Materiały źródłowe

• #1 Tourette Syndrome: Clinical Features, Pathophysiology, and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10958485/

  Tourette syndrome is a chronic neurodevelopmental disorder characterised by motor and phonic tics that can substantially diminish the quality of life of affected individuals. […] The underlying pathophysiology of Tourette syndrome is not fully understood, but recent research in the past 5 years has brought new insights into the genetic variations and the alterations in neurophysiology and brain networks contributing to its pathogenesis. […] Although the pathophysiology of Tourette syndrome is not fully understood, various genetic and neurophysiological factors are likely to contribute. […] Recent progress in the past 5 years has been made in refining the pathophysiological models and genetics of Tourette syndrome, and in the further development of pharmacological, behavioural, and neuromodulation interventions.

• #1 Tourette syndrome: Pathogenesis, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/tourette-syndrome-pathogenesis-clinical-features-and-diagnosis

  Tourette syndrome (TS) is thought to result from a complex interaction between social and environmental factors and multiple genetic risk factors. […] TS likely results from a disturbance in the cortico-striatal-thalamic-cortical (mesolimbic) circuit, which leads to disinhibition of the motor and limbic system. […] Advanced neuroimaging studies have found evidence of structural, functional, and metabolic changes in the brain associated with TS. […] Reductions in caudate volume are the most commonly reported structural changes. […] Based on functional magnetic resonance imaging (MRI) studies, the insula plays a key role in premonitory sensations and urges, often preceding motor or phonic tics.

• #1 Frontiers | Tourette Syndrome: A Mini-Review

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2018.00139/full

  The cause of TS is not yet known. It is assumed that the development of the disorder is conditioned by the participation of the genetic and nongenetic (epidemiological) factors. TS belongs to polygenic hereditary disorders, where several different genes are involved in the disorder. Even though chromosomal aberrations rarely occurred in patients with TS, a clear genetic cause has not yet been revealed. The negative effects of the environment are mainly prenatal intakes (maternal stress in pregnancy, smoking, infections, fetal hypoxia) and stressful events in the child’s life. […] Tourette syndrome pathophysiological mechanisms have not yet been elucidated. Many findings are indicative of organic origin. Although tics are at least partially influenced by will, neurophysiological studies show that tics are not driven by normal motor ways designed to control free movements. Tics are not preceded by common preparatory potential (Bereitschaftspotential), and polysomnography has shown tics at various stages of sleep. Strong evidence shows changes in central neurotransmitters, especially in dopaminergic modulation. Dopamine antagonists and depleters improve tics, while drugs that augment central dopaminergic activity worsen them. The most interesting hypothesis assumes that the underlying TS is a developmental disorder leading to dopaminergic hyperinnervation of the striatum. Anatomical and functional links between the basal ganglia and the limbic system can explain the current occurrence of tics and complex behavioral problems in TS. It was proved that basal ganglia, particularly the caudatus nucleus and ventral striatolimbic complex played a significant role in the pathogenesis of OCD and primitive reproductive behavior. The influence of sex hormones on the development of these structures can explain the difference in TS among sexes, the exacerbation of puberty and estrogenic stages of the menstrual cycle, and the characteristic occurrence of complex motor and sound tics, as well as behavioral manifestations with sexual content.

• #1

  https://step1.medbullets.com/psychiatry/114059/tourette-syndrome

  Tourette syndrome is a neuropsychiatric disorder with an onset before age 18 that is characterized by motor and vocal tics for 1 year. […] Pathophysiology remains unknown, but the basal ganglia and inferior frontal cortex have been implicated in the pathophysiology of Tourette syndrome. […] Majority of cases are familial; prevalence in first-degree relatives is 10 times the prevalence in the general population.

• #1 Tourette’s Syndrome | AAFP

  https://www.aafp.org/pubs/afp/issues/2008/0301/p651.html

  There are high concordance rates in monozygotic, but not dizygotic, twins. […] Segregation analyses supported an autosomal-dominant hypothesis, but investigators now favor intermediate modes of inheritance or a polygenic model. […] Another possibility is bilineal transmission, because a history of tics and/or comorbidities may be found in both maternal and paternal family members. […] Recently, alterations in the gene sequence of SLITRK1 were associated with some cases of Tourette’s syndrome.

• #1 Tourette syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/tourette-syndrome/

  Tourette syndrome involves both motor tics, which are uncontrolled body movements, and vocal or phonic tics, which are outbursts of sound. […] A variety of genetic and environmental factors likely play a role in causing Tourette syndrome. Most of these factors are unknown, and researchers are studying risk factors before and after birth that may contribute to this complex disorder. Scientists believe that tics may result from changes in brain chemicals (neurotransmitters) that are responsible for producing and controlling voluntary movements. […] Variants (also called mutations) involving the SLITRK1 gene have been identified in a small number of people with Tourette syndrome. This gene provides instructions for making a protein that is active in the brain. The SLITRK1 protein probably plays a role in the development of nerve cells, including the growth of specialized extensions (axons and dendrites) that allow each nerve cell to communicate with nearby cells. It is unclear how variants in the SLITRK1 gene can lead to this disorder.

• #1 Tourette Syndrome: Clinical Features, Pathophysiology, and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10958485/

  Collectively, genetic and environmental factors are likely to result in widespread neuronal network dysfunction and the potential emergence of symptoms related to Tourette syndrome. […] On a network level, tics might be a product of inhibitory dysfunction within the sensorimotor cortico-basal ganglia network, namely from alterations of striatal inhibitory microcircuitry and problems with automatic inhibition of actions. […] An alternative hypothesis is that tics could represent exaggerated and persistent motor habits that are reinforced by aberrant increased phasic dopamine release. […] The current model of premonitory urges proposes that abnormal interoceptive and exteroceptive processing might generate premonitory urges, leading to action initiation and subsequent tic execution via the cortico-basal ganglia sensorimotor network.

• #1 Tourette syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Tourette_syndrome

  Cortico-striato-thalamo-cortical (CSTC) circuits, or neural pathways, provide inputs to the basal ganglia from the cortex. These circuits connect the basal ganglia with other areas of the brain to transfer information that regulates planning and control of movements, behavior, decision-making, and learning. […] Involuntary movements may result from impairments in these CSTC circuits, including the sensorimotor, limbic, language and decision making pathways. Abnormalities in these circuits may be responsible for tics and premonitory urges. […] The release of dopamine in the basal ganglia is higher in people with Tourette’s, implicating biochemical changes from „overactive and dysregulated dopaminergic transmissions”.

• #1

  https://link.springer.com/article/10.1007/s00415-003-1102-4

  Tics are involuntary movements that can affect one or more muscles producing simple or complex movements. […] Dysfunction of basal ganglia-thalamo-cortical projections affects sensorimotor, language and limbic cortical circuits, and may explain why patients with Tourette syndrome have difficulty in inhibiting unwanted behaviors and impulses.

• #1 Tourette Syndrome and Other Tic Disorders: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/289457-overview

  Tourette syndrome (TS) is a common genetic neurological disorder characterized by chronic motor and vocal tics beginning before adulthood. […] The pathophysiology underlying TS remains unknown. Biochemical, imaging, neurophysiologic and genetic studies support the hypothesis that TS is an inherited, developmental disorder of neurotransmission. […] The basal ganglia and inferior frontal cortex have been implicated in the pathogenesis of TS, as well as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). Neuropathological studies, however, have failed to reveal any consistent structural abnormalities in these areas. […] Volumetric MRI studies have suggested that the normal asymmetry of the basal ganglia is lost in affected individuals. […] Little is known about the role of the thalamus in the pathogenesis of TS.

• #1 Tourette Syndrome and Other Tic Disorders: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1182258-overview

  The pathophysiology underlying TS remains unknown. Biochemical, imaging, neurophysiologic and genetic studies support the hypothesis that TS is an inherited, developmental disorder of neurotransmission. […] The basal ganglia and inferior frontal cortex have been implicated in the pathogenesis of TS, as well as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). Neuropathological studies, however, have failed to reveal any consistent structural abnormalities in these areas. […] Volumetric MRI studies have suggested that the normal asymmetry of the basal ganglia is lost in affected individuals. Healthy right-handed males normally demonstrate a predominance of the left putamen but this appears to be absent in TS, supporting the possibility of a developmental abnormality.

• #1 Tourette syndrome: Review of literature

  https://arquivosdeorl.org.br/conteudo/acervo_eng.asp?id=813

  The studies of neural imaging has enabled a better understanding about the neural base of TS, such as, its probable pathogenesis. […] Abnormalities in the volume of the basic ganglia in the callous body also were observed in the TS carriers. […] In the neurochemical point of view, many hypothesis suggest the involvement from the system dopaminergic in the pathogenesis of TS, since the neuroleptic, dopamine antagonists, are considered effective in the treatment of this disease, because promote great reduction of the tic. […] The evidence of involvement from the noradrenergic system in the physiopathology of the syndrome is based in the good benefits of clonidine and guanfacine, which are traditionally selective agonists from the D2 receptor adrenergic.

• #1 Tourette syndrome: Pathogenesis, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/tourette-syndrome-pathogenesis-clinical-features-and-diagnosis/print

  Tourette syndrome (TS) is thought to result from a complex interaction between social and environmental factors and multiple genetic risk factors. […] TS likely results from a disturbance in the cortico-striatal-thalamic-cortical (mesolimbic) circuit, which leads to disinhibition of the motor and limbic system. […] Advanced neuroimaging studies have found evidence of structural, functional, and metabolic changes in the brain associated with TS. […] Reductions in caudate volume are the most commonly reported structural changes. […] Positron emission tomography (PET) studies have shown variable rates of glucose utilization in the basal ganglia in patients with TS compared with controls. […] Based on functional magnetic resonance imaging (MRI) studies, the insula plays a key role in premonitory sensations and urges, often preceding motor or phonic tics.

• #1 Researchers uncover mechanism controlling Tourette Syndrome tics | ScienceDaily

  https://www.sciencedaily.com/releases/2013/12/131211104127.htm

  A mechanism in the brain which controls tics in children with Tourette Syndrome (TS) has been discovered by scientists at The University of Nottingham. […] This new study is very important as it indicates that motor and vocal tics in children may be controlled by brain changes that alter the excitability of brain cells ahead of voluntary movements. […] Scientists believe that the tics that affect children with TS are caused by faulty wiring in the brain that leads to hyper excitability in the brain regions controlling motor function. […] This clinical observation suggests that there are mechanisms in the brain that are involved in controlling tics and undergo development or re-organisation during the teenage years. […] The research is based on the general hypothesis that an area in the brain called the striatum is overactive as a result of alterations in the early development of the brain. As a result, the signals that are relayed to the brain’s cortex region lead to hyper-excitability and cause tics to occur.

• #1 The Dysfunctional Mechanisms Throwing Tics: Structural and Functional Changes in Tourette Syndrome

  https://www.mdpi.com/2076-328X/13/8/668

  Tourette Syndrome (TS) is a high-incidence multifactorial neuropsychiatric disorder characterized by motor and vocal tics co-occurring with several diverse comorbidities, including obsessive-compulsive disorder and attention-deficit hyperactivity disorder. […] The origin of TS is multifactorial, with strong genetic, perinatal, and immunological influences. […] Although almost all neurotransmitter systems have been implicated in TS pathophysiology, a comprehensive neurophysiological model explaining the dynamics of expression and inhibition of tics is still lacking. […] The genesis and maintenance of motor and non-motor aspects of TS are thought to arise from functional and/or structural modifications of the basal ganglia and related circuitry. […] Importantly, striatal circuits exhibit bidirectional forms of synaptic plasticity that differ in many respects from hippocampal and neocortical plasticity, including sensitivity to metaplastic molecules such as dopamine.

• #1 Tourette Syndrome and Other Tic Disorders: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/289457-overview

  In summary, clinical evidence suggests that dopaminergic function is abnormal in TS. However, the site of dopamine involvement within the pathway remains unknown. […] The implication is that at a minimum, careful clinical assessment, including information about OCD or ADHD symptoms, is required when the results of any new neuroimaging study are interpreted in individuals with TS.

• #1 Tourette Syndrome and Other Tic Disorders: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/289457-overview

  Abnormalities of central neurotransmitters have been implicated as a cause of TS. […] Affected individuals have also been shown to have an increased rate of binding of 3H-mazindol to the presynaptic dopamine-uptake-carrier sites. […] Several studies using single-photon emission computed tomography (SPECT) have found an increase in the density of the presynaptic dopamine transporter and the postsynaptic D2 dopamine receptor. […] TS may therefore result from abnormal regulation of dopamine uptake and release. […] Dopaminergic innervation of striatum has several characteristics that would allow generation of such abnormal epochs of striatal activity; these include dopamine’s modulation of the resting membrane potential set point and the influence of dopamine on long-term potentiation or long-term depression.

• #1 Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation | Journal of Neuroscience

  https://www.jneurosci.org/content/31/35/12387

  Dopamine dysfunction is considered a prime abnormality in TS based on tic suppression with the use of dopamine antagonists (antipsychotics), results from various nuclear imaging protocols, CSF analysis, and postmortem studies. […] In summary, further investigations are required to identify the underlying biochemical defect in this complex disorder.

• #1 The Dysfunctional Mechanisms Throwing Tics: Structural and Functional Changes in Tourette Syndrome

  https://www.mdpi.com/2076-328X/13/8/668

  As mentioned, TS seems to be characterized by an excess of dopamine or supersensitivity of postsynaptic dopaminergic receptors at the BG level, resulting in an imbalance of CSCT circuits. […] The activation of the direct pathway leads to a reduction in the inhibitory activity of the GPi and the overall promotion of movement. […] Compromised neuronal activity and enhanced dopaminergic transmission in the striatum of TS patients are thought to undermine the physiological selection of motor programs and promote their activation, thus leading to tic behavior. […] As presented in the previous paragraphs, both structural and functional anomalies of BG have been widely documented and are supposed to contribute to the induction and expression of TS. […] Focusing on the neuronal microcircuitry, one of the known manifestations in TS patients is a ~60% reduction of parvalbumin-positive (PV+) neurons in both associative and sensorimotor portions of the dorsal striatum.

• #1 Tourette Syndrome and Other Tic Disorders: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1182258-overview

  Little is known about the role of the thalamus in the pathogenesis of TS. A recent study using conventional measures of volumes and surface morphology demonstrated enlargement of the thalamus of more than 5% in affected patients of all ages. These findings raise the possibility of activity-dependent hypertrophy and therefore suggest that TS may involve previously unsuspected motor pathways. […] Abnormalities of central neurotransmitters have been implicated as a cause of TS. Limited post mortem studies have shown low brainstem serotonin, low levels of glutamate in the globus pallidus, and low levels of cyclic adenosine monophosphate (AMP) in the cortex. […] Affected individuals have also been shown to have an increased rate of binding of 3H-mazindol to the presynaptic dopamine-uptake-carrier sites. This observation has led some investigators to conclude that TS results from dopaminergic hyperinnervation of the ventral striatum and associated limbic system.

• #1 Tourette Syndrome and Other Tic Disorders: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1182258-overview

  Several studies using single-photon emission computed tomography (SPECT) have found an increase in the density of the presynaptic dopamine transporter and the postsynaptic D2 dopamine receptor. […] Some neuropathological studies have supported these findings. TS may therefore result from abnormal regulation of dopamine uptake and release. […] The role of glutamate, the brain’s predominant excitatory transmitter, needs further study. One postmortem report showed markedly different glutamate levels in the internal segment of globus pallidus (GPi), but this finding awaits confirmation. […] In summary, clinical evidence suggests that dopaminergic function is abnormal in TS. However, the site of dopamine involvement within the pathway remains unknown. […] Several studies have examined dopamine-related candidate genes for association with a diagnosis of TS. Studies suggest a possible association with the dopamine D2 or D4 receptors.

• #1

  https://journals.lww.com/co-neurology/fulltext/2016/08000/tics_and_tourette_s__update_on_pathophysiology_and.17.aspx

  To describe recent advances in the pathophysiology of tics and Tourette syndrome, and novel insights on tic control. […] The cortico-basal ganglia-thalamo-cortical loops are implicated in generation of tics. Disruption of GABAergic inhibition lies at the core of tic pathophysiology, but novel animal models also implicate cholinergic and histaminergic neurotransmission. […] The study of Tourette syndrome pathophysiology involves different neural disciplines and provides novel, exciting insights of brain function in health and disease.

• #1 Causes and origins of Tourette syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Causes_and_origins_of_Tourette_syndrome

  Research presents considerable evidence that abnormal activity of the brain chemical, or neurotransmitter, dopamine is involved. Dopamine excess or supersensitivity of the postsynaptic dopamine receptors may be an underlying mechanism of Tourette syndrome. […] Multiple neurotransmitters, like histamine (H3R), dopamine, serotonin, GABA and glutamate are involved in the etiology. After 2010, the central role of histamine (H3-receptor in the basal ganglia) came into focus in the pathophysiology of Tourette syndrome.

• #1 Neuroinflammation and pathways that contribute to tourette syndrome | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-025-01874-3

  The activation of calcium-calmodulin-dependent protein kinase II (CaMKII) has been linked to movement disorders, such as TS. […] The JAK2/STAT3 pathway is considered one of the most important inflammatory pathways that induces the expression of inflammation-related genes. […] Microglia can be activated by LPS through the NF-B signaling pathway, leading to neuroinflammation. […] TS is a neuropsychiatric disorder associated with inflammation-mediated immune response. This article describes the pathogenesis of TS associated with immune responses caused by infection or allergy.

• #1 Tourette’s Syndrome – Medical Clinical Policy Bulletins | Aetna

  https://www.aetna.com/cpb/medical/data/400_499/0480.html

  A modified function of these promoter polymorphisms may contribute to the complex interplay of serotonin and dopamine and then to the manifestation of TS. […] The authors concluded that these findings suggested that iron deficiency may be associated with more severe tics with higher impact on TS children, independent of the presence of OCD, ADHD, or anxiety. […] The authors concluded that these findings indicated a close association between peripheral immune activation and TS; however, the most direct and meaningful interaction between peripheral immune status and microglial activation in the central nervous system in TS patients requires further investigation. […] The authors concluded that the existing data indicated glutamate alterations in OCD, and possible immunological abnormalities in OCD and TS. […] The authors concluded that the findings of this proof-of-concept study need to be validated by well-designed studies.

• #1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3181853/

  Tourette’s syndrome (TS) is a disorder characterized by simple and complex motor tics, vocal tics, and frequently obsessive-compulsive symptoms, its onset occurs before the age of 21. […] The pathological mechanism is still unclear. Neuroanatomical and neuroimaging studies, as well as effective treatment using antipsychotics, suggest that a disturbance of the dopaminergic system in the basal ganglia plays an important role in the pathogenesis of TS. […] Several possibly causative mechanisms of the disturbed dopaminergic neurotransmission are discussed, with the main emphasis on the infection-triggered inflammatory immune process. […] Cases of childhood TS are proposed to be caused by such a post-streptococcal mechanism, being part of a spectrum of childhood neurobehavioral disorders termed pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS).

• #1 Neuroinflammation and pathways that contribute to tourette syndrome | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-025-01874-3

  Pathogens cause neurotransmitter imbalances through the following mechanisms. They can damage neurons by activating T cells to produce inflammatory factors or B cells to produce anti-neuronal antibodies. Both these factors may lead to the onset of TS. […] Pathogenic infections can lead to hyperactivation of the peripheral immune system and release of excessive inflammatory factors. These inflammatory factors may lead to the dysfunction of neural-immune crosstalk, which may cause an imbalance in neurotransmitters, such as DA and Glu, which can lead to tics. […] Anti-neuronal antibodies have been considered to cross-react with streptococci and antigens in the basal ganglia. The pathogenesis of TS-associated antibodies is speculated to involve cross-reactions between anti-neuronal antibodies and the basal ganglia.

• #1 Synaptic processes and immune-related pathways implicated in Tourette syndrome | Translational Psychiatry

  https://www.nature.com/articles/s41398-020-01082-z

  In this study, we took advantage of the increased sample size of the second wave TS GWAS and the mechanics of the two distinct methods to identify gene sets associated with TS that provide a novel insight into the pathogenesis of TS, and substantiate the role of neural processes in this neuropsychiatric disorder. […] Individuals with TS are reported to present elevated markers of immune activation. […] In addition, a number of studies have implicated neuroimmune responses with the pathogenesis of TS. […] The rs1933437 variant in FLT3 is an eQTL in the brain cortex and the cerebellum, and has also been implicated in the age at the onset of menarche. […] FLT3 could play a role in neuroinflammation as supported by its intriguing association with peripheral neuropathic pain. […] The CATS gene set involves many cell adhesion molecules, with the top signals found in CDH26.

• #1

  https://link.springer.com/article/10.1007/s00702-011-0739-x

  Tourette syndrome is a neurodevelopmental disorder clinically characterized by multiple motor and phonic tics. It is likely that a neurobiological susceptibility to the disorder is established during development by the interaction of genetic, biochemical, immunological, and environmental factors. […] This study sought to investigate the possible correlation of several immunological and biochemical markers with Tourette syndrome. […] Compared with the control group, the Tourette syndrome group had significantly higher levels of ferritin (p = 0.01) and hemoglobin (p = 0.02), a lower level of zinc (p = 0.05), and a lower percentage of non-ceruloplasmin copper (p = 0.01). […] Analysis of the immunological markers revealed no significant between-group differences in IgA, IgM or IgG; however, IgE and IgG-4 levels were significantly higher in the Tourette syndrome group (p= 0.04 and p = 0.02, respectively). […] Children with Tourette syndrome have high levels of biochemical indices of oxidative stress and the quantitative immunoglobulins. These findings add to the still-limited knowledge on the pathogenesis of Tourette syndrome and may have implications for the development of novel therapeutic modalities.

• #1 Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg201522

  Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. […] We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis. […] Despite the relative modest sample size, our gene-set analysis revealed a significant association between the astrocyte carbohydrate metabolism pathway and Tourette syndrome. […] This association could be further narrowed down to the ANMC subprocess, and we showed the effect of this gene set was not because of an effect of a single gene, but was because of an overall, combined effect of many genetic variants of small effect.

• #1 Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg201522

  This is the first study to point to the involvement of ANMC function in Tourette syndrome, probably through altered glycogen and glutamate/GABA metabolism, and in line with previously hypothesized mechanisms underlying Tourette syndrome pathogenesis that involve perturbations in the balance between excitatory glutamatergic and inhibitory GABAergic transmission within regulatory cortico-striato-thalamocortical circuits. […] Thus, genetic alterations in glycolysis and glutamate metabolism can have profound influences on astrocyte modulation of synapse function. Such perturbations in the balance between excitatory glutamatergic and inhibitory GABAergic transmission within regulatory cortico-striato-thalamocortical circuits have long been hypothesized as a core defect in Tourette syndrome pathogenesis. […] Taken together, our findings highlight an often underestimated function of astrocytes in supporting synaptic function and suggest that abnormalities in this process may contribute to the etiology of Tourette syndrome.

• #1 The Dysfunctional Mechanisms Throwing Tics: Structural and Functional Changes in Tourette Syndrome

  https://www.mdpi.com/2076-328X/13/8/668

  Synaptic plasticity has been widely characterized in the striatum of rats and mice both functionally and molecularly. […] Dopamine-dependent synaptic plasticity of corticostriatal excitatory projections represents a powerful mechanism for the regulation of BG functioning and, more in general, motor programs. […] Striatal synaptic plasticity might also contribute to the maintenance of tic-like behaviors over time. […] In the context of striatal plasticity, immunopathogenic mediators are thought to be involved in TS development, and their role might be central.

• #1 Tourette Syndrome: Clinical Features, Pathophysiology, and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10958485/

  Neurophysiological studies in humans can identify markers of tics during surgery to implant deep brain stimulation devices, during externalised lead studies, or via neurostimulators capable of recording neural activity. […] Additional alternative hypotheses related to Tourette syndrome pathogenesis include Tourette syndrome being a disorder of social behavioural networks.

• #1 The Dysfunctional Mechanisms Throwing Tics: Structural and Functional Changes in Tourette Syndrome

  https://www.mdpi.com/2076-328X/13/8/668

  TS etiology is very complex, with strong genetic influences, repeated streptococcal infections, and also pre and perinatal phenomena. […] There is accumulating evidence that immune dysregulation contributes to the pathophysiology of OCD, TS, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). […] Importantly, blood flow and metabolism studies assessed the implication of dopaminergic transmission in the pathophysiology of TS, especially in or around portions of the caudate nucleus of the ventral striatum, a key region for motor and behavioral expression. […] TS appears to be associated with a specific cerebral network characterized by a reduction in the activity of the BG and thalamocortical circuits. […] A cortical-striatum-pallidus-cortical semi-open loop plastic model has been proposed, in which the BG use reinforcing signals and local competitive learning to reduce sparse cortical information.

• #1 The implication of neuroactive steroids in Tourette syndrome pathogenesis: a role for 5α-reductase?

  https://kuscholarworks.ku.edu/entities/publication/38438d4f-425c-443a-8219-71301353d587

  Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. […] Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. […] In particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. […] In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis.

• #1 The implication of neuroactive steroids in Tourette syndrome pathogenesis: a role for 5α-reductase?

  https://kuscholarworks.ku.edu/entities/publication/38438d4f-425c-443a-8219-71301353d587

  Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. […] We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS.

• #1 3D Organoid Models Show Brain Mechanisms of Tourette Syndrome < Yale School of Medicine

  https://medicine.yale.edu/news-article/3d-organoid-models-show-brain-mechanisms-of-tourette-syndrome/

  The study suggested a relationship between the extent of abnormalities in the basal ganglia organoids and tic severity. […] Identifying potential differences in the neurobiology of TS at the developmental level may one day lead to earlier diagnoses and new methods to manage the disorder. […] Now that the team has identified differences in the basal ganglia and a potential mechanism, it plans to study the genetic and epigenetic backgrounds of TS patients and understand how those might contribute to this abnormal response. […] Vaccarino hopes her group’s ongoing work could lead to potential therapeutic interventions.

• #1 Tourette syndrome: clinical features, pathophysiology, and treatment | CoLab

  https://colab.ws/articles/10.1016%2FS1474-4422%2822%2900303-9

  Tourette syndrome is a chronic neurodevelopmental disorder characterised by motor and phonic tics that can substantially diminish the quality of life of affected individuals. […] The underlying pathophysiology of Tourette syndrome is not fully understood, but recent research in the past 5 years has brought new insights into the genetic variations and the alterations in neurophysiology and brain networks contributing to its pathogenesis. […] Multicentre data sharing initiatives have enabled several advances in our understanding of the genetics and pathophysiology of Tourette syndrome and will be crucial for future large-scale research and in refining effective treatments.

• #2 Tourette syndrome: clinical features, pathophysiology, and treatment | CoLab

  https://colab.ws/articles/10.1016%2FS1474-4422%2822%2900303-9

  Tourette syndrome is a chronic neurodevelopmental disorder characterised by motor and phonic tics that can substantially diminish the quality of life of affected individuals. […] The underlying pathophysiology of Tourette syndrome is not fully understood, but recent research in the past 5 years has brought new insights into the genetic variations and the alterations in neurophysiology and brain networks contributing to its pathogenesis. […] Multicentre data sharing initiatives have enabled several advances in our understanding of the genetics and pathophysiology of Tourette syndrome and will be crucial for future large-scale research and in refining effective treatments.

• #2 Tourette syndrome: Pathogenesis, clinical features, and diagnosis – UpToDate

  https://www.uptodate.com/contents/tourette-syndrome-pathogenesis-clinical-features-and-diagnosis/print

  Tourette syndrome (TS) is thought to result from a complex interaction between social and environmental factors and multiple genetic risk factors. […] TS likely results from a disturbance in the cortico-striatal-thalamic-cortical (mesolimbic) circuit, which leads to disinhibition of the motor and limbic system. […] Advanced neuroimaging studies have found evidence of structural, functional, and metabolic changes in the brain associated with TS. […] Reductions in caudate volume are the most commonly reported structural changes. […] Positron emission tomography (PET) studies have shown variable rates of glucose utilization in the basal ganglia in patients with TS compared with controls. […] Based on functional magnetic resonance imaging (MRI) studies, the insula plays a key role in premonitory sensations and urges, often preceding motor or phonic tics.

• #2 Tourette Syndrome and Other Tic Disorders: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1182258-overview

  The pathophysiology underlying TS remains unknown. Biochemical, imaging, neurophysiologic and genetic studies support the hypothesis that TS is an inherited, developmental disorder of neurotransmission. […] The basal ganglia and inferior frontal cortex have been implicated in the pathogenesis of TS, as well as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). Neuropathological studies, however, have failed to reveal any consistent structural abnormalities in these areas. […] Volumetric MRI studies have suggested that the normal asymmetry of the basal ganglia is lost in affected individuals. Healthy right-handed males normally demonstrate a predominance of the left putamen but this appears to be absent in TS, supporting the possibility of a developmental abnormality.

• #2 Tourette Syndrome and Other Tic Disorders: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1182258-overview

  Several studies using single-photon emission computed tomography (SPECT) have found an increase in the density of the presynaptic dopamine transporter and the postsynaptic D2 dopamine receptor. […] Some neuropathological studies have supported these findings. TS may therefore result from abnormal regulation of dopamine uptake and release. […] The role of glutamate, the brain’s predominant excitatory transmitter, needs further study. One postmortem report showed markedly different glutamate levels in the internal segment of globus pallidus (GPi), but this finding awaits confirmation. […] In summary, clinical evidence suggests that dopaminergic function is abnormal in TS. However, the site of dopamine involvement within the pathway remains unknown. […] Several studies have examined dopamine-related candidate genes for association with a diagnosis of TS. Studies suggest a possible association with the dopamine D2 or D4 receptors.

• #2

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3181853/

  The overlap between TS and PANDAS is discussed, and a critical view of the PANDAS concept is presented. […] The therapeutic implications of the different pathological mechanisms are described, taking into consideration not only the acute or chronic natures of different infections, but also an autoimmune process. […] Recent studies suggest that an inflammatory process, due to an acute or chronic infection or a postinfectious immune response, may be involved in the pathogenesis of TS. […] Although the pathological mechanism in TS is unclear, contribution of an immunological dysfunction or an inflammatory process has been discussed. […] This finding – in addition to others with cross-reacting antibodies – shows that a poststreptococcal autoimmune process is involved in TS. […] A multifactorial pathogenesis has been proposed, with the involvement of an (immuno)genetic predisposition and environmental factors such as infection or postinfectious phenomena.

• #2 Tourette’s syndrome: clinical features, pathophysiology, and therapeutic approaches – SEARCH

  https://primo.qatar-weill.cornell.edu/discovery/fulldisplay/cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3181853/974WCMCIQ_INST:VU1

  Extrapyramidal movement disorders are known to occur as a symptom of poststreptococcal disease, such as in Sydenham’s chorea. Cases of childhood TS are proposed to be caused by such a post-streptococcal mechanism, being part of a spectrum of childhood neurobehavioral disorders termed pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) […] The overlap between TS and PANDAS is discussed, and a critical view of the PANDAS concept is presented […] The therapeutic implications of the different pathological mechanisms are described, taking into consideration not only the acute or chronic natures of different infections, but also an autoimmune process […] Moreover, therapeutic strategies using typical and atypical antipsychotics, and also experimental therapies such as repetitive transcranial magnetic stimulation and deep brain stimulation, are critically discussed.

• #2 Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis

  https://escholarship.org/uc/item/7s42q903

  Tourette Syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genomewide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. […] We report association of Tourette Syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette Syndrome pathogenesis.

• #3 Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation | Journal of Neuroscience

  https://www.jneurosci.org/content/31/35/12387

  Dopamine dysfunction is considered a prime abnormality in TS based on tic suppression with the use of dopamine antagonists (antipsychotics), results from various nuclear imaging protocols, CSF analysis, and postmortem studies. […] In summary, further investigations are required to identify the underlying biochemical defect in this complex disorder.

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