© 2016-2020, Kevin J. Black. This work is licensed under a Creative Commons Attribution 4.0 International License.

© 2016, Kevin J. Black. This work is licensed under a Creative Commons Attribution 4.0 International License.

Many (though not all) of my patients who have tried marijuana have felt that their tics improved after using it. Such self-treatment is not rare (poster P94 here), and other doctors report similar results (see for example poster P6 here). Pharmacological benefits from cannabis products are plausible, since cannabinoid receptors in the brain's basal ganglia are well positioned to affect movement . Of course, in addition to any real benefit from marijuana, there could be expectation effects, or one could simply care less about tics when high. Random allocation clinical trials with blind rating of benefit (RCTs) are essential to demonstrating whether marijuana has any true benefit for tics. Müller-Vahl and colleagues carried out two RCTs about 15 years ago in Tourette syndrome (TS) using THC (tetrahydrocannabinol), the main intoxicating ingredient in cannabis . Both trials showed benefit, but the trials were relatively small. Two to 3 years ago, the Tourette Association of America funded two pilot studies in this field, but results have not yet been reported. One trial, at Yale, was to study the FAAH (fatty acid amide hydrolase) inhibitor PF-04457845 in TS , but the trial was placed on clinical hold pending results from a different trial. Investigators at Toronto Western Hospital were funded for a trial in TS of medical cannabis products with varying concentrations of THC and cannabidiol . Cannabidiol is being studied in several brain disorders, including epilepsy, with hopes that it may provide benefit without the psychological side effects of THC. Not surprisingly, the paucity of data has led to different viewpoints. Müller-Vahl has argued that THC may be appropriate in some TS patients , whereas an American Academy of Neurology review and a Cochrane-style review in JAMA concluded that the evidence was insufficient to recommend THC for tic disorders . The clinical utility of cannabinoids in TS was one of two clinical controversies debated at the 2015 First World Congress on Tourette Syndrome and Tic Disorders .

This article presents highlights chosen from research that appeared during 2016 on Tourette syndrome and other tic disorders. Selected articles felt to represent meaningful advances in the field are briefly summarized.

Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting to quantify the effects of intentional tic suppression in Tourette syndrome. The present article describes a Java program that automates record keeping and reward dispensing during the several experimental conditions of the TSP. The software optionally can be connected to a commercial reward token dispenser to further automate reward delivery to the participant. The timing of all tics, 10-second tic-free intervals, and dispensed rewards is recorded in plain text files for later analysis. Expected applications include research on Tourette syndrome and related disorders.

IntroductionA colleague recently proposed submitting an article about work to which my lab had contributed to the journal Neurology. I said, Neurology is a fine journal—some of my favorite authors have published there (smile)—but, like many traditional journals, they don't allow authors to re-use their own words for future book chapters. That's true even if a pre-publication version ends up later on PubMed Central. At least, they don't allow this without their deciding whether to deign to grant permission in each case. It may surprise you to know that many traditional / "hybrid" journals that tout an Open Access option—usually an expensive one—allow only a noncommercial license (like the CC BY-NC license). That sounds fine until you learn that adapting your own words to contribute to a book or to a site like eMedicine counts as commercial use! Personally, in an age in which the "Paper User Interface" is almost obsolete, and I almost always find papers from PubMed or Google, giving my rights away to a journal (by copyright transfer or an exclusive license to publish) is just ridiculous.I replied to my colleague suggesting she submit instead to a journal that allowed the authors to re-use their own words freely (as with the CC BY license), and went on to explain other benefits of fully open access publishing. I've discussed some of these advantages elsewhere \cite{25580234}. She replied, "I'm curious to know how publishing in these open access platforms has been received by your department? There's a clear message in mine that they want to see pubs in journals with good impact factors, especially for promotion consideration." This is a reasonable concern, of course, and a common one, and I acknowledged that at my career stage the pressure is not on me to the same extent. But I gave her some thoughts anyway, and then I realized that others might find them interesting. So here they are.The real answerThe real answer is for leaders to judge papers (much less faculty) on different metrics. The JIF was never meant to grade the quality of an individual paper, and it does it poorly. Even collectively, higher impact factor journals are more likely to publish articles that are retracted than are lower impact factor journals (among other reasons, think about this: “novel” results imply a lower prior probability of truth). Besides, if by impact you mean total number of citations, some OA journals are way in front (e.g. Frontiers in Psychology is the most cited multidisciplinary psychology journal in the world, and there have been something over 200,000 citations to articles in PLOS ONE).Being down on the journal impact factor (JIF) is not just my opinion. You can listen to some Nobel laureates criticizing it here.Some young scientists are adopting an open-only policy and let the chips fall where they may, and several of these scientists have been quite successful. In the meantime . . .But in the meantime, here are some options for those in my colleague's position. First, there are open access  journals with a high JIF. Here is a short list of a few open access journals I've published in or considered, to show the wide range of JIFs for journals that allow authors to keep their rights:

Early in the course of Parkinson disease (PD), treatment usually goes well. However, after five to ten years, things start to change as treatment requires higher doses of medications and side effects become more problematic. One of the most difficult problems is the development of hallucinations or delusions. Throughout the 20th century, treatment options were unproven and unsatisfactory, but the past 20 years have brought important changes. Two medications that are well tolerated in PD have now proved efficacious in randomized, controlled trials, and others are in development. Here I summarize this history briefly and provide a general plan for treating the patient with PD complicated by psychotic symptoms.

Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson’s disease (PD). Levodopa is the precursor for dopamine, and intravenous dopamine would strongly affect vascular tone, but peripheral decarboxylase inhibitors are intended to block such effects. Pulse and blood pressure, with orthostatic changes, were recorded before and after intravenous levodopa or placebo—after oral carbidopa—in 13 adults with a chronic tic disorder and 16 tic-free adult control subjects. Levodopa caused no statistically or clinically significant changes in blood pressure or pulse. These data add to previous data that support the safety of i.v. levodopa when given with adequate peripheral inhibition of DOPA decarboxylase.

ABSTRACT OBJECTIVE: To compile a comprehensive summary of published human experience with levodopa given intravenously, with a focus on information required by regulatory agencies. BACKGROUND: While safe intravenous use of levodopa has been documented for over 50 years, regulatory supervision for pharmaceuticals given by a route other than that approved by the U.S. Food and Drug Administration (FDA) has become increasingly cautious. If delivering a drug by an alternate route raises the risk of adverse events, an investigational new drug (IND) application is required, including a comprehensive review of toxicity data. METHODS: Over 200 articles referring to intravenous levodopa (IVLD) were examined for details of administration, pharmacokinetics, benefit and side effects. RESULTS: We identified 144 original reports describing IVLD use in humans, beginning with psychiatric research in 1959-1960 before the development of peripheral decarboxylase inhibitors. At least 2781 subjects have received IVLD, and reported outcomes include parkinsonian signs, sleep variables, hormones, hemodynamics, CSF amino acid composition, regional cerebral blood flow, cognition, perception and complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy subjects and 190 with Parkinson disease. Side effects were those expected from clinical experience with oral levodopa and dopamine agonists. No articles reported deaths or induction of psychosis. CONCLUSION: At least 2781 patients have received i.v. levodopa with a safety profile comparable to that seen with oral administration.

We present selected highlights from research that appeared during 2015 on Tourette syndrome and other tic disorders. Topics include phenomenology, comorbidities, developmental course, genetics, animal models, neuroimaging, electrophysiology, pharmacology, and treatment. We briefly summarize articles whose results we believe may lead to new treatments, additional research or modifications in current models of TS.

BACKGROUND AND THEORY The use of non-invasive brain stimulation for the treatment of various neuropsychiatric disorders, including major depressive disorder (MDD), has rapidly expanded recently. Transcranial direct current electrical stimulation (tDCS), variants of which have been used experimentally for psychiatric , neurologic , and physical rehabilitation applications, has garnered a great deal of attention. While it is not yet FDA-approved for any indication, its promise is related to its low cost and wide range of applications; although the breadth of its applicability has been questioned due to heterogeneous data , this heterogeneity has been attributed to methodological variability . The safety and tolerability of tDCS were outlined by an early study including 567 sessions in 102 patients. The most common adverse effects were mild tingling/itching at the stimulation site and moderate fatigue. Less frequent effects included headaches (11.8%), nausea (2.9%), and insomnia (0.98%), all of which were mild and transient . The underlying theory is that tDCS modulates the excitability of certain cortical regions by passage of a small electrical current through conducting pads applied to the scalp in a minimally painful manner. While the precise mechanism is not fully understood, it likely enhances cortical excitability at the anode and depresses it at the cathode . Proposed mechanisms have been based on data demonstrating relationships between tDCS stimulation and neuropharmacologic effects, cortical electrophysiology, and functional neuroimaging changes. Effects of tDCS on neuroplasticity and cortical excitability have been shown to be differentially modulated by agents affecting neurotransmission via serotonin (citalopram), dopamine (L-dopa), NMDA (dextromethorphan and d-cycloserine), and GABA (lorazepam). Electrophysiologic changes include differential modulation in the presence of agents that modulate sodium channels (carbamazepine) and calcium channels (flunarizine) . Active tDCS shows significant increases in prefrontal cortex activity as measured by functional near infrared spectroscopy (fNIRS), a technique used to measure cortical oxygenation, during and after stimulation – notably, fNIRS measurements may be limited by interference due extracranial blood flow and inability to assess deeper structures, so they merely approximate the functional magnetic resonance imaging (fMRI) signal in superficial structures . Stimulation also increases fMRI activation and connectivity of the underlying cortical regions and hippocampi, though the clinical significance of this is uncertain given that this same study found no behavioral changes .

ABSTRACT OBJECTIVE: We investigated the utility of the Temperament and Character Inventory (TCI) in predicting antidepressant response to rTMS. BACKGROUND: Although rTMS of the dorsolateral prefrontal cortex (DLPFC) is an established antidepressant treatment, little is known about predictors of response. The TCI measures multiple personality dimensions (harm avoidance, novelty seeking, reward dependence, persistence, self-directedness, self-transcendence, and cooperativeness), some of which have predicted response to antidepressants and cognitive-behavioral therapy. A previous study suggested a possible association between higher self-directedness and rTMS response specifically in melancholic depression, although this was limited by the fact that melancholic depression is associated with a limited range of TCI profiles. METHODS: Sixteen patients in a major depressive episode completed a TCI prior to a clinical course of rTMS over the DLPFC. Treatment response was defined as ≥50% decrease in Hamilton Depression Rating Scale (HDRS). Baseline scores on each TCI dimension were compared between responders and non-responders via paired t-test with Bonferroni correction. Temperament/character scores were also subjected to regression analysis against percentage improvement in HDRS. RESULTS: Ten of the sixteen patients responded to rTMS. T-scores for Persistence were significantly higher in responders (48.3, 95% CI 40.9-55.7) than in non-responders (35.3, 95% CI 29.2-39.9) (p=0.006). Linear regression revealed a correlation between persistence score and percentage improvement in HRDS (R=0.65±0.29). CONCLUSIONS: Higher persistence predicted antidepressant response to rTMS. This may be explained by rTMS-induced enhancement of cortical excitability, which has been found to be decreased in patients with high persistence. Personality assessment that includes measurement of TCI persistence may be a useful component of precision medicine initiatives in rTMS for depression.

Copyright © 2017-2018, the authors.Abstract This is the fourth yearly article in the Tourette syndrome Research Highlights series, summarizing research from 2017 relevant to Tourette syndrome (TS) and other tic disorders. The authors briefly summarize reports they consider most important or interesting. The highlights from 2018 article is being drafted on the Authorea online authoring platform, and readers are encouraged to add references or give feedback on our selections using the comments feature on that page. After the calendar year ends, the article is submitted as the annual update for the Tics collection on F1000Research.  Introduction This article is meant to disseminate recent scientific progress on Gilles de la Tourette Syndrome (TS). MethodsWe searched PubMed from time to time during 2017 using the search strategy “("Tic Disorders"[MeSH] OR Tourette NOT Tourette[AU]) AND 2017[PDAT] NOT 1950:2016[PDAT]”. On 06 July 2018 this search returned 212 citations. Colleagues also recommended articles, and we attended selected medical conferences. We selected material to be discussed in this review subjectively, guided by our judgment of possible future impact on the field.Results 

We present here a work in progress, summarizing research from 2017 relevant to Tourette syndrome. This working draft aims towards a preprint that we plan to submit for publication around the end of 2017. The authors briefly summarize a few reports they consider most important or interesting, and provide links to others. We welcome article suggestions and thoughtful FEEDBACK FROM READERS, who can comment using the text balloon icons that appear if you hover the mouse pointer over the upper right edge of each section of the article.

A central problem in convex algebra is the extension of left-smooth functions. Let \( \) be a combinatorially right-multiplicative, ordered, standard function. We show that \( {}_{I,\Lambda}} \ni {}}_{},}} \) and that there exists a Taylor and positive definite sub-algebraically projective triangle. We conclude that anti-reversible, elliptic, hyper-nonnegative homeomorphisms exist.

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A TITILLATING TITLE (AT LEAST FOR DOCTORS AND TIC RESEARCHERS) Adult-onset tics are rare, and usually secondary (_i.e._ due to some other neurological insult). However, there must be exceptions, and they are of interest both to patients and for understanding what factors cause tics and modify their course. I am aware of at least one study with relevant information. A multicenter German family study of Tourette syndrome and OCD found that 5 relatives were convinced that tics started between ages 21 and 25 . Their symptoms and course were in other ways typical of TS. Of course some could have had childhood tics that were not noticed at the time, but alternatively, there is no strong reason to expect that a tic disorder starting at age 22 is so very different from a tic disorder starting at age 17. Today the journal TREMOR AND OTHER HYPERKINETIC MOVEMENTS shows on its main page, under "in press," this new article: "How much do we know about adult-onset primary tics? Prevalence, epidemiology, and clinical features," by Yale's Daphne Robakis. Their group previously reported the more common occurrence of tic exacerbation during adulthood . The new article is not yet live, but I am eager to read it when it is published. TREMOR claims an average time from acceptance to publication of about 3 weeks, so hopefully the wait will be short.