Aggressive Form of Mycosis Fungoides With Bilateral Testicular Involvement and Salivary Gland Mass, Exhibiting Phenotypic Switch.

ABSTRACT: We report the case of a 72-year-old man with bilateral testicular involvement by mycosis fungoides (MF). The patient was diagnosed with MF 6 months prior, and testicular involvement was found upon staging. The rare behavior of MF, with early visceral involvement and no hematolymphoid organs affected, had a poor prognosis with patient death 14 months after the original diagnosis despite surgery and chemotherapy. The neoplastic cells showed a phenotypic switch from a CD4 + /CD8 - profile in the skin to a CD4 - /CD8 - in the testis and the same clone, confirmed with T-cell receptor gene rearrangement studies, making this the third reported case of MF affecting the testis and the first with clonality studies to confirm it. The clinical evolution may be related to its distinctive biology showcased in the neoplastic cell's switch to a more aggressive CD4 - /CD8 - profile and the early extension of the disease to an uncommon visceral site.

Primary Cutaneous Anaplastic Large Cell Lymphoma With 6p25.3 Rearrangement and Epidermotropism.

ABSTRACT: Primary cutaneous anaplastic large cell lymphoma may harbor a 6p25.3 rearrangement, which has been associated with an epidermotropic small cell component. We report the case of a patient with said lymphoma harboring that rearrangement. It presented as a forehead nodule, histologically composed of an intermediate-to-large cell dermal component alongside a small-to-intermediate cell epidermotropic component. After multiple cutaneous and regional lymph node relapses, disease progression has been documented to a distant lymph node, despite local radiotherapy of the cutaneous lesions, chemotherapy, and anti-CD30 therapy, albeit with an indolent course over 6 years. Cases of pcALCL with nonregional lymph node involvement are unusual. Nevertheless, in this case, progression to a distant lymph node was not associated with an aggressive transformation of the disease.

Malignant Solitary Fibrous Tumor of the Liver: AIRP Best Cases in Radiologic-Pathologic Correlation.

Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP).

Changes in corticostriatal connectivity during reinforcement learning in humans.

Many computational models assume that reinforcement learning relies on changes in synaptic efficacy between cortical regions representing stimuli and striatal regions involved in response selection, but this assumption has thus far lacked empirical support in humans. We recorded hemodynamic signals with fMRI while participants navigated a virtual maze to find hidden rewards. We fitted a reinforcement-learning algorithm to participants' choice behavior and evaluated the neural activity and the changes in functional connectivity related to trial-by-trial learning variables. Activity in the posterior putamen during choice periods increased progressively during learning. Furthermore, the functional connections between the sensorimotor cortex and the posterior putamen strengthened progressively as participants learned the task. These changes in corticostriatal connectivity differentiated participants who learned the task from those who did not. These findings provide a direct link between changes in corticostriatal connectivity and learning, thereby supporting a central assumption common to several computational models of reinforcement learning.

Emphysematous vaginitis.

BACKGROUND: Emphysematous vaginitis is a rare condition, characterized by the presence of multiple gas-filled cysts in the vaginal and/or exocervical mucosa. Although its etiology is not completely understood, it is self-limited, with a benign clinical course. Vaginal discharge, sometimes bloody, and pruritus are the most common symptoms. Chronic and acute inflammation can be found, and diseases that impair the immune system and pregnancy have been associated with this condition. CASE REPORT: A 48-year-old postmenopausal woman, with a history of hysterectomy with several comorbidities, presented with a 4-month history of bloody discharge and vulvar pruritus. Examination showed multiple cystic lesions, 1 to 5 mm, occupying the posterior and right lateral vaginal walls. Speculum examination produced crepitus. Vaginal wet mount was normal, except for diminished lactobacilli; results of Trichomonas vaginalis DNA test and vaginal cultures were negative. Lugol's iodine applied to the vagina was taken up by the intact lesions. Biopsy result showed typical features of emphysematous vaginitis. CONCLUSIONS: This is an unusual entity, presenting with common gynecological complaints, and both physicians and pathologists should be aware to prevent misdiagnosis and overtreatment.

Reduced functional connectivity within the limbic cortico-striato-thalamo-cortical loop in unmedicated adults with obsessive-compulsive disorder.

Cortico-striato-thalamo-cortical (CSTC) loops project from the cortex to the striatum, then from the striatum to the thalamus via the globus pallidus, and finally from the thalamus back to the cortex again. These loops have been implicated in Obsessive-Compulsive Disorder (OCD) with particular focus on the limbic CSTC loop, which encompasses the orbitofrontal and anterior cingulate cortices, as well as the ventral striatum. Resting state functional-connectivity MRI (rs-fcMRI) studies, which examine temporal correlations in neural activity across brain regions at rest, have examined CSTC loop connectivity in patients with OCD and suggest hyperconnectivity within these loops in medicated adults with OCD. We used rs-fcMRI to examine functional connectivity within CSTC loops in unmedicated adults with OCD (n = 23) versus healthy controls (HCs) (n = 20). Contrary to prior rs-fcMRI studies in OCD patients on medications that report hyperconnectivity in the limbic CSTC loop, we found that compared with HCs, unmedicated OCD participants had reduced connectivity within the limbic CSTC loop. Exploratory analyses revealed that reduced connectivity within the limbic CSTC loop correlated with OCD symptom severity in the OCD group. Our finding of limbic loop hypoconnectivity in unmedicted OCD patients highlights the potential confounding effects of antidepressants on connectivity measures and the value of future examinations of the effects of pharmacological and/or behavioral treatments on limbic CSTC loop connectivity.

The Association Between Physical Distancing Behaviors to Avoid COVID-19 and Health-Related Quality of Life in Immunocompromised and Nonimmunocompromised Individuals: Patient-Informed Protocol for the Observational, Cross-Sectional EAGLE Study.

BACKGROUND: Immunocompromised individuals are known to respond inadequately to SARS-CoV-2 vaccines, placing them at high risk of severe or fatal COVID-19. Thus, immunocompromised individuals and their caregivers may still practice varying degrees of social or physical distancing to avoid COVID-19. However, the association between physical distancing to avoid COVID-19 and quality of life has not been comprehensively evaluated in any study. OBJECTIVE: We aim to measure physical distancing behaviors among immunocompromised individuals and the association between those behaviors and person-centric outcomes, including health-related quality of life (HRQoL) measures, health state utilities, anxiety and depression, and work and school productivity impairment. METHODS: A patient-informed protocol was developed to conduct the EAGLE Study, a large cross-sectional, observational study, and this paper describes that protocol. EAGLE is designed to measure distancing behaviors and outcomes in immunocompromised individuals, including children (aged ≥6 mo) and their caregivers, and nonimmunocompromised adults in the United States and United Kingdom who report no receipt of passive immunization against COVID-19. We previously developed a novel self- and observer-reported instrument, the Physical Distancing Scale for COVID-19 Avoidance (PDS-C19), to measure physical distancing behavior levels cross-sectionally and retrospectively. Using an interim or a randomly selected subset of the study population, the PDS-C19 psychometric properties will be assessed, including structural validity, internal consistency, known-group validity, and convergent validity. Associations (correlations) will be assessed between the PDS-C19 and validated HRQoL-related measures and utilities. Structural equation modeling and regression will be used to assess these associations, adjusting for potential confounders. Participant recruitment and data collection took place from December 2022 to June 2023 using direct-to-patient channels, including panels, clinician referral, patient advocacy groups, and social media, with immunocompromising diagnosis confirmation collected and assessed for a randomly selected 25% of immunocompromised participants. The planned total sample size is 3718 participants and participant-caregiver pairs. Results will be reported by immunocompromised status, immunocompromising condition category, country, age group, and other subgroups. RESULTS: All data analyses and reporting were planned to be completed by December 2023. Results are planned to be submitted for publication in peer-reviewed journals in 2024-2025. CONCLUSIONS: This study will quantify immunocompromised individuals' physical distancing behaviors to avoid COVID-19 and their association with HRQoL as well as health state utilities. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/52643.

A Rare Case Report of Intraventricular Anaplastic Pleomorphic Xanthoastrocytoma.

We describe a rare case of a 33-year-old man presenting with a three-day history of dizziness and memory impairment. On clinical examination, he had a wide-based gait and postural instability. Laboratory tests were unremarkable. The patient underwent a CT scan, which showed an intraventricular heterogeneous mass, with calcifications. An MRI scan was performed, revealing a well-defined intraventricular lesion, with cystic and necrotic areas, hemorrhagic components, areas of restricted diffusion, and a peripheral solid component with post-contrast enhancement. This lesion was ultimately diagnosed as an anaplastic form of pleomorphic xanthoastrocytoma (PXA) (WHO grade 3). Prototypical PXA is a rare low-grade astrocytic tumor, almost always hemispheric. To our knowledge, this is only the third case report to describe an intraventricular PXA. Anaplastic forms of PXA have a more aggressive behavior and should be distinguished from other high-grade astrocytic neoplasms, especially from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype variants (GB). Histopathological features of anaplastic forms of PXA (WHO grade 3) with epithelioid features are very similar to those of epithelioid glioblastoma and its differentiation is a common diagnostic challenge that should prompt genetic testing. Distinguishing between these two entities is crucial since the former is associated with significantly more survival benefits from targeted therapies (MAPK pathway inhibitors).

Extramedullary T-lymphoblastic Crisis in a Myelodysplastic/Myeloproliferative Neoplasm with a t(12;22)/MN1::ETV6 Translocation.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are not a single disease, but rather a heterogenous group of entities which are increasingly subclassified according to recurrent genetic abnormalities. Chromosomal translocations involving meningioma 1 (MN1) and ETS variant 6 (ETV6) genes are extremely rare, but recurrent in myeloid neoplasms. We describe the case of a patient with a myelodysplastic/myeloproliferative neoplasm with neutrophilia, who developed an extramedullary T-lymphoblastic crisis with the t(12;22)(p13;q12) translocation as the only cytogenetic abnormality. This case shares several clinical and molecular features with myeloid/lymphoid neoplasms with eosinophilia. The treatment of this patient was challenging, as the disease proved to be highly refractory to chemotherapy, with allogenic stem cell transplantation as the only curative option. This clinical presentation has not been reported in association with these genetic alterations and supports the concept of a hematopoietic neoplasm originating in an early uncommitted precursor cell. Additionally, it stresses the importance of molecular characterization in the classification and prognostic stratification of these entities.

Adaptation to conflict via context-driven anticipatory signals in the dorsomedial prefrontal cortex.

Behavioral interference elicited by competing response tendencies adapts to contextual changes. Recent nonhuman primate research suggests a key mnemonic role of distinct prefrontal cells in supporting such context-driven behavioral adjustments by maintaining conflict information across trials, but corresponding prefrontal functions have yet to be probed in humans. Using event-related functional magnetic resonance imaging, we investigated the human neural substrates of contextual adaptations to conflict. We found that a neural system comprising the rostral dorsomedial prefrontal cortex and portions of the dorsolateral prefrontal cortex specifically encodes the history of previously experienced conflict and influences subsequent adaptation to conflict on a trial-by-trial basis. This neural system became active in anticipation of stimulus onsets during preparatory periods and interacted with a second neural system engaged during the processing of conflict. Our findings suggest that a dynamic interaction between a system that represents conflict history and a system that resolves conflict underlies the contextual adaptation to conflict.

Benefits and Risks of Sharing Genomic Data for Research: Comparing the Views of Rare Disease Patients, Informal Carers and Healthcare Professionals.

Assessing public and patients' expectations and concerns about genomic data sharing is essential to promote adequate data governance and engagement in rare diseases genomics research. This cross-sectional study compared the views of 159 rare disease patients, 478 informal carers and 63 healthcare professionals in Northern Portugal about the benefits and risks of sharing genomic data for research, and its associated factors. The three participant groups expressed significantly different views. The majority of patients (84.3%) and informal carers (87.4%) selected the discovery of a cure for untreatable diseases as the most important benefit. In contrast, most healthcare professionals revealed a preference for the development of new drugs and treatments (71.4%), which was the second most selected benefit by carers (48.3%), especially by the more educated (OR (95% CI): 1.58 (1.07-2.34)). Lack of security and control over information access and the extraction of information exceeding research objectives were the two most often selected risks by patients (72.6% and 50.3%, respectively) and carers (60.0% and 60.6%, respectively). Conversely, professionals were concerned with genomic data being used to discriminate citizens (68.3%), followed by the extraction of information exceeding research objectives (54.0%). The latter risk was more frequently expressed by more educated carers (OR (95% CI): 1.60 (1.06-2.41)) and less by those with blue-collar (OR (95% CI): 0.44 (0.25-0.77) and other occupations (OR (95% CI): 0.44 (0.26-0.74)). Developing communication strategies and consent approaches tailored to participants' expectations and needs can benefit the inclusiveness of genomics research that is key for patient-centred care.

The attenuation of dysfunctional emotional processing with stimulant medication: an fMRI study of adolescents with ADHD.

Functional neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) have focused on the neural correlates of cognitive control. However, for many youths with ADHD, emotional lability is an important clinical feature of the disorder. We aimed to identify the neural substrates associated with emotional lability that were distinct from impairments in cognitive control and to assess the effects that stimulants have on those substrates. We used functional magnetic resonance imaging (fMRI) to assess neural activity in adolescents with (N=15) and without (N=15) ADHD while they performed cognitive and emotional versions of the Stroop task that engage cognitive control and emotional processing, respectively. The participants with ADHD were scanned both on and off stimulant medication in a counterbalanced fashion. Controlling for differences in cognitive control, we found that during the emotional Stroop task, adolescents with ADHD as compared with controls demonstrated atypical activity in the medial prefrontal cortex (mPFC). Stimulants attenuated activity in the mPFC to levels comparable with controls.

Mathematical Characterization of Changes in Fear During Exposure Therapy.

BACKGROUND: During exposure therapy, patients report increases in fear that generally decrease within and across exposure sessions. Our main aim was to characterize these changes in fear ratings mathematically; a secondary aim was to test whether the resulting model would help to predict treatment outcome. METHODS: We applied tools of computational psychiatry to a previously published dataset in which 30 women with spider phobia were randomly assigned to virtual-reality exposures in a single context or in multiple contexts (n = 15 each). Patients provided fear ratings every minute during exposures. We characterized fear decrease within exposures and return of fear between exposures using a set of mathematical models; we selected the best model using Bayesian techniques. In the multiple-contexts group, we tested the predictions of the best model in a separate, test exposure, and we investigated the ability of model parameters to predict treatment outcome. RESULTS: The best model characterized fear decrease within exposures in both groups as an exponential decay with constant decay rate across exposures. The best model for each group had only two parameters but captured with remarkable accuracy the patterns of fear change, both at the group level and for individual subjects. The best model also made remarkably accurate predictions for the test exposure. One of the model's parameters helped predict treatment outcome. CONCLUSIONS: Individual patterns of fear change during exposure therapy can be characterized mathematically. This mathematical characterization helps predict treatment outcome.

People exert more effort to avoid losses than to obtain gains.

Loss aversion is a fundamental tenet of behavioral economics and has led to many real-world applications. These applications, and some laboratory studies, show that people perform better under loss-avoidance than under gain incentives. This increased performance under loss-avoidance incentives has ubiquitously been explained by the notion that loss aversion causes people to exert more effort to avoid losses than to obtain gains. Only limited work, however, has directly examined whether people indeed choose to exert more effort to avoid losses than to obtain gains. Our primary aim was therefore to test this proposition. In an experiment with adults (N = 32) and in a subsequent experiment with children and adolescents (N = 29), we found that participants indeed exerted more effort to avoid losses than to obtain numerically equivalent gains. The effect sizes were large, with the effect being evident for most individual participants. As a secondary aim, in the study with adults, we also investigated whether the greater effort to avoid losses related to loss aversion measured using a task involving choices between prospects. Unexpectedly, the greater effort to avoid losses persisted robustly even after controlling for the effects of loss aversion measured using the task involving choices between prospects. We discuss two possible interpretations for this finding: our effort task may have been a more sensitive assessment of loss aversion than the task involving choices between prospects; alternatively, the processes underlying how much effort people choose to exert may partially differ from those engaged by choices between prospects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

De novo Gastrinoma: A Case Report.

Gastrinomas are neuroendocrine tumors characterized by gastrin overexpression - 80% are sporadic and 20% are associated with multiple endocrine neoplasia type 1. A 75-year-old male patient, surgically treated at the age of 50 years for gastrinoma, followed on an outpatient basis because of chronic non-bloody diarrhea, was admitted to our hospital because of abdominal pain, watery diarrhea, and nonbiliary vomits. He was hypotensive and showed no response to fluids. Blood cultures were positive for Salmonella, and a diagnosis of septic shock due to Salmonella infection was made. The patient's condition improved, but the history of chronic diarrhea was still not explained. To investigate chronic diarrhea, gastrinoma recurrence was considered. Serum gastrin measurement was five times higher than the upper limit of the normal range (536 pg/mL). A positive somatostatin receptor scintigraphy was diagnostic for neuroendocrine tumor. Metastases were excluded. The patient was proposed to curative surgery, and a diagnosis of a well-differentiated neuroendocrine tumor was made.

Gastrinomas são tumores neuroendócrinos caracterizados por hipersecreção de gastrina - 80% são esporádicos e 20% associados a neoplasia endócrina múltipla tipo 1 (MEN1). Apresenta-se o caso de um homem, de 75 anos, tratado cirurgicamente aos 50 anos por gastrinoma, seguido em consulta de Medicina Interna por diarreia crónica não-sanguinolenta, internado no nosso hospital por dor abdominal, diarreia aquosa e vómitos não biliares. À admissão, apresentava-se hipotenso e pouco responsivo a fluidoterapia. As hemoculturas foram positivas para Salmonella e foi feito o diagnóstico de choque séptico por Salmonella. O doente melhorou, mas a história prévia de diarreia crónica não estava esclarecida. Para investigar a diarreia crónica, foi colocada como hipótese recidiva de gastrinoma. A medição de gastrina sérica foi cinco vezes superior ao limite superior do normal (536 pg/mL). A cintigrafia com receptores de somatostatina foi diagnóstica para tumor neuroendócrino. Foram excluídas metástases. O doente foi proposto para cirurgia curativa e foi feito o diagnóstico de tumor neuroendócrino bem diferenciado.

Placental site trophoblastic tumour: the rarest subtype of gestational trophoblastic disease.

Placental site trophoblastic tumour (PSTT) is a very rare form of gestational trophoblastic disease that grows slowly, secretes low levels of beta-subunit of human chorionic gonadotropin (ß-hCG), presents late-onset metastatic potential and is resistant to several chemotherapy regimens. Here, we report a case of PSTT in a 36-year-old woman who presented with amenorrhea and persistently elevated serum level of ß-hCG after a miscarriage. Transvaginal ultrasound revealed a hypovascular ill-defined solid lesion of the uterine fundus and MRI showed a tumour infiltrating the external myometrium with discrete early enhancement and signal restriction on diffusion-weighted imaging. PSTT was suspected, and after endometrial biopsy by hysteroscopy and posterior hysterectomy, microscopic examination allowed the final diagnosis. The level of ß-hCG dropped significantly in about a month after surgical treatment. Due to the rarity of PSTT, reporting new cases is crucial to improve the diagnosis and managing of these patients.

Reinforcement learning, conditioning, and the brain: Successes and challenges.

The field of reinforcement learning has greatly influenced the neuroscientific study of conditioning. This article provides an introduction to reinforcement learning followed by an examination of the successes and challenges using reinforcement learning to understand the neural bases of conditioning. Successes reviewed include (1) the mapping of positive and negative prediction errors to the firing of dopamine neurons and neurons in the lateral habenula, respectively; (2) the mapping of model-based and model-free reinforcement learning to associative and sensorimotor cortico-basal ganglia-thalamo-cortical circuits, respectively; and (3) the mapping of actor and critic to the dorsal and ventral striatum, respectively. Challenges reviewed consist of several behavioral and neural findings that are at odds with standard reinforcement-learning models, including, among others, evidence for hyperbolic discounting and adaptive coding. The article suggests ways of reconciling reinforcement-learning models with many of the challenging findings, and highlights the need for further theoretical developments where necessary. Additional information related to this study may be downloaded from http://cabn.psychonomic-journals.org/content/supplemental.

The neural bases of obsessive-compulsive disorder in children and adults.

Functional imaging studies have reported with remarkable consistency hyperactivity in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and caudate nucleus of patients with obsessive-compulsive disorder (OCD). These findings have often been interpreted as evidence that abnormalities in cortico-basal ganglia-thalamo-cortical loops involving the OFC and ACC are causally related to OCD. This interpretation remains controversial, however, because such hyperactivity may represent either a cause or a consequence of the symptoms. This article analyzes the evidence for a causal role of these loops in producing OCD in children and adults. The article first reviews the strong evidence for anatomical abnormalities in these loops in patients with OCD. These findings are not sufficient to establish causality, however, because anatomical alterations may themselves be a consequence rather than a cause of the symptoms. The article then reviews three lines of evidence that, despite their own limitations, permit stronger causal inferences: the development of OCD following brain injury, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, and neurosurgical lesions that attenuate OCD. Converging evidence from these various lines of research supports a causal role for the cortico-basal ganglia-thalamo-cortical loops that involve the OFC and ACC in the pathogenesis of OCD in children and adults.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): impact on the reclassification of thyroid nodules.

The 2017 edition of the WHO book on Classification of Tumours of Endocrine Organs includes a new section entitled 'Other encapsulated follicular-patterned thyroid tumours', in which the newly created NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) is identified and described in detail. Despite deleting the word 'carcinoma' from its name, NIFTP is not a benign tumor either and is best regarded as a neoplasm with 'very low malignant potential'. The main goal of the introduction of NIFTP category is to prevent overdiagnosis and overtreatment. Sampling constraints, especially when dealing with heterogeneous and/or large nodules, and difficulties in the invasiveness evaluation, are the major weaknesses of the histological characterization of NIFTP. At the cytological level, NIFTP can be separated from classic papillary carcinoma (cPTC) but not from encapsulated, invasive follicular variant PTC. The impact of NIFTP individualization for cytopathology is the drop of rates of malignancy for each Bethesda category in general and for indeterminate categories in particular. The biggest impact will be seen in institutions with a high frequency of FVPTC. The introduction of NIFTP has changed the utility of predictive values of molecular tests because RAS mutations and PAX8-PPARg rearrangements are frequently detected in NIFTP. This turns less promising the application of mutation detection panels as indicators of malignancy and will probably contribute to switch to a rule-out approach of molecular testing. Selection for surgery will go on being determined by a combined detection of clinical, cytological and ultrasound suspicious features.

Dopaminergic Disturbances in Tourette Syndrome: An Integrative Account.

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.