Physiological and introspective antecedents of tics and movements in adults with tic disorders.

OBJECTIVE: To investigate the subjective phenomenon and the neural underpinnings of tics compared with voluntary movements in patients with tic disorders. METHODS: We recorded electroencephalographic and electromyographic data while subjects completed a Libet clock paradigm. Patients and healthy volunteers reported the times of W (willing to move) and M (movement occurrence) while performing voluntary movements. This was repeated only for the patients for the tics. RESULTS: In the patients, W and M times preceding voluntary movements and tics did not significantly differ from voluntary movements of healthy volunteers. The Bereitschaftspotentials in the patients were similar to healthy volunteers. Tics were only assessable for 7 patients due to artifacts. Two subjects did not show Bereitschaftspotentials, and they reported the lowest levels of tic voluntariness. 5 subjects did not show beta band event-related desynchronization before tics. CONCLUSIONS: For patients, the sense of volition for tics is similar to that of their voluntary movements which is similar to normal. Patients showed dissociations between the Bereitschaftspotential and beta desynchronization for tics, with 5/7 showing normal Bereitschaftspotentials and 2/7 showing desynchronization. The absence of desynchronization may suggest attempts to suppress tics. SIGNIFICANCE: This physiology shows a difference for most tics compared with normal movements.

A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease.

A randomized thorough QT study was conducted to assess the effects of apomorphine sublingual film (SL-APO) on corrected QT interval (QTc) and other cardiac conduction parameters in patients with Parkinson's disease (PD) and "OFF" episodes. Patients were titrated to an SL-APO dose that resulted in FULL "ON," followed by up to two additional doses (maximum 60 mg), then randomized at the highest tolerated dose to a treatment sequence of SL-APO, placebo, and moxifloxacin (400 mg, positive control) in a three-way crossover design. Changes from baseline in time-matched, placebo-adjusted Fridericia-corrected QTc interval (ΔΔQTcF) and Bazett-corrected QTc interval (ΔΔQTcB) were analyzed from postdose electrocardiograms. Forty patients were randomized and received single doses of study treatments. Upper limits of 90% confidence intervals (CIs) for ΔΔQTcF of SL-APO were below the 10-millisecond regulatory threshold at all prespecified timepoints, demonstrating no clinically significant effect on QTcF. Lower limits of 90% CIs for ΔΔQTcF of moxifloxacin exceeded the 5-millisecond regulatory threshold at all timepoints up to 3 hours, confirming assay sensitivity. SL-APO had no clinically meaningful effects on QTcB, PR/QRS intervals, heart rate, or electrocardiogram-derived morphology (EudraCT identifier: 2016-001762-29; ClinicalTrials.gov identifier: NCT03187301).

Dose optimization of apomorphine sublingual film for treating "OFF" episodes in Parkinson's disease.

INTRODUCTION: Apomorphine sublingual film is approved for the "on-demand" treatment of "OFF" episodes in Parkinson's disease (PD). Patients must undergo dose titration to determine their most effective and tolerable dose. We assessed whether higher doses than those that provide an initial "ON" response could yield more effective treatment. METHODS: Patients with PD were assessed in the "OFF" state and the apomorphine sublingual film dose was titrated to a level that provided a tolerable "ON" response. The dose was then increased by up to two dose levels, if tolerated. A comparison in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores was made following administration of the dose that provided the initial "ON" response and following the higher dose. Treatment-emergent adverse events were also reported. RESULTS: Thirty-five patients were titrated to higher apomorphine sublingual film doses than those that provided an initial "ON" response. A mean improvement in MDS-UPDRS Part III score was observed compared with the initial dose of 5.6 points (P = 0.034), 4.4 points (P = 0.009), and 3.7 points (P = 0.018) at 30, 60, and 90 min postdose, respectively. Adverse events were mild or moderate and resolved with dose reduction without concomitant treatment. CONCLUSION: Higher doses of apomorphine sublingual film than those initially perceived to provide an "ON" response can be tolerated and provide additional improvement in motor function in many patients.

Timing of the Sense of Volition in Patients With Schizophrenia.

Schizophrenic patients often do not have the sense that they direct their own movements or author their own thoughts (passivity phenomena). As willing must precede movement to be causal and thus generate the sense of agency, it is possible that the timing between the senses of willing and movement is shortened in schizophrenia. We tested the subjective perception of this time interval in patients with schizophrenia using a method based on Libet's paradigm, in which subjects specify a time W - the time of willing a movement - and a time M - the time that movement occurred. Patients with schizophrenia and healthy volunteers made voluntary movements at times of their own choice while looking at a fast-rotating clock on a computer screen and reported when their movements were willed and made. We recorded surface electromyography to determine the time of actual movement, and electroencephalography to record brain potentials associated with movement. Results showed a significantly reduced interval between the reported M and W in patients with respect to the healthy volunteers (p < 0.05). Specifically, patients did not report a significant difference in the timing of W at 19 ms prior to movement onset and M at 7.4 ms prior to movement onset (p > 0.05), while the control group experienced a time W at 100 ms prior to movement onset and this differed significantly from their time M at 19 ms prior to movement onset (p < 0.01). These results suggest that patients with schizophrenia do have an altered timing of awareness of action - or an impaired judgment of the sequence of events - and that this might be etiologic in the development of the abnormal sense of agency.

Prospective Home-use Study on Non-invasive Neuromodulation Therapy for Essential Tremor.

Highlights: This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients. Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use. Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey. Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TETRAS) and 68% (BF-ADL) of 'severe' or 'moderate' patients improving to 'mild' or 'slight'. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported. Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients.

Blepharospasm: A genetic screening study in 132 patients.

INTRODUCTION: Blepharospasm is a common type of focal dystonia that involves involuntary eyelid spasms and eye closure. In familial cases, an autosomal dominant pattern of inheritance is noted with reduced penetrance. Few genes have been associated with the disease including GNAL and CIZ1. A whole exome sequencing study published lately suggested TOR2A and REEP4 as potential candidate genes. METHODS: Sanger sequencing of GNAL, CIZ1, TOR2A and REEP4 exons including exon-intron boundaries in 132 patients diagnosed primarily with blepharospasm and/or Meige's syndrome. RESULTS: All variants detected in GNAL, CIZ1 and TOR2A seem to be benign. Sequencing of REEP4 revealed the presence of two nonsynonymous SNVs, one potential splice site variant and one indel all predicted to be damaging by in silico algorithms. CONCLUSION: Sequencing REEP4 in larger blepharospasm cohorts and functional studies will need to be performed to further elucidate the association between REEP4 and the disease.

Estradiol-Induced Potentiation of Dopamine Release in Dorsal Striatum Following Amphetamine Administration Requires Estradiol Receptors and mGlu5.

Estradiol potentiates behavioral sensitization to cocaine as well as self-administration of cocaine and other drugs of abuse in female rodents. Furthermore, stimulated dopamine (DA) in the dorsolateral striatum (DLS) is rapidly enhanced by estradiol, and it is hypothesized that this enhanced DA release mediates the more rapid escalation of drug taking seen in females, compared with males. The mechanisms mediating the effect of estradiol to enhance stimulated DA release were investigated in this study. Using in vivo microdialysis and high performance liquid chromatography coupled with electrochemical detection, we first examined the effect of estradiol on amphetamine-induced DA increase in the DLS of ovariectomized rats. We then tested whether the potentiation of this DA increase could be blocked by the estradiol receptor antagonist, ICI 182,780 (ICI), or an antagonist to the metabotropic glutamate receptor subtype 5 (mGlu5), 2-methyl-6-(phenylethynyl)pyridine (MPEP). There is evidence that estradiol receptors collaborate with mGlu5 within caveoli in DLS and mGlu5 is hypothesized to mediate many of the effects of estradiol in the addiction processes in females. Our data show that estradiol enhances the DA response to amphetamine. Either ICI or MPEP prevented the effect of estradiol to enhance DA release. Importantly, our results also showed that neither ICI or MPEP alone is able to influence the DA response to amphetamine when estradiol is not administrated, suggesting that ICI and MPEP act via estradiol receptors. Together, our findings demonstrate that estradiol potentiates amphetamine-stimulated DA release in the DLS and this effect requires both estradiol receptors and mGlu5.

Auditory and Lower Limb Tactile Prepulse Inhibition in Primary Restless Legs Syndrome: Clues to Its Pathophysiology.

The resting sensory discomfort transiently relieved upon movement of the affected area in restless legs syndrome suggests that sensorimotor integration mechanisms, specifically gating, may be altered in the disease. The authors sought to determine the effects of prepulse auditory and tactile stimulation applied to lower limbs on the blink reflex of patients with restless legs syndrome and healthy subjects. Seventeen patients with restless legs syndrome and 17 age- and sex-matched healthy controls were investigated. Auditory stimuli and tactile lower limb stimulation were applied as prepulses. The R2 response of the blink reflex induced by electrical stimulation applied to the right supraorbital nerve was selected as the test stimulus. Time intervals between prepulses and response-eliciting stimuli were 40, 70, 90, 110, and 200 milliseconds. There were no differences in either the auditory or tactile prepulse conditions between patients and controls and no differences between these measures within subject groups. We concluded that the tactile lower limb and the auditory prepulse effects on the brainstem interneurons mediating the blink reflex share common neural pathways. Because forebrain interneurons mediate these prepulse effects, they are likely not involved in the disordered sensorimotor interaction of restless legs syndrome.

Estradiol acts during a post-pubertal sensitive period to shorten free-running circadian period in male Octodon degus.

The free-running circadian period is approximately 30 min shorter in adult male than in adult female Octodon degus. The sex difference emerges after puberty, resulting from a shortened free-running circadian period in males. Castration before puberty prevents the emergence of the sex difference, but it is not a function of circulating gonadal hormones as such, because castration later in life does not affect free-running circadian period. The aim of this study was to determine whether or not the shortening of the free-running circadian period in male degus results from exposure to gonadal hormones after puberty. We hypothesized that masculinization of the circadian period results from an organizational effect of androgen exposure during a post-pubertal sensitive period. Male degus were castrated before puberty and implanted with capsules filled with dihydrotestosterone (DHT), 17ß-estradiol (E2) or empty capsules at one of three ages: peri-puberty (2-7 months), post-puberty (7-12 months), or adulthood (14-19 months). Long-term exposure to DHT or E2 did not result in a shortened free-running circadian period when administered at 2-7 or 14-19 months of age. However, E2 treatment from 7 to 12 months of age decreased the free-running circadian period in castrated males. This result was replicated in a subsequent experiment in which E2 treatment was limited to 8-12 months of age. E2 treatment at 7-12 months of age had no effect on the free-running circadian period in ovariectomized females. Thus, there appears to be a post-pubertal sensitive period for sexual differentiation of the circadian system of degus, during which E2 exposure decreases the free-running circadian period in males. These data demonstrate that gonadal hormones can act during adolescent development to permanently alter the circadian system.

Role of gonadal hormones on mu-opioid-stimulated [³5S]GTPγS binding and morphine-mediated antinociception in male and female Sprague-Dawley rats.

RATIONALE: Male rats are more sensitive to morphine-mediated antinociception than female rats. A role for gonadal hormones in this sex difference has not been clearly defined. OBJECTIVES: To test the hypothesis that in vivo manipulation of gonadal hormones alters morphine-mediated G protein activation and leads to changes in morphine-mediated antinociception. METHODS: Adult male and female rats were gonadectomized and treated with either estradiol or testosterone in the females or testosterone in the male for up to 10 days. The ability of morphine and the peptidic mu-opioid agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) to stimulate [(35)S]GTPγS binding was measured in brain slices. In separate groups of identically treated rats, the antinociceptive response to morphine was determined using the warm-water tail-withdrawal assay. RESULTS: In the thalamus, morphine- and DAMGO-stimulated [(35)S]GTPγS binding was reduced by estradiol treatment of gonadectomized females compared to gonadectomized females treated with vehicle or testosterone. In the nucleus accumbens, the morphine-stimulated [(35)S]GTPγS binding was increased by estradiol treatment of gonadectomized females. In males, castration caused an increase in agonist-stimulated binding in the thalamus and a reduction in the amygdala compared with intact males. No significant changes were seen in mu-opioid agonist-stimulated [(35)S]GTPγS binding in other brain regions. There was no difference in antinociception following the systemic administration of morphine across the different hormonal manipulation conditions and the greater sensitivity of males was maintained irrespective of the treatment conditions. CONCLUSIONS: The modulation of mu-opioid receptor activation of G proteins by manipulation of sex hormones is region-specific and not reflected in antinociceptive responsiveness to morphine.

Changes in circadian rhythms during puberty in Rattus norvegicus: developmental time course and gonadal dependency.

During puberty, humans develop a later chronotype, exhibiting a phase-delayed daily rest/activity rhythm. The purpose of this study was to determine: 1) whether similar changes in chronotype occur during puberty in a laboratory rodent species, 2) whether these changes are due to pubertal hormones affecting the circadian timekeeping system. We tracked the phasing and distribution of wheel-running activity rhythms during post-weaning development in rats that were gonadectomized before puberty or left intact. We found that intact peripubertal rats had activity rhythms that were phase-delayed relative to adults. Young rats also exhibited a bimodal nocturnal activity distribution. As puberty progressed, bimodality diminished and late-night activity phase-advanced until it consolidated with early-night activity. By late puberty, intact rats showed a strong, unimodal rhythm that peaked at the beginning of the night. These pubertal changes in circadian phase were more pronounced in males than females. Increases in gonadal hormones during puberty partially accounted for these changes, as rats that were gonadectomized before puberty demonstrated smaller phase changes than intact rats and maintained ultradian rhythms into adulthood. We investigated the role of photic entrainment by comparing circadian development under constant and entrained conditions. We found that the period (τ) of free-running rhythms developed sex differences during puberty. These changes in τ did not account for pubertal changes in entrained circadian phase, as the consolidation of activity at the beginning of the subjective night persisted under constant conditions in both sexes. We conclude that the circadian system continues to develop in a hormone-sensitive manner during puberty.

Psychogenic movement disorders.

Psychogenic movement disorders (PMDs) represent a challenging dilemma for the treating neurologist. The terminology to classify this disorder is confusing and making the diagnosis is difficult. Once the diagnosis has been established, treatment options are limited, and the patient generally does not accept the diagnosis.

The TOR1A polymorphism rs1182 and the risk of spread in primary blepharospasm.

We studied the influence of the rs1182 polymorphism of the TOR1A gene on the risk of dystonia spread in two representative cohorts of patients presenting with primary blepharospasm (BSP), one from Italy and the other from the United States of America. The relationship between rs1182 polymorphism and spread was estimated by Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted by age and sex, age of BSP onset. In both series, patients carrying the T allele (G/T or T/T) in the rs1182 polymorphism were more likely to have dystonia spread as compared with the homozygous carriers of the common G allele. The comparable findings obtained in two independent cohorts support a genetic contribution to BSP spread.

Essential tremor, deceptively simple....

The diagnosis and management of essential tremor appears deceptively simple. However, isolated mild tremor may be difficult to classify, and if the patients have any additional features the diagnosis is more difficult. Management can be challenging, despite the numerous treatments available, because so many patients are not benefited adequately and some not at all. However, as we gain a better understanding of the disorder, more effective therapies with fewer adverse effects are sure to follow.

Assessing the role of DRD5 and DYT1 in two different case-control series with primary blepharospasm.

Primary blepharospasm is a common adult-onset focal dystonia. Polymorphisms of the genes encoding TorsinA (DYT1) and the D5 dopamine receptor (DRD5) have previously been associated with lifetime risk for focal dystonia. We describe here experiments testing common variability within these two genes in two independent cohorts of Italian and North American patients with primary blepharospasm. We have failed to identify a consistent association with disease in the two patient groups examined here; however, analysis of the Italian group reveals an association with the same risk genotype in DYT1 as previously described in an Icelandic population. We have also found global significant DYT1 haplotype differences between patients and controls in the Italian series. These data suggest that further examination is warranted of the role genetic variability at this locus plays in the risk for primary dystonia.

Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals.

The recent hapmap effort has placed focus on the application of genome-wide SNP analysis to assess the contribution of genetic variability, particularly SNPs, to traits such as disease. Here, we describe the utility of genome-wide SNP analysis in the direct detection of extended homozygosity and structural genomic variation. We use this approach to assess the frequency of genomic alterations resulting from the lymphoblast immortalization and culture processes commonly used in cell repositories. We have assayed 408 804 SNPs in 276 DNA samples extracted from Epstein-Barr virus immortalized cell lines, which were derived from lymphocytes of elderly neurologically normal subjects. These data reveal extended homozygosity (contiguous tracts >5 Mb) in 9.5% (26/272) and 340 structural genomic alterations in 182 (66.9%) DNA samples assessed, 66% of which did not overlap with previously described structural variations. Examination of DNA extracted directly from the blood of 30 of these subjects confirmed all examined instances of extended homozygosity (6/6), 75% of structural genomic alteration <5 Mb in size (12/16) and 13% (1/8) of structural genomic alteration >5 Mb in size. These data suggest that structural genomic variation is a common phenomenon in the general population. While a proportion of this variability may be caused or its relative abundance altered by the immortalization and clonal process this will have only a minor effect on genotype and allele frequencies in a large cohort. It is likely that this powerful methodology will augment existing techniques in the identification of chromosomal abnormalities.

Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data.

BACKGROUND: Several genes underlying rare monogenic forms of Parkinson's disease have been identified over the past decade. Despite evidence for a role for genetics in sporadic Parkinson's disease, few common genetic variants have been unequivocally linked to this disorder. We sought to identify any common genetic variability exerting a large effect in risk for Parkinson's disease in a population cohort and to produce publicly available genome-wide genotype data that can be openly mined by interested researchers and readily augmented by genotyping of additional repository subjects. METHODS: We did genome-wide, single-nucleotide-polymorphism (SNP) genotyping of publicly available samples from a cohort of Parkinson's disease patients (n=267) and neurologically normal controls (n=270). More than 408,000 unique SNPs were used from the Illumina Infinium I and HumanHap300 assays. FINDINGS: We have produced around 220 million genotypes in 537 participants. This raw genotype data has been and as such is the first publicly accessible high-density SNP data outside of the International HapMap Project. We also provide here the results of genotype and allele association tests. INTERPRETATION: We generated publicly available genotype data for Parkinson's disease patients and controls so that these data can be mined and augmented by other researchers to identify common genetic variability that results in minor and moderate risk for disease.

Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats.

Male rats are more sensitive to the antinociceptive effects of morphine than female rats. This difference is seen across several rat strains using a variety of nociceptive stimuli. However, the literature in regard to sex differences in antinociceptive responses to mu-opioids other than morphine is less consistent. The present study was designed to examine whether there is a structure-activity rationale that determines which mu-opioids will show a differential antinociceptive response between male and female rats. A series of morphinans closely related in structure to morphine, namely, codeine, heroin, hydrocodone, hydromorphone, oxymorphone, and oxycodone, were examined for their antinociceptive activity in male and female Sprague-Dawley rats and compared with the structurally unrelated mu-opioid agonists methadone and fentanyl. Antinociception was measured by the warm-water tail-withdrawal assay. The results show that morphine is more potent in males compared with females > hydromorphone = hydrocodone = oxymorphone, but there was no observable sex difference in the antinociceptive potency of codeine, heroin, oxycodone, methadone, or fentanyl. The potency to stimulate guanosine 5'-O-(3-[35 S]thio)triphosphate ([35S]GTPgammaS) binding and binding affinity of the various morphinans was compared in rat glioma C6 cells expressing the rat mu-opioid receptor; relative efficacy was also compared by stimulation of [35S]GTPgammaS binding in slices of rat brain thalamus. The presence of a sex difference in antinociceptive responsiveness was not related to drug potency, efficacy, or affinity. Consequently, it is likely that differential metabolism of the opioid, possibly by glucuronidation, determines the presence or absence of a sex difference.

Comparison of the antinociceptive effect of acute morphine in female and male Sprague-Dawley rats using the long-lasting mu-antagonist methocinnamox.

Male rats are more sensitive than female rats to the antinociceptive action of morphine. The present study used age-matched (9-10 weeks old) male and female Sprague-Dawley rats to investigate whether this difference is due to variation in micro-opioid receptor binding and G protein activation. In the warm-water tail-withdrawal assay at both 50 degrees C and 55 degrees C, morphine was 2-3 times more potent in males than females. In contrast, micro-opioid receptor number and the binding affinity of the micro-opioid agonists morphine and DAMGO in membranes from whole brain, cortex, thalamus, and spinal cord were not different between males and females. Similarly, morphine and DAMGO stimulation of G protein, determined using GTPase and [(35)S]GTPgammaS binding assays, did not show a difference between the sexes. The long-lasting micro-opioid receptor antagonist methocinnamox (0.32 mg/kg), given 24 h prior to morphine, reduced micro-opioid receptor number by approximately 50% in thalamic and spinal cord tissue from female and male rats and reduced the antinociceptive potency of morphine. Pretreatment of male rats with 0.32 mg/kg methocinnamox reduced the antinociceptive potency of morphine to that observed in female rats expressing a full complement of micro-opioid receptors. However, with increasing pretreatment doses of methocinnamox, the maximal antinociceptive effect of morphine was decreased in females but not males. The results suggest that pathways downstream of the micro-opioid receptor and G protein are more efficient in male rats than in female rats such that there is a larger receptor reserve for morphine-mediated antinociception.