No Abuse Potential of Silexan in Healthy Recreational Drug Users: A Randomized Controlled Trial.

BACKGROUND: Silexan is a lavender essential oil with established anxiolytic and calming efficacy. Here we asked whether there is a potential for abuse in human patients. METHODS: We carried out a phase I abuse liability single-center, double-blind, 5-way crossover study in healthy users of recreational central nervous system depressants. They received single oral doses of 80 mg (therapeutic dose) and 640 mg Silexan, 2 mg and 4 mg lorazepam (active control) and placebo in randomized order, with 4- to 14-day washout periods between treatments. Pharmacodynamic measures included validated visual analogue scales assessing positive, negative, and sedative drug effects and balance of effects; a short form of the Addiction Research Center Inventory; and a drug similarity assessment. The primary outcome measure was the individual maximum value on the drug liking visual analogue scale during 24 hours post-dose. RESULTS: Forty participants were randomized and 34 were evaluable for pharmacodynamic outcomes. In intraindividual head-to-head comparisons of the drug liking visual analogue scale maximum value, both doses of Silexan were rated similar to placebo whereas differences were observed between Silexan and lorazepam and between placebo and lorazepam (P < .001). These data were supported by all secondary measures of positive drug effects and of balance of effects. Differences between placebo and both doses of Silexan were always negligible in magnitude. Moreover, Silexan showed no sedative effects and was not perceived to be similar to commonly used drugs that participants had used in the past. CONCLUSIONS: Silexan did not exhibit any abuse potential in a standard abuse potential detection screen study and is unlikely to be recreationally abused.

Benefits of Music Training for Perception of Emotional Speech Prosody in Deaf Children With Cochlear Implants.

OBJECTIVES: Children who use cochlear implants (CIs) have characteristic pitch processing deficits leading to impairments in music perception and in understanding emotional intention in spoken language. Music training for normal-hearing children has previously been shown to benefit perception of emotional prosody. The purpose of the present study was to assess whether deaf children who use CIs obtain similar benefits from music training. We hypothesized that music training would lead to gains in auditory processing and that these gains would transfer to emotional speech prosody perception. DESIGN: Study participants were 18 child CI users (ages 6 to 15). Participants received either 6 months of music training (i.e., individualized piano lessons) or 6 months of visual art training (i.e., individualized painting lessons). Measures of music perception and emotional speech prosody perception were obtained pre-, mid-, and post-training. The Montreal Battery for Evaluation of Musical Abilities was used to measure five different aspects of music perception (scale, contour, interval, rhythm, and incidental memory). The emotional speech prosody task required participants to identify the emotional intention of a semantically neutral sentence under audio-only and audiovisual conditions. RESULTS: Music training led to improved performance on tasks requiring the discrimination of melodic contour and rhythm, as well as incidental memory for melodies. These improvements were predominantly found from mid- to post-training. Critically, music training also improved emotional speech prosody perception. Music training was most advantageous in audio-only conditions. Art training did not lead to the same improvements. CONCLUSIONS: Music training can lead to improvements in perception of music and emotional speech prosody, and thus may be an effective supplementary technique for supporting auditory rehabilitation following cochlear implantation.

Oral Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users.

OBJECTIVES: A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the oral abuse potential and pharmacokinetics (PK) of HYD intact, chewed, or milled to fine particles in comparison with hydrocodone solution or placebo. DESIGN: Single-center, double-blind, randomized, five-period, five-treatment crossover study. SUBJECTS: Healthy adult, nondependent, recreational opioid users. METHODS: Forty subjects received orally administered treatments of hydrocodone 60 mg solution, HYD 60 mg intact, HYD 60 mg chewed, HYD 60 mg milled to fine particles, or placebo, separated by a five- to seven-day washout. Assessments over 36 hours postdose included subjective measures of drug liking and willingness to take drug again (assessed using visual analog scales [VAS]), pupillometry, PK, and safety measures. RESULTS: Following oral administration, HYD intact, HYD chewed, and HYD fine particles led to significantly lower "at this moment" drug liking compared with hydrocodone solution. HYD intact and chewed were significantly different from hydrocodone solution on overall drug liking, take drug again, and good effects. Pupil constriction, as measured by pupillometry, occurred later with HYD intact and HYD chewed than with hydrocodone solution. Across treatments (hydrocodone solution, HYD fine particles, HYD chewed, and HYD intact, respectively), mean C max and rate of absorption (C max /T max ) values decreased, respectively, and median T max values increased, respectively. Safety was consistent with the known effects of opioid agonists. CONCLUSION: HYD demonstrated reduced oral abuse potential compared with hydrocodone solution in healthy adult, nondependent, recreational opioid users.

Intranasal Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users.

OBJECTIVES: A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. DESIGN: Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. SUBJECTS: Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. METHODS: During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. RESULTS: Insufflation of both HYD coarse and fine particles led to lower "At this Moment" Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. CONCLUSIONS: HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder.

Emotions and their cognitive control in children with cerebellar tumors.

A constellation of deficits, termed the cerebellar cognitive affective syndrome (CCAS), has been reported following acquired cerebellar lesions. We studied emotion identification and the cognitive control of emotion in children treated for acquired tumors of the cerebellum. Participants were 37 children (7-16 years) treated for cerebellar tumors (19 benign astrocytomas (AST), 18 malignant medulloblastomas (MB), and 37 matched controls (CON). The Emotion Identification Task investigated recognition of happy and sad emotions in music. In two cognitive control tasks, we investigated whether children could identify emotion in situations in which the emotion in the music and the emotion in the lyrics was either congruent or incongruent. Children with cerebellar tumors identified emotion as accurately and quickly as controls (p > .05), although there was a significant interaction of emotions and group (p < .01), with the MB group performing less accurately identifying sad emotions, and both cerebellar tumor groups were impaired in the cognitive control of emotions (p < .01). The fact that childhood acquired cerebellar tumors disrupt cognitive control of emotion rather than emotion identification provides some support for a model of the CCAS as a disorder, not so much of emotion as of the regulation of emotion by cognition.

Perception of strong-meter and weak-meter rhythms in children with spina bifida meningomyelocele.

Neurodevelopmental disorders such as spina bifida meningomyelocele (SBM) are often associated with dysrhythmic movement. We studied rhythm discrimination in 21 children with SBM and in 21 age-matched controls, with the research question being whether both groups showed a strong-meter advantage whereby rhythm discrimination is better for rhythms with a strong-meter, in which onsets of longer intervals occurred on the beat, than those with a weak-meter, in which onsets of longer intervals occurred off the beat. Compared to controls, the SBM group was less able to discriminate strong-meter rhythms, although they performed comparably in discriminating weak-meter rhythms. The attenuated strong-meter advantage in children with SBM shows that their rhythm deficits occur at the level of both perception and action, and may represent a central processing disruption of the brain mechanisms for rhythm.

Music Perception Testing Reveals Advantages and Continued Challenges for Children Using Bilateral Cochlear Implants.

A modified version of the child's Montreal Battery of Evaluation of Amusia (cMBEA) was used to assess music perception in children using bilateral cochlear implants. Our overall aim was to promote better performance by children with CIs on the cMBEA by modifying the complement of instruments used in the test and adding pieces transposed in frequency. The 10 test trials played by piano were removed and two high and two low frequency trials added to each of five subtests (20 additional). The modified cMBEA was completed by 14 children using bilateral cochlear implants and 23 peers with normal hearing. Results were compared with performance on the original version of the cMBEA previously reported in groups of similar aged children: 2 groups with normal hearing (n = 23: Hopyan et al., 2012; n = 16: Polonenko et al., 2017), 1 group using bilateral cochlear implants (CIs) (n = 26: Polonenko et al., 2017), 1 group using bimodal (hearing aid and CI) devices (n = 8: Polonenko et al., 2017), and 1 group using unilateral CI (n = 23: Hopyan et al., 2012). Children with normal hearing had high scores on the modified version of the cMBEA and there were no significant score differences from children with normal hearing who completed the original cMBEA. Children with CIs showed no significant improvement in scores on the modified cMBEA compared to peers with CIs who completed the original version of the test. The group with bilateral CIs who completed the modified cMBEA showed a trend toward better abilities to remember music compared to children listening through a unilateral CI but effects were smaller than in previous cohorts of children with bilateral CIs and bimodal devices who completed the original cMBEA. Results confirmed that musical perception changes with the type of instrument and is better for music transposed to higher rather than lower frequencies for children with normal hearing but not for children using bilateral CIs. Overall, the modified version of the cMBEA revealed that modifications to music do not overcome the limitations of the CI to improve music perception for children.

Sad and happy emotion discrimination in music by children with cochlear implants.

Children using cochlear implants (CIs) develop speech perception but have difficulty perceiving complex acoustic signals. Mode and tempo are the two components used to recognize emotion in music. Based on CI limitations, we hypothesized children using CIs would have impaired perception of mode cues relative to their normal hearing peers and would rely more heavily on tempo cues to distinguish happy from sad music. Study participants were children with 13 right CIs and 3 left CIs (M = 12.7, SD = 2.6 years) and 16 normal hearing peers. Participants judged 96 brief piano excerpts from the classical genre as happy or sad in a forced-choice task. Music was randomly presented with alterations of transposed mode, tempo, or both. When music was presented in original form, children using CIs discriminated between happy and sad music with accuracy well above chance levels (87.5%) but significantly below those with normal hearing (98%). The CI group primarily used tempo cues, whereas normal hearing children relied more on mode cues. Transposing both mode and tempo cues in the same musical excerpt obliterated cues to emotion for both groups. Children using CIs showed significantly slower response times across all conditions. Children using CIs use tempo cues to discriminate happy versus sad music reflecting a very different hearing strategy than their normal hearing peers. Slower reaction times by children using CIs indicate that they found the task more difficult and support the possibility that they require different strategies to process emotion in music than normal.

Normal-like motor speech parameters measured in children with long-term cochlear implant experience using a novel objective analytic technique.

IMPORTANCE: Although voice has been studied extensively in children who use cochlear implants (CIs), speech production has not been studied in this population using the Motor Speech Profile. Whether children who receive CIs gain normal speech production abilities is unknown. OBJECTIVE: To assess speech and articulation in deaf, long-term CI users who had undergone early unilateral cochlear implantation, compared with their normal-hearing peers. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at a tertiary pediatric hospital of 16 children aged 8 to 17 years who had undergone early implantation, are longstanding users, and had excellent audiogram and speech perception scores. Results were compared with a historical pediatric normal-hearing group. INTERVENTION: Unilateral cochlear implantation. MAIN OUTCOMES AND MEASURES: The Motor Speech Profile, an objective method for assessing motor speech in children. RESULTS: The CI users had normal articulation and timing but poorer than normal intonation stimulability, particularly frequency variability. Diadochokinesis rates were within the 95% confidence interval of age-matched pediatric norms for 11 of 16 (69%) and 11 of 15 (73%) children with CI when they were performing /pa/ and /pataka/ tasks, respectively. The magnitude and rate of the second formant transitions were within normal limits for 9 of 16 (56%) and 10 of 12 (83%) children, respectively. The variability in frequency and amplitude of intonation stimulability domains were within normal limits for 7 of 16 (44%) and 16 of 16 (100%) children, respectively. The syllabic rate and duration were both within normal limits for 14 of 16 children (88%). CONCLUSIONS AND RELEVANCE: Despite significant improvements in speech after cochlear implantation, abnormalities remain, particularly in frequency variability. Such deviations can present as a decreased expression of emotion in speech and likely reflects decreased auditory frequency resolution provided by the CI. These deficits have been the focus of ongoing work to advance CI technologies and speech-processing strategies.

Children using cochlear implants capitalize on acoustical hearing for music perception.

Cochlear implants (CIs) electrically stimulate the auditory nerve providing children who are deaf with access to speech and music. Because of device limitations, it was hypothesized that children using CIs develop abnormal perception of musical cues. Perception of pitch and rhythm as well as memory for music was measured by the children's version of the Montreal Battery of Evaluation of Amusia (MBEA) in 23 unilateral CI users and 22 age-matched children with normal hearing. Children with CIs were less accurate than their normal hearing peers (p < 0.05). CI users were best able to discern rhythm changes (p < 0.01) and to remember musical pieces (p < 0.01). Contrary to expectations, abilities to hear cues in music improved as the age at implantation increased (p < 0.01). Because the children implanted at older ages also had better low frequency hearing prior to cochlear implantation and were able to use this hearing by wearing hearing aids. Access to early acoustical hearing in the lower frequency ranges appears to establish a base for music perception, which can be accessed with later electrical CI hearing.

Strong-meter and weak-meter rhythm identification in spina bifida meningomyelocele and volumetric parcellation of rhythm-relevant cerebellar regions.

Children with spina bifida meningomyelocele (SBM) are impaired relative to controls in terms of discriminating strong-meter and weak-meter rhythms, so congenital cerebellar dysmorphologies that affect rhythmic movements also disrupt rhythm perception. Cerebellar parcellations in children with SBM showed an abnormal configuration of volume fractions in cerebellar regions important for rhythm function: a smaller inferior-posterior lobe, and larger anterior and superior-posterior lobes.