trial using probiotics Lactobacillus plantarum PS128 as an intervention to examine if probiotics improve symptoms of children with Tourette syndrome. This study enrolled children aged 5 to 18 years old who fulfilled DSM-V diagnostic criteria for Tourette syndrome. Patients were assessed before initiating the trial, at one month, and at two months after randomization. The primary outcome was evaluated by Yale Global Tic Severity Scale (YGTSS), and the secondary outcome studied the possible comorbidities in these children. The results revealed no significant difference in improvement in YGTSS between the control group and the PS128 group. As for secondary endpoints, an analysis of Conners’ Continuous Performance Test (CPT) showed improvement in commission and detectability in the PS128 group. In conclusion, although probiotics may not have tic-reducing effects in children with Tourette syndrome, it may have benefits on comorbidities such as attention deficit and hyperactivity disorder (ADHD). Further studies are needed to clarify the effects of probiotics on the comorbidities of Tourette syndrome children.
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27
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Schüller CB, Wagner BJ, Schüller T, Baldermann JC, Huys D, Kerner auch Koerner J, Niessen E, Münchau A, Brandt V, Peters J, Kuhn J. Temporal discounting in adolescents and adults with Tourette syndrome. PLoS One 2021; 16:e0253620. [PMID: 34143854 PMCID: PMC8213148 DOI: 10.1371/journal.pone.0253620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 06/08/2021] [Indexed: 12/18/2022] Open
Abstract
Tourette syndrome is a neurodevelopmental disorder associated with hyperactivity in dopaminergic networks. Dopaminergic hyperactivity in the basal ganglia has previously been linked to increased sensitivity to positive reinforcement and increases in choice impulsivity. In this study, we examine whether this extends to changes in temporal discounting, where impulsivity is operationalized as an increased preference for smaller-but-sooner over larger-but-later rewards. We assessed intertemporal choice in two studies including nineteen adolescents (age: mean[sd] = 14.21[±2.37], 13 male subjects) and twenty-five adult patients (age: mean[sd] = 29.88 [±9.03]; 19 male subjects) with Tourette syndrome and healthy age- and education matched controls. Computational modeling using exponential and hyperbolic discounting models via hierarchical Bayesian parameter estimation revealed reduced temporal discounting in adolescent patients, and no evidence for differences in adult patients. Results are discussed with respect to neural models of temporal discounting, dopaminergic alterations in Tourette syndrome and the developmental trajectory of temporal discounting. Specifically, adolescents might show attenuated discounting due to improved inhibitory functions that also affect choice impulsivity and/or the developmental trajectory of executive control functions. Future studies would benefit from a longitudinal approach to further elucidate the developmental trajectory of these effects.
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Affiliation(s)
- Canan Beate Schüller
- Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | | | - Thomas Schüller
- Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Juan Carlos Baldermann
- Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Daniel Huys
- Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Julia Kerner auch Koerner
- Educational Psychology, Helmut-Schmidt-University, Hamburg, Germany
- Center for Individual Development and Adaptive Education of Children at Risk, Frankfurt am Main, Germany
| | - Eva Niessen
- Department of Individual Differences and Psychological Assessment, University of Cologne, Cologne, Germany
| | - Alexander Münchau
- Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany
| | - Valerie Brandt
- Center for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, Hampshire, United Kingdom
| | - Jan Peters
- Department of Biology Psychology, University of Cologne, Cologne, Germany
| | - Jens Kuhn
- Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of Psychiatry, Psychotherapy and Psychosomatic, Johanniter Hospital Oberhausen, EVKLN, Oberhausen, Germany
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28
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Caravaggio F, Porco N, Kim J, Torres-Carmona E, Brown E, Iwata Y, Nakajima S, Gerretsen P, Remington G, Graff-Guerrero A. Measuring amphetamine-induced dopamine release in humans: A comparative meta-analysis of [ 11 C]-raclopride and [ 11 C]-(+)-PHNO studies. Synapse 2021; 75:e22195. [PMID: 33471400 DOI: 10.1002/syn.22195] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/02/2021] [Accepted: 01/13/2021] [Indexed: 02/06/2023]
Abstract
The radiotracers [11 C]-raclopride and [11 C]-(+)-PHNO are commonly used to measure differences in amphetamine-induced dopamine release between healthy persons and persons with neuropsychiatric diseases. As an agonist radiotracer, [11 C]-(+)-PHNO should theoretically be roughly 2.7 times more sensitive to displacement by endogenous dopamine than [11 C]raclopride. To date, only one study has been published comparing the sensitivity of these two radiotracers to amphetamine-induced dopamine release in healthy persons. Unfortunately, conflicting findings in the literature suggests that the dose of amphetamine they employed (0.3 mg/kg, p.o.) may not reliably reduce [11 C]-raclopride binding in the caudate. Thus, it is unclear whether the preponderance of evidence supports the theory that [11 C]-(+)-PHNO is more sensitive to displacement by amphetamine in humans than [11 C]-raclopride. In order to clarify these issues, we conducted a comparative meta-analysis summarizing the effects of amphetamine on [11 C]-raclopride and [11 C]-(+)-PHNO binding in healthy humans. Our analysis indicates that amphetamine given at 0.3 mg/kg, p.o. does not reliably reduce [11 C]-raclopride binding in the caudate. Second, the greater sensitivity of [11 C]-(+)-PHNO is evidenced at 0.5 mg/kg, p.o., but not at lower doses of amphetamine. Third, our analysis suggests that [11 C]-(+)-PHNO may be roughly 1.5 to 2.5 times more sensitive to displacement by amphetamine than [11 C]-raclopride in healthy persons. We recommend that future displacement studies with these radiotracers employ 0.5 mg/kg, p.o. of amphetamine with a dose, post-scan interval of at least 3 hr. Using this dose of amphetamine, [11 C]-raclopride studies should employ at least n = 34 participants per group, while [11 C]-(+)-PHNO studies should employ at least n = 6 participants per group, in order to be sufficiently powered (80%) to detect changes in radiotracer binding within the caudate.
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Affiliation(s)
- Fernando Caravaggio
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Natasha Porco
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Julia Kim
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Edgardo Torres-Carmona
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Eric Brown
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Yusuke Iwata
- Department of Neuropsychiatry, University of Yamanashi, Chuo, Japan
| | | | - Philip Gerretsen
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Gary Remington
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Ariel Graff-Guerrero
- Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.,Department of Psychiatry, University of Toronto, Toronto, ON, Canada
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29
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Hsu CJ, Wong LC, Lee WT. Immunological Dysfunction in Tourette Syndrome and Related Disorders. Int J Mol Sci 2021; 22:ijms22020853. [PMID: 33467014 PMCID: PMC7839977 DOI: 10.3390/ijms22020853] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 12/28/2022] Open
Abstract
Chronic tic disorder and Tourette syndrome are common childhood-onset neurological diseases. However, the pathophysiology underlying these disorders is unclear, and most studies have focused on the disinhibition of the corticostriatal–thalamocortical circuit. An autoimmune dysfunction has been proposed in the pathogenetic mechanism of Tourette syndrome and related neuropsychiatric disorders such as obsessive–compulsive disorder, autism, and attention-deficit/hyperactivity disorder. This is based on evidence from animal model studies and clinical findings. Herein, we review and give an update on the clinical characteristics, clinical evidence, and genetic studies in vitro as well as animal studies regarding immune dysfunction in Tourette syndrome.
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Affiliation(s)
- Chia-Jui Hsu
- Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 300, Taiwan;
| | - Lee-Chin Wong
- Department of Pediatrics, Cathay General Hospital, Taipei 106, Taiwan;
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan
| | - Wang-Tso Lee
- Department of Pediatric Neurology, National Taiwan University Children’s Hospital, Taipei 100, Taiwan
- Department of Pediatrics, National Taiwan University College of Medicine, Taipei 100, Taiwan
- Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei 100, Taiwan
- Correspondence: ; Tel.: +886-2-2312-3456 (ext. 71545); Fax: +886-2-2314-7450
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30
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Petibon Y, Alpert NM, Ouyang J, Pizzagalli DA, Cusin C, Fava M, El Fakhri G, Normandin MD. PET imaging of neurotransmission using direct parametric reconstruction. Neuroimage 2020; 221:117154. [PMID: 32679252 PMCID: PMC7800040 DOI: 10.1016/j.neuroimage.2020.117154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 11/18/2022] Open
Abstract
Receptor ligand-based dynamic Positron Emission Tomography (PET) permits the measurement of neurotransmitter release in the human brain. For single-scan paradigms, the conventional method of estimating changes in neurotransmitter levels relies on fitting a pharmacokinetic model to activity concentration histories extracted after PET image reconstruction. However, due to the statistical fluctuations of activity concentration data at the voxel scale, parametric images computed using this approach often exhibit low signal-to-noise ratio, impeding characterization of neurotransmitter release. Numerous studies have shown that direct parametric reconstruction (DPR) approaches, which combine image reconstruction and kinetic analysis in a unified framework, can improve the signal-to-noise ratio of parametric mapping. However, there is little experience with DPR in imaging of neurotransmission and the performance of the approach in this application has not been evaluated before in humans. In this report, we present and evaluate a DPR methodology that computes 3-D distributions of ligand transport, binding potential (BPND) and neurotransmitter release magnitude (γ) from a dynamic sequence of PET sinograms. The technique employs the linear simplified reference region model (LSRRM) of Alpert et al. (2003), which represents an extension of the simplified reference region model that incorporates time-varying binding parameters due to radioligand displacement by release of neurotransmitter. Estimation of parametric images is performed by gradient-based optimization of a Poisson log-likelihood function incorporating LSRRM kinetics and accounting for the effects of head movement, attenuation, detector sensitivity, random and scattered coincidences. A 11C-raclopride simulation study showed that the proposed approach substantially reduces the bias and variance of voxel-wise γ estimates as compared to standard methods. Moreover, simulations showed that detection of release could be made more reliable and/or conducted using a smaller sample size using the proposed DPR estimator. Likewise, images of BPND computed using DPR had substantially improved bias and variance properties. Application of the method in human subjects was demonstrated using 11C-raclopride dynamic scans and a reward task, confirming the improved quality of the estimated parametric images using the proposed approach.
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Affiliation(s)
- Yoann Petibon
- Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| | - Nathaniel M Alpert
- Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jinsong Ouyang
- Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Diego A Pizzagalli
- Center for Depression, Anxiety & Stress Research, McLean Hospital and Harvard Medical School, Belmont, MA, USA
| | - Cristina Cusin
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Maurizio Fava
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Georges El Fakhri
- Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marc D Normandin
- Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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31
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Hsu CJ, Wong LC, Wang HP, Lee WT. The multimodality neuroimage findings in individuals with Tourette syndrome. Pediatr Neonatol 2020; 61:467-474. [PMID: 32284198 DOI: 10.1016/j.pedneo.2020.03.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/28/2020] [Accepted: 03/06/2020] [Indexed: 01/03/2023] Open
Abstract
Chronic tic disorder and Gilles de la Tourette syndrome are very common childhood-onset diseases. However, the pathophysiology underlying these disorders is not yet clear and most studies focus on the disinhibition of the cortico-striatal-thalamo-cortical circuit. Although dysfunction of this circuit is possible, routine clinical neuroimaging studies such as T1-weighted or T2-weighted MRI usually reveal normal results. Therefore, special neuroimaging techniques may be needed to investigate the possible microstructural or functional changes in the brain. Previous structural studies, such as those using diffusion tensor imaging, and volumetric MRI studies, revealed the main abnormalities to be located in the cortico-striatal-thalamo-cortical circuit and to be related to brain regions such as basal ganglion, thalamus, frontal cortex, and motor cortex. Some other potential regions, such as the amygdala, hippocampus or cerebellum, are also occasionally reported. Perfusion studies, such as those using positron emission tomography or functional MRI, also suggest hemodynamic changes over those brain regions related to the cortico-striatal-thalamo-cortical circuit. However, the results can be different in adult and pediatric groups, and neuroimaging findings are also inconsistent between different studies, which may reflect the high diversity of this disease or differences in enrolled patient groups with different comorbidities. Therefore, in this review article, we will focus on the neuroimaging findings relating to Tourette syndrome in different age groups using different imaging techniques.
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Affiliation(s)
- Chia-Jui Hsu
- Department of Pediatrics, Taipei City Hospital, Yangming Branch, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan; Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Lee Chin Wong
- Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsin-Pei Wang
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Wang-Tso Lee
- Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Pediatric Neurology, National Taiwan University Children's Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan.
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Maqsood A, Akram S, Akram F. Chlorpromazine-Induced Relapse of Tourette Syndrome in a Patient With Intellectual Disability, Attention Deficit Hyperactivity Disorder, and Schizophrenia. Cureus 2020; 12:e10732. [PMID: 33145137 PMCID: PMC7599051 DOI: 10.7759/cureus.10732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by recurrent multiple motor and vocal tics that last for at least one year and follow a waxing and waning course. A fundamental step in the pathophysiology of TS is the hyperactivity of dopaminergic system leading to increased dopamine release in the cortical-basal ganglia-thalamo-cortical (CBGTC) circuits, thereby providing the rationale for treatment with dopamine receptor, in particular D2, antagonists. Although antipsychotics have shown considerable efficacy against tics in most patients, there have been cases of paradoxical onset of tics in individuals without history, and relapse or exacerbation of tics in individuals with a history of tic disorders upon initiation of antipsychotics. Here we report a case of an individual with intellectual disability, attention deficit hyperactivity disorder (ADHD), and schizophrenia, who experienced a relapse of TS symptoms after initiation of chlorpromazine therapy.
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Affiliation(s)
- Anum Maqsood
- Internal Medicine, Howard University Hospital, Washington, DC, USA
| | - Salman Akram
- Internal Medicine, Rawalpindi Medical University, Gujranwala, PAK
| | - Faisal Akram
- Psychiatry, Department of Behavioral Health, Saint Elizabeths Hospital, Washington, DC, USA
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33
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Tourette syndrome or PANDAS-a case report. Wien Med Wochenschr 2020; 171:289-292. [PMID: 32955635 DOI: 10.1007/s10354-020-00779-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 08/12/2020] [Indexed: 10/23/2022]
Abstract
Tourette syndrome (TS), a relatively common disorder, has been gaining more attention during the past two decades because of an increased number of reports. Nevertheless, it is still not completely understood. Furthermore, a clinical entity called "pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections" (PANDAS) has been introduced, which describes a tic disorder, accompanied by psychiatric disorders such as obsessive compulsive disorder (OCD), after a streptococcal infection in childhood. We present a case report of a 19-year-old adolescent Ukrainian female, with a history of anxiety disorder and OCD, who, despite TS remission during childhood, presented with new-onset motor and phonic tics after 1 month of severe tonsillitis. Blood and cerebrospinal cultures showed Streptococcus pyogenes, with magnetic resonance imaging revealing hypo-intense changes in the caudate nucleus on both sides. Treatment with clonazepam and fluoxetine, along with behavioral therapy, have improved the severity of her condition. This report presents a case of TS reemergence against the background of immunological reaction or PANDAS with a late adolescent onset.
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Abstract
Background:Tics, defined as quick, rapid, sudden, recurrent, non-rhythmic motor movements or vocalizations are required components of Tourette Syndrome (TS) - a complex disorder characterized by the presence of fluctuating, chronic motor and vocal tics, and the presence of co-existing neuropsychological problems. Despite many advances, the underlying pathophysiology of tics/TS remains unknown.Objective:To address a variety of controversies surrounding the pathophysiology of TS. More specifically: 1) the configuration of circuits likely involved; 2) the role of inhibitory influences on motor control; 3) the classification of tics as either goal-directed or habitual behaviors; 4) the potential anatomical site of origin, e.g. cortex, striatum, thalamus, cerebellum, or other(s); and 5) the role of specific neurotransmitters (dopamine, glutamate, GABA, and others) as possible mechanisms (Abstract figure).Methods:Existing evidence from current clinical, basic science, and animal model studies are reviewed to provide: 1) an expanded understanding of individual components and the complex integration of the Cortico-Basal Ganglia-Thalamo-Cortical (CBGTC) circuit - the pathway involved with motor control; and 2) scientific data directly addressing each of the aforementioned controversies regarding pathways, inhibition, classification, anatomy, and neurotransmitters.Conclusion:Until a definitive pathophysiological mechanism is identified, one functional approach is to consider that a disruption anywhere within CBGTC circuitry, or a brain region inputting to the motor circuit, can lead to an aberrant message arriving at the primary motor cortex and enabling a tic. Pharmacologic modulation may be therapeutically beneficial, even though it might not be directed toward the primary abnormality.
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Affiliation(s)
- Harvey S. Singer
- Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, United States
| | - Farhan Augustine
- Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, United States
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Liu S, Tian M, He F, Li J, Xie H, Liu W, Zhang Y, Zhang R, Yi M, Che F, Ma X, Zheng Y, Deng H, Wang G, Chen L, Sun X, Xu Y, Wang J, Zang Y, Han M, Wang X, Guan H, Ge Y, Wu C, Wang H, Liang H, Li H, Ran N, Yang Z, Huang H, Wei Y, Zheng X, Sun X, Feng X, Zheng L, Zhu T, Luo W, Chen Q, Yan Y, Huang Z, Jing Z, Guo Y, Zhang X, Schaaf CP, Xing J, Wang C, Yu F, Guan JS. Mutations in ASH1L confer susceptibility to Tourette syndrome. Mol Psychiatry 2020; 25:476-490. [PMID: 31673123 DOI: 10.1038/s41380-019-0560-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 08/12/2019] [Accepted: 08/19/2019] [Indexed: 12/31/2022]
Abstract
Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.
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Affiliation(s)
- Shiguo Liu
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.,The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Miaomiao Tian
- School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Fan He
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Jiani Li
- Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Hong Xie
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.,Institute of Brain-Intelligence Technology, Zhangjiang Laboratory & Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China
| | - Wenmiao Liu
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.,The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yeting Zhang
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Ru Zhang
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.,The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mingji Yi
- Developmental Behavioral Pediatric Department, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Fengyuan Che
- Department of Neurology, Linyi People's Hospital, Linyi, China
| | - Xu Ma
- National Research Institute for Family Planning, Beijing, China
| | - Yi Zheng
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Hao Deng
- Center for Experimental Medicine & Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Guiju Wang
- Child Healthcare Department, Rizhao people's Hospital, Rizhao, China
| | - Lang Chen
- Department of Pediatrics, Fujian Provincial Hospital, Provincial Clinical Medical College Affiliated to Fujian Medical University, Fuzhou, China
| | - Xue Sun
- Department of Medical Record, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yinglei Xu
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.,The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jingli Wang
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.,The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yucui Zang
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.,The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mengmeng Han
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.,The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiuhai Wang
- Department of Biology, Qingdao University, Qingdao, China
| | - Hongzai Guan
- Department of Clinical Laboratory Diagnosis, Qingdao University, Qingdao, China
| | - Yinlin Ge
- Department of Biochemistry and Molecular Biology, Qingdao University, Qingdao, China
| | - Chunmei Wu
- Department of Clinical Laboratory Diagnosis, Qingdao University, Qingdao, China
| | - Haiyan Wang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hui Liang
- Department of Public Health, Qingdao University, Qingdao, China
| | - Hui Li
- Physical Examination Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ni Ran
- Developmental Behavioral Pediatric Department, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhaochuan Yang
- Developmental Behavioral Pediatric Department, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Huanhuan Huang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Yanzhao Wei
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Xueping Zheng
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiangrong Sun
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.,The Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xueying Feng
- Developmental Behavioral Pediatric Department, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lanlan Zheng
- Department of Psychiatry, The Third Hospital of Chaoyang District of Beijing, Beijing, China
| | - Tao Zhu
- School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China
| | - Wenhan Luo
- School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Qinan Chen
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Yuze Yan
- School of Life Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Zuzhou Huang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhongcui Jing
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yixia Guo
- Developmental Behavioral Pediatric Department, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xuzhan Zhang
- Physical Examination Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Christian P Schaaf
- Department of Molecular and Human Genetics, Baylor College of Medicine, Department of Genetics; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Jinchuan Xing
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Chuanyue Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Institute for Brain Disorders Center of Schizophrenia, Beijing Anding Hospital, Capital Medical University, Beijing, China.
| | - Fuli Yu
- Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
| | - Ji-Song Guan
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. .,CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
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Abstract
PURPOSE OF REVIEW The purpose of this article is to present current information on the phenomenology, epidemiology, comorbidities, and pathophysiology of tic disorders and discuss therapy options. It is hoped that a greater understanding of each of these components will provide clinicians with the necessary information to deliver thoughtful and optimal care to affected individuals. RECENT FINDINGS Recent advances include the finding that Tourette syndrome is likely due to a combination of several different genes, both low-effect and larger-effect variants, plus environmental factors. Pathophysiologically, increasing evidence supports involvement of the cortical-basal ganglia-thalamocortical circuit; however, the primary location and neurotransmitter remain controversial. Behavioral therapy is first-line treatment, and pharmacotherapy is based on tic severity. Several newer therapeutic agents are under investigation (eg, valbenazine, deutetrabenazine, cannabinoids), and deep brain stimulation is a promising therapy. SUMMARY Tics, defined as sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations, are essential components of Tourette syndrome. Although some tics may be mild, others can cause significant psychosocial, physical, and functional difficulties that affect daily activities. In addition to tics, most affected individuals have coexisting neuropsychological difficulties (attention deficit hyperactivity disorder, obsessive-compulsive disorder, anxiety, mood disorder, disruptive behaviors, schizotypal traits, suicidal behavior, personality disorder, antisocial activities, and sleep disorders) that can further impact social and academic activities or employment.
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Elle T, Alam M, Voigt C, Krauss JK, John N, Schwabe K. Deep brain stimulation of the thalamic centromedian-parafascicular nucleus improves behavioural and neuronal traits in a rat model of Tourette. Behav Brain Res 2020; 378:112251. [DOI: 10.1016/j.bbr.2019.112251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/17/2019] [Accepted: 09/17/2019] [Indexed: 01/23/2023]
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Kreilaus F, Chesworth R, Eapen V, Clarke R, Karl T. First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder. Behav Brain Res 2019; 374:112057. [PMID: 31233820 DOI: 10.1016/j.bbr.2019.112057] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/20/2019] [Accepted: 06/20/2019] [Indexed: 11/26/2022]
Abstract
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder, which shares some clinical features with Autism spectrum disorder (ASD). The genetic factors relevant to the development of both disorders are yet to be fully understood, however, some genetic association studies have identified inner mitochondrial membrane peptidase subunit 2 (IMMP2L) as a potential risk gene for both GTS and ASD. The impact of Immp2l deficiency on behavioural domains is currently unknown. A new genetic mouse model for Immp2l was developed. Adult heterozygous (HET) and homozygous (HOMO) Immp2l knockdown (Immp2l KD) mice of both sexes were compared to wild type-like (WT) littermates in the open field (OF), social interaction, novel object recognition, marble burying, and prepulse inhibition (PPI). The effect of acute dexamphetamine (2 mg/kg) on OF behaviour was also determined. OF locomotion was significantly higher in HET compared to HOMO male littermates. Male and female HOMO mice were much more sensitive to the locomotor-stimulating effects of dexamphetamine (DEX), whereas only HOMO males exhibited significant increased DEX-induced OF exploration compared to control groups. HOMO females failed to habituate to an acoustic startle stimulus. Furthermore, compared to HOMO females, HET females showed reduced social interaction, and a similar trend was seen in HET males. The Immp2l KD mouse model possesses moderate face validity for preclinical research into GTS and ASD, in particular as dysfunctional dopaminergic neurotransmission appears to be one mechanism leading to disease presentation. The sex-dependent differences observed in most findings reinforce the strong influence of sex in the pathophysiology of GTS and ASD.
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Affiliation(s)
- Fabian Kreilaus
- School of Medicine, Western Sydney University, NSW 2560, Australia
| | - Rose Chesworth
- School of Medicine, Western Sydney University, NSW 2560, Australia
| | - Valsamma Eapen
- School of Psychiatry, Faculty of Medicine and Ingham Institute, University of New South Wales, NSW, 2052, Australia
| | - Raymond Clarke
- School of Psychiatry, Faculty of Medicine and Ingham Institute, University of New South Wales, NSW, 2052, Australia.
| | - Tim Karl
- School of Medicine, Western Sydney University, NSW 2560, Australia; Neuroscience Research Australia (NeuRA), NSW, 2031, Australia; School of Medical Sciences, University of New South Wales, NSW, 2052, Australia.
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Wang Y, Li A. Regulatory effects of Ningdong granule on dopaminergic and serotonergic neurotransmission in a rat model of Tourette syndrome assessed by PET. Mol Med Rep 2019; 20:191-197. [PMID: 31115527 DOI: 10.3892/mmr.2019.10243] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 03/20/2019] [Indexed: 11/06/2022] Open
Abstract
Dysfunctions in dopamine (DA) and serotonin (5‑HT) metabolism have been widely implicated in Tourette syndrome (TS); however, the exact nature of these dysfunctions remains unclear. The objective of the present study was to investigate the variation in DA and 5‑HT metabolism in a rat model of TS, and to evaluate the therapeutic effect of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation used specifically for the treatment of TS. Rats were treated with 3,3'‑iminodipropionitrile for 7 days to induce the model of TS, and were then intragastrically administered NDG each day. After 8 weeks of treatment, micro‑positron emission tomography was used to measure the binding of DA D2 receptors (D2Rs), DA transporters (DATs), 5‑HT2A receptors (5‑HT2ARs) and 5‑HT transporters (SERTs) in brain regions of interest. The results indicated that NDG could significantly reduce the typical characteristics of TS in the rat model. Decreased D2R binding and increased DAT binding were detected in the striatum compared with the binding activities in untreated rats. The density of 5‑HT2AR was also significantly increased in the striatum following NDG treatment; however, SERT levels were decreased in certain brain regions, including the striatum, cortex, nucleus accumbens and amygdala. Taken together, the current results demonstrated that NDG may be effective in treating patients with TS.
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Affiliation(s)
- Yuan Wang
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Anyuan Li
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Abstract
Novel pharmacological treatments are needed for Tourette syndrome. Our goal was to examine the current evidence base and biological rationale for the use of cannabis-derived medications or medications that act on the cannabinoid system in Tourette syndrome. We conducted a comprehensive literature search of PubMed for randomized controlled trials or clinical trials of cannabis-derived medications in Tourette syndrome. Data regarding the population, intervention, safety profile, and outcomes for each trial were extracted and reported and the evidence supporting use of individual cannabis-derived medications was critiqued. There is a strong biological rationale regarding how cannabis-derived medications could affect tic severity. Anecdotal case reports and series have noted that many patients report that their tics improve after using cannabis. However, only two small randomized, placebo-controlled trials of Δ9-tetrahydrocannabinol have been published; these suggested possible benefits of cannabis-derived agents for the treatment of tics. Trials examining other agents active on the cannabinoid system for tic disorders are currently ongoing. Cannabinoid-based treatments are a promising avenue of new research for medications that may help the Tourette syndrome population. However, given the limited research available, the overall efficacy and safety of cannabinoid-based treatments is largely unknown. Further trials are needed to examine dosing, active ingredients, and optimal mode of administration of cannabis-derived compounds, assuming initial trials suggest efficacy. Clinical use for refractory patients should at the very least be restricted to adult populations, given the uncertain efficacy and risk of developmental adverse effects that cannabinoids may have in children. Even in adult populations, cannabis-derived medications are associated with significant issues such as the effects they have on driving safety and the fact that they cause positive urine drug screens that can affect employment.
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Affiliation(s)
- Bekir B Artukoglu
- Yale University, Yale Child Study Center, PO Box 207900, New Haven, CT, 06520, USA.
| | - Michael H Bloch
- Department of Psychiatry, Yale University, Yale Child Study Center, New Haven, CT, USA
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Khalil R, Godde B, Karim AA. The Link Between Creativity, Cognition, and Creative Drives and Underlying Neural Mechanisms. Front Neural Circuits 2019; 13:18. [PMID: 30967763 PMCID: PMC6440443 DOI: 10.3389/fncir.2019.00018] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 03/04/2019] [Indexed: 11/13/2022] Open
Abstract
Having a creative mind is one of the gateways for achieving fabulous success and remarkable progress in professional, personal and social life. Therefore, a better understanding of the neural correlates and the underlying neural mechanisms related to creative ideation is crucial and valuable. However, the current literature on neural systems and circuits underlying creative cognition, and on how creative drives such as motivation, mood states, and reward could shape our creative mind through the associated neuromodulatory systems [i.e., the dopaminergic (DA), the noradrenergic (NE) and the serotonergic (5-HT) system] seems to be insufficient to explain the creative ideation and production process. One reason might be that the mentioned systems and processes are usually investigated in isolation and independent of each other. Through this review, we aim at advancing the current state of knowledge by providing an integrative view on the interactions between neural systems underlying the creative cognition and the creative drive and associated neuromodulatory systems (see Figure 1).
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Affiliation(s)
- Radwa Khalil
- Department of Psychology and Methods, Jacobs University Bremen, Bremen, Germany
| | - Ben Godde
- Department of Psychology and Methods, Jacobs University Bremen, Bremen, Germany
| | - Ahmed A Karim
- Department of Psychology and Methods, Jacobs University Bremen, Bremen, Germany.,Department of Psychiatry and Psychotherapy, University Clinic Tübingen, Tübingen, Germany.,Department of Health Psychology and Neurorehabilitation, SRH Mobile University, Riedlingen, Germany
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42
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Augustine F, Singer HS. Merging the Pathophysiology and Pharmacotherapy of Tics. Tremor Other Hyperkinet Mov (N Y) 2019; 8:595. [PMID: 30643668 PMCID: PMC6329776 DOI: 10.7916/d8h14jtx] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 09/28/2018] [Indexed: 12/14/2022] Open
Abstract
Background Anatomically, cortical-basal ganglia-thalamo-cortical (CBGTC) circuits have an essential role in the expression of tics. At the biochemical level, the proper conveyance of messages through these circuits requires several functionally integrated neurotransmitter systems. In this manuscript, evidence supporting proposed pathophysiological abnormalities, both anatomical and chemical is reviewed. In addition, the results of standard and emerging tic-suppressing therapies affecting nine separate neurotransmitter systems are discussed. The goal of this review is to integrate our current understanding of the pathophysiology of Tourette syndrome (TS) with present and proposed pharmacotherapies for tic suppression. Methods For this manuscript, literature searches were conducted for both current basic science and clinical information in PubMed, Google-Scholar, and other scholarly journals to September 2018. Results The precise primary site of abnormality for tics remains undetermined. Although many pathophysiologic hypotheses favor a specific abnormality of the cortex, striatum, or globus pallidus, others recognize essential influences from regions such as the thalamus, cerebellum, brainstem, and ventral striatum. Some prefer an alteration within direct and indirect pathways, whereas others believe this fails to recognize the multiple interactions within and between CBGTC circuits. Although research and clinical evidence supports involvement of the dopaminergic system, additional data emphasizes the potential roles for several other neurotransmitter systems. Discussion A greater understanding of the primary neurochemical defect in TS would be extremely valuable for the development of new tic-suppressing therapies. Nevertheless, recognizing the varied and complex interactions that exist in a multi-neurotransmitter system, successful therapy may not require direct targeting of the primary abnormality.
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Affiliation(s)
- Farhan Augustine
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Harvey S. Singer
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Maia TV, Conceição VA. Dopaminergic Disturbances in Tourette Syndrome: An Integrative Account. Biol Psychiatry 2018; 84:332-344. [PMID: 29656800 DOI: 10.1016/j.biopsych.2018.02.1172] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 02/04/2018] [Accepted: 02/25/2018] [Indexed: 12/28/2022]
Abstract
Tourette syndrome (TS) is thought to involve dopaminergic disturbances, but the nature of those disturbances remains controversial. Existing hypotheses suggest that TS involves 1) supersensitive dopamine receptors, 2) overactive dopamine transporters that cause low tonic but high phasic dopamine, 3) presynaptic dysfunction in dopamine neurons, or 4) dopaminergic hyperinnervation. We review evidence that contradicts the first two hypotheses; we also note that the last two hypotheses have traditionally been considered too narrowly, explaining only small subsets of findings. We review all studies that have used positron emission tomography and single-photon emission computerized tomography to investigate the dopaminergic system in TS. The seemingly diverse findings from those studies have typically been interpreted as pointing to distinct mechanisms, as evidenced by the various hypotheses concerning the nature of dopaminergic disturbances in TS. We show, however, that the hyperinnervation hypothesis provides a simple, parsimonious explanation for all such seemingly diverse findings. Dopaminergic hyperinnervation likely causes increased tonic and phasic dopamine. We have previously shown, using a computational model of the role of dopamine in basal ganglia, that increased tonic dopamine and increased phasic dopamine likely increase the propensities to express and learn tics, respectively. There is therefore a plausible mechanistic link between dopaminergic hyperinnervation and TS via increased tonic and phasic dopamine. To further bolster this argument, we review evidence showing that all medications that are effective for TS reduce signaling by tonic dopamine, phasic dopamine, or both.
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Affiliation(s)
- Tiago V Maia
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
| | - Vasco A Conceição
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
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Eddy CM, Cook JL. Emotions in action: The relationship between motor function and social cognition across multiple clinical populations. Prog Neuropsychopharmacol Biol Psychiatry 2018; 86:229-244. [PMID: 29857027 DOI: 10.1016/j.pnpbp.2018.05.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 05/17/2018] [Accepted: 05/25/2018] [Indexed: 01/05/2023]
Affiliation(s)
- Clare M Eddy
- National Centre for Mental Health and College of Medical and Dental Sciences, BSMHFT, University of Birmingham, Birmingham, UK
| | - Jennifer L Cook
- School of Psychology, University of Birmingham, Birmingham, B15 2TT, UK.
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Striatal dopaminergic alterations in Tourette's syndrome: a meta-analysis based on 16 PET and SPECT neuroimaging studies. Transl Psychiatry 2018; 8:143. [PMID: 30072700 PMCID: PMC6072751 DOI: 10.1038/s41398-018-0202-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 05/17/2018] [Accepted: 06/05/2018] [Indexed: 01/07/2023] Open
Abstract
Despite intense research, the underlying mechanisms and the etiology of Tourette's syndrome (TS) remain unknown. Data from molecular imaging studies targeting the dopamine system in Tourette patients are inconclusive. For a better understanding of the striatal dopamine function in adult dopamine-antagonist-free patients we performed a systematic review in August 2017 identifying 49 PET and SPECT studies on the topic of TS. A total of 8 studies appraised the dopamine transporter (DAT) with 111 Tourette patients and 93 healthy controls, and could be included in a meta-analytic approach. We found a significantly increased striatal DAT binding in Tourette patients (Hedges' g = 0.49; 95% CI: (0.01-0.98)), although this effect did not remain significant after correcting for age differences between cohorts. A second meta-analysis was performed for the striatal dopamine receptor including 8 studies with a total of 72 Tourette patients and 71 controls. This analysis revealed a nonsignificant trend toward lower dopamine 2/3 receptor binding in striatum of Tourette patients. Other analyses regarding study population characteristics in both the DAT and receptor meta-analysis did not show any meaningful results. Our results indicate that dopaminergic alterations in TS are likely and thereby this data would be in line with the current pathophysiological hypotheses of a dysfunction in the dopamine system, e.g., the hypothesis of tonic-phasic dysfunction. However, these analyses suffer from low effect sizes probably due to the heterogeneity of TS and highlight the need for further large-scaled neuroimaging studies.
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Grados M, Huselid R, Duque-Serrano L. Transcranial Magnetic Stimulation in Tourette Syndrome: A Historical Perspective, Its Current Use and the Influence of Comorbidities in Treatment Response. Brain Sci 2018; 8:brainsci8070129. [PMID: 29986411 PMCID: PMC6071080 DOI: 10.3390/brainsci8070129] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 06/25/2018] [Accepted: 06/28/2018] [Indexed: 11/25/2022] Open
Abstract
Background. Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder consisting of impairing motor and vocal tics which often persists adolescent and adult years. In this older refractory group, standard treatments such as pharmacotherapy and psychotherapeutic interventions may only have limited effects. Based on electrical cortical dysregulation in individuals with TS, a novel approach has employed brain stimulation strategies to modulate the putative aberrant neural electrical activity in pathways that may underlie tics, such as insula-supplementary motor area (SMA) connectivity. Methods. This review will examine all published clinical trials employing transcranial magnetic stimulation (TMS) to ameliorate tics, and discuss a framework for the pathophysiology of TS in relation to electrical brain activity. A framework for future research in tic disorders using TMS and imaging targeting neuroplasticity will be discussed. Results. Therapeutic electrical brain activity modulation with TMS has been carried out in stroke neuro-rehabilitation and neuropsychiatry, including trials in TS. Eleven trials document the use of TMS in TS targeting several brain areas, a positive effect is seen for those trials targeting the SMA. In particular, it appears that younger individuals with concurrent attention-deficit hyperactivity disorder (ADHD) benefit the most. Conclusions. TMS can be used as an effective tool to explore the psychophysiology of TS and potentially provide a therapeutic option. Ultimately, translational research using TMS in TS needs to explore connectivity differences pre- and post-treatment in individuals with TS that are linked to improvement in tic symptoms, with an emphasis on approaches using functional neuroimaging as well as other probes of neuroplasticity.
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Affiliation(s)
- Marco Grados
- Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
| | - Rachel Huselid
- Johns Hopkins University Krieger School of Arts & Sciences, Baltimore, MD 21205, USA.
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Qi C, Ji X, Zhang G, Kang Y, Huang Y, Cui R, Li S, Cui H, Shi G. Haloperidol ameliorates androgen-induced behavioral deficits in developing male rats. J Endocrinol 2018; 237:193-205. [PMID: 29563235 DOI: 10.1530/joe-17-0642] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 03/21/2018] [Indexed: 01/06/2023]
Abstract
The purpose of present study was to infer the potential effects of testosterone increase in some male-based childhood-onset neuropsychiatric disorders, such as Tourette syndrome. Thus, the influence of early postnatal androgen exposure upon the neurobehaviors and its possible neural basis were investigated in the study. Male pup rats received consecutive 14-day testosterone propionate (TP) subcutaneous injection from postnatal day (PND) 7. The TP treatment produced the hyperactive motor behavior and grooming behavior as well as the increased levels of dopamine, tyrosine hydroxylase and dopamine transporter in the mesodopaminergic system and the elevated levels of serotonin in the nucleus accumbens, without affecting the levels of glutamate, γ-aminobutyric acid, norepinephrine and histamine in the caudate putamen and nucleus accumbens of PND21 and PND49 rats. Dopamine D2 receptor antagonist haloperidol was administered to the early postnatal TP-exposed PND21 and PND49 male rats 30 min prior to open field test. Haloperidol significantly ameliorated the motor behavioral and grooming behavioral defects induced by early postnatal TP exposure. The results demonstrated that early postnatal androgen exposure significantly disturbed the brain activity of developing male rats via enhancing the mesodopaminergic activity. It was suggested that abnormal increments of testosterone levels during the early postnatal development might be a potential risk factor for the incidence of some male-based childhood-onset neuropsychiatric disorders by affecting the mesodopaminergic system.
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Affiliation(s)
- Chunxiao Qi
- Department of NeurobiologyHebei Medical University, Shijiazhuang, People's Republic of China
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Xiaoming Ji
- Department of NeurobiologyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Guoliang Zhang
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Yunxiao Kang
- Department of NeurobiologyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Yuanxiang Huang
- Grade 2015 Eight-year Clinical Medicine ProgramSchool of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Rui Cui
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Shuangcheng Li
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Huixian Cui
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
- Neuroscience Research CenterHebei Medical University, Shijiazhuang, People's Republic of China
| | - Geming Shi
- Department of NeurobiologyHebei Medical University, Shijiazhuang, People's Republic of China
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
- Neuroscience Research CenterHebei Medical University, Shijiazhuang, People's Republic of China
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Takeuchi H, Kawashima R. Mean Diffusivity in the Dopaminergic System and Neural Differences Related to Dopaminergic System. Curr Neuropharmacol 2018; 16:460-474. [PMID: 29119929 PMCID: PMC6018195 DOI: 10.2174/1570159x15666171109124839] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 05/29/2017] [Accepted: 11/07/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The mean diffusivity (MD) parameter obtained by diffusion tensor imaging provides a measure of how freely water molecules move in brain tissue. Greater tissue density conferred by closely arrayed cellular structures is assumed to lower MD by inhibiting the free diffusion of water molecules. METHODS In this paper, we review studies showing MD variation among regions of the brain dopaminergic system (MDDS), especially subcortical structures such as the putamen, caudate nucleus, and globus pallidus, in different conditions with known associations to dopaminergic system function or dysfunction. The methodologies and background related to MD and MDDS are also discussed. RESULTS Past studies indicate that MDDS is sensitive to pathological derangement of dopaminergic activity, neural changes caused by cognitive and pharmacological interventions that are known to affect the dopaminergic system, and individual character traits related to dopaminergic function. CONCLUSION These results suggest that MDDS can be one useful tool to tap the neural differences related to the dopaminergic system.
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Affiliation(s)
- Hikaru Takeuchi
- Address correspondence to this author at the Division of Developmental Cognitive Neuroscience, IDAC, Tohoku University, 4-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; Tel/Fax: +81-22-717-7988;, E-mail:
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Abstract
Autism spectrum disorder (ASD) is a condition with onset in early childhood characterized by marked deficits in interpersonal interactions and communication and by a restricted and repetitive range of interests and activities. This review points out key recent findings utilizing molecular imaging including magnetic resonance spectroscopy (MRS) and nuclear neuroimaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). MRS indicates an excitatory/inhibitory imbalance in high-functioning autism. Dysfunction of neurotransmitter and glucose metabolism has been demonstrated by PET and SPECT. Levels of serotonin synthesis in typically developing children are approximately twice those of adults; after the age of 5 years, levels decrease to those of adults. In contrast, levels of serotonin synthesis of children with ASD increase between ages 2 and 15 to 1.5-times adult values. The dopamine transporter is increased in the orbitofrontal cortex of men with ASD. The serotonin transporter is reduced in the brains of children, adolescents, and adults with ASD. Reduced serotonin receptors in the thalamus of adults with ASD are associated with communication difficulties. Glucose metabolism is reduced in the brains of people with ASD. Molecular imaging will provide the preliminary data for promising therapeutic interventions.
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Affiliation(s)
- Brian Jaeho Hwang
- a Department of Neuroscience , Zanvyl Krieger School of Arts and Sciences, Johns Hopkins University , Baltimore , MD , USA
| | - Mona Adel Mohamed
- b Division of Neuroradiology, The Russell H. Morgan Department of Radiology and Radiological Science School of Medicine , Johns Hopkins University , Baltimore , MD , USA
| | - James Robert Brašić
- c Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science , School of Medicine, Johns Hopkins University , Baltimore , MD , USA
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Maia TV, Conceição VA. The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression. Biol Psychiatry 2017; 82:401-412. [PMID: 28734459 DOI: 10.1016/j.biopsych.2017.05.025] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/08/2017] [Accepted: 05/28/2017] [Indexed: 01/26/2023]
Abstract
Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively.
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Affiliation(s)
- Tiago V Maia
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
| | - Vasco A Conceição
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
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