Dopaminergic manipulations affect the modulation and meta-modulation of movement speed: Evidence from two pharmacological interventions.

A body of research implicates dopamine in the average speed of simple movements. However, naturalistic movements span a range of different shaped trajectories and rarely proceed at a single constant speed. Instead, speed is reduced when drawing "corners" compared to "straights" (i.e., speed modulation), and the extent of this slowing down is dependent upon the global shape of the movement trajectory (i.e., speed meta-modulation) - for example whether the shape is an ellipse or a rounded square. At present, it is not known how (or whether) dopaminergic function controls continuous changes in speed during movement execution. The current paper reports effects on these kinematic features of movement following two forms of dopamine manipulation: Study One highlights movement differences in individuals with PD both ON and OFF their dopaminergic medication (N = 32); Study Two highlights movement differences in individuals from the general population on haloperidol (a dopamine receptor blocker, or "antagonist") and placebo (N = 43). Evidence is presented implicating dopamine in speed, speed modulation and speed meta-modulation, whereby low dopamine conditions are associated with reductions in these variables. These findings move beyond vigour models implicating dopamine in average movement speed, and towards a conceptualisation that involves the modulation of speed as a function of contextual information.

Medication improves velocity, reaction time, and movement time but not amplitude or error during memory-guided reaching in Parkinson's disease.

The motor impairments experienced by people with Parkinson's disease (PD) are exacerbated during memory-guided movements. Despite this, the effect of antiparkinson medication on memory-guided movements has not been elucidated. We evaluated the effect of antiparkinson medication on motor control during a memory-guided reaching task with short and long retention delays in participants with PD and compared performance to age-matched healthy control (HC) participants. Thirty-two participants with PD completed the motor section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) and performed a memory-guided reaching task with two retention delays (0.5 s and 5 s) while on and off medication. Thirteen HC participants completed the MDS-UPDRS III and performed the memory-guided reaching task. In the task, medication increased movement velocity, decreased movement time, and decreased reaction time toward what was seen in the HC. However, movement amplitude and reaching error were unaffected by medication. Shorter retention delays increased movement velocity and amplitude, decreased movement time, and decreased error, but increased reaction times in the participants with PD and HC. Together, these results imply that antiparkinson medication is more effective at altering the neurophysiological mechanisms controlling movement velocity and reaction time compared with other aspects of movement control.

Electrophysiological predictors of early response to antidepressants in major depressive disorder.

BACKGROUND: Psychomotor retardation (PMR) is a core feature of major depressive disorder (MDD), which is characterized by abnormalities in motor control and cognitive processes. PMR in MDD can predict a poor antidepressant response, suggesting that PMR may serve as a marker of the antidepressant response. However, the neuropathological relationship between treatment outcomes and PMR remains uncertain. Thus, this study examined electrophysiological biomarkers associated with poor antidepressant response in MDD. METHODS: A total of 142 subjects were enrolled in this study, including 49 healthy controls (HCs) and 93 MDD patients. All participants performed a simple right-hand visuomotor task during magnetoencephalography (MEG) scanning. Patients who exhibited at least a 50 % reduction in disorder severity at the endpoint (>2 weeks) were considered to be responders. Motor-related beta desynchronization (MRBD) and inter- and intra-hemispheric functional connectivity were measured in the bilateral motor network. RESULTS: An increased MRBD and decreased inter- and intra-hemispheric functional connectivity in the motor network during movement were observed in non-responders, relative to responders and HCs. This dysregulation predicted the potential antidepressant response. CONCLUSION: Abnormal local activity and functional connectivity in the motor network indicate poor psychomotor function, which might cause insensitivity to antidepressant treatment. This could be regarded as a potential neural mechanism for the prediction of a patient's treatment response.

Acute methamphetamine and alcohol usage alters gaze behaviour during driving: A randomised, double-blind, placebo-controlled study.

BACKGROUND: Methamphetamine is frequently co-consumed with alcohol, yet combined effects on visually guided behaviours have not been experimentally assessed. This study examined whether methamphetamine and alcohol-induced changes in gaze behaviour can be accurately detected and indexed during a simulated driving task to establish characteristic patterns relevant to traffic safety. METHODS: In a randomised, placebo-controlled, cross-over study design, the effects of acute oral methamphetamine (0.42 mg/kg) were assessed with and without low doses of alcohol (target 0.04% blood alcohol content) on gaze behaviour during driving. Twenty healthy adults (mean age 29.5 years (SD ± 4.9), 40% female) completed four, 1-h simulated drives with simultaneous eye monitoring using the SensoMotoric Instruments cap-mounted eye tracker over a 4-week experimental paradigm. Gaze entropy measures were used to quantify visual scanning efficiency, expressed as gaze transition entropy and stationary gaze entropy. Fixations, recorded as duration (milliseconds, ms) and rate (count) per minute, were examined in 10-min bins over the duration of the drive. Driving performance was assessed by the standard deviation of lateral position, standard deviation of speed and steering variability. RESULTS: Methamphetamine increased the rate and duration of fixations and produced a less dispersed but more disorganised pattern of gaze during highway driving while preserving performance. Alcohol alone impaired both oculomotor control and driving performance, even when consumed at levels well below the legal limit stipulated in many international jurisdictions. CONCLUSIONS: Methamphetamine-affected drivers display inefficient exploration in a limited visual range during driving. Eye-tracking metrics thus show potential for indexing intoxication due to psychoactive substance usage.

The effect of experimentally induced sleep fragmentation and estradiol suppression on neurobehavioral performance and subjective sleepiness in premenopausal women.

STUDY OBJECTIVES: Menopause is associated with nighttime sleep fragmentation, declining estradiol, and impaired cognition. In a model of pharmacologically induced estradiol suppression mimicking menopause, we examined the impact of menopause-pattern sleep fragmentation on daytime neurobehavioral performance and sleepiness in premenopausal women. METHODS: Twenty premenopausal women completed two five-night inpatient studies in the mid-to-late follicular phase (estrogenized) and after pharmacological estradiol suppression (hypo-estrogenized). During each study, participants had an uninterrupted 8-hour sleep opportunity for two nights, followed by three nights where sleep was experimentally fragmented to mimic menopause-pattern sleep disturbance, and during which the sleep opportunity was extended to prevent shortening of the sleep duration. Neurobehavioral performance and subjective sleepiness were measured using the Psychomotor Vigilance Task and Karolinska Sleepiness Scale (KSS). RESULTS: Compared to unfragmented sleep, sleep fragmentation increased attentional lapses (+ 0.6 lapses, p < .05), slowed reaction time (+ 9.4 milliseconds, p < .01), and increased daytime sleepiness (+ 0.5 KSS score, p < .001). Estradiol suppression increased attentional lapses (+ 0.8; p < .001) and reaction time (+ 12.3, p < .01) but did not significantly affect daytime sleepiness. The effect of sleep fragmentation on neurobehavioral performance differed by estradiol state, such that the adverse effects of sleep fragmentation on attentional lapses (+ 0.9, trend p = .06) and reaction time (+ 15, p < .05) were observed only when estrogenized. CONCLUSIONS: Menopause-pattern sleep fragmentation and estradiol suppression worsened neurobehavioral performance and daytime sleepiness, even while sleep duration was not reduced. The adverse effects of sleep fragmentation in the context of an adequate sleep duration highlight the importance of sleep continuity as a vital aspect of good sleep health.

Evaluating possible 'next day' impairment in insomnia patients administered an oral medicinal cannabis product by night: a pilot randomized controlled trial.

Cannabis and its major constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being widely used to treat sleep disturbances. However, THC can cause acute cognitive and psychomotor impairment and there are concerns that driving and workplace safety might be compromised the day after evening use. Here, we examined possible 'next day' impairment following evening administration of a typical medicinal cannabis oil in adults with insomnia disorder, compared to matched placebo. This paper describes the secondary outcomes of a larger study investigating the effects of THC/CBD on insomnia disorder. Twenty adults [16 female; mean (SD) age, 46.1 (8.6) y] with physician-diagnosed insomnia who infrequently use cannabis completed two 24 h in-laboratory visits involving acute oral administration of combined 10 mg THC and 200 mg CBD ('THC/CBD') or placebo in a randomised, double-blind, crossover trial design. Outcome measures included 'next day' (≥9 h post-treatment) performance on cognitive and psychomotor function tasks, simulated driving performance, subjective drug effects, and mood. We found no differences in 'next day' performance on 27 out of 28 tests of cognitive and psychomotor function and simulated driving performance relative to placebo. THC/CBD produced a small decrease (-1.4%, p=.016, d=-0.6) in accuracy on the Stroop-Colour Task (easy/congruent) but not the Stroop-Word Task (hard/incongruent). THC/CBD also produced a small increase (+8.6, p=.042, d=0.3) in self-ratings of Sedated at 10 h post-treatment, but with no accompanying changes in subjective ratings of Alert or Sleepy (p's>0.05). In conclusion, we found a lack of notable 'next day' impairment to cognitive and psychomotor function and simulated driving performance following evening use of 10 mg oral THC, in combination with 200 mg CBD, in an insomnia population who infrequently use cannabis.

Cholinergic modulation of motor sequence learning.

The cholinergic system plays a key role in motor function, but whether pharmacological modulation of cholinergic activity affects motor sequence learning is unknown. The acetylcholine receptor antagonist biperiden, an established treatment in movement disorders, reduces attentional modulation, but whether it influences motor sequence learning is not clear. Using a randomized, double-blind placebo-controlled crossover design, we tested 30 healthy young participants and showed that biperiden impairs the ability to learn sequential finger movements, accompanied by widespread oscillatory broadband power changes (4-25 Hz) in the motor sequence learning network after receiving biperiden, with greater power in the theta, alpha and beta bands over ipsilateral motor and bilateral parietal-occipital areas. The reduced early theta power during a repeated compared with random sequence, likely reflecting disengagement of top-down attention to sensory processes, was disrupted by biperiden. Alpha synchronization during repeated sequences reflects sensory gating and lower visuospatial attention requirements compared with visuomotor responses to random sequences. After biperiden, alpha synchronization was greater, potentially reflecting excessive visuospatial attention reduction, affecting visuomotor responding required to enable sequence learning. Beta oscillations facilitate sequence learning by integrating visual and somatosensory inputs, stabilizing repeated sequences and promoting prediction of the next stimulus. The beta synchronization after biperiden fits with a disruption of the selective visuospatial attention enhancement associated with initial sequence learning. These findings highlight the role of cholinergic processes in motor sequence learning.

Guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance in Japan: A tiered approach for the assessment of clinically meaningful driving impairment.

In December 2022, the Ministry of Health, Labour and Welfare (MHLW) of Japan issued and implemented the guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance. This guideline recommends the use of a tiered approach to assess clinically meaningful driving impairment. It is noted that adverse events cannot be solely explained by pharmacokinetics, as the onset and duration of these events vary. Among these adverse events, those affecting alertness, such as drowsiness caused by psychotropic drugs on driving performance, are more frequently observed during initial treatment stages and dose escalation. Hence, when evaluating the effects of psychotropic drugs on driving performance, it becomes crucial to assess the persistence of clinically meaningful impairment. Therefore, the MHLW guideline, developed by the authors, emphasizes the need to assess the temporal profile of adverse events affecting driving in all clinical trials. Additionally, the guideline states that when conducting driving studies, the timing of multiple dosing should consider not only the pharmacokinetics of the investigational drug but also its tolerance.

Psychiatric symptoms, associated pharmacological treatments and cognitive function: A population-based study of men.

BACKGROUND: Psychiatric symptomatology and medications used in their treatment may be modifiable risk factors associated with cognitive function, although findings from population-based studies spanning the full adult age range are lacking. This study aimed to investigate associations between psychiatric symptomatology, psychotropic medication use and cognitive function in a population-based sample of men. METHODS: Data for 537 men were drawn from the Geelong Osteoporosis Study. Cognitive function (psychomotor function, attention, working memory and visual learning) was determined using the Cog-State Brief Battery. Current depressive and anxiety symptomatology was determined using the Hospital Anxiety and Depression Scale, and psychotropic medication use was self-reported. Linear regression models were developed to determine associations between psychiatric symptomatology and psychotropic medication use with each cognitive measure. RESULTS: Depressive symptomatology was associated with lower overall cognitive function (b-0.037 ± 0.010, η2 = 0.025, p < 0.001), psychomotor function (b 0.006 ± 0.002, η2 = 0.028 p < 0.001) and attention (b 0.004 ± 0.001, η2 = 0.021, p < 0.001), whereas psychotropic use was associated with lower overall cognitive function (b - 0.174 ± 0.075, η2 = 0.010, p = 0.021), attention (b 0.017 ± 0.008, η2 = 0.008, p = 0.038 and working memory (b 0.031 ± 0.012, η2 = 0.010, p = 0.010). Anticonvulsant use was associated with lower overall cognitive function (b - 0.723 ± 0.172, η2 = 0.032, p < 0.001), attention (b 0.065 ± 0.018, η2 = 0.029, p < 0.001) and working memory (b 0.088 ± 0.026, η2 = 0.022, p < 0.001). All relationships were found to have a small effect. There were no significant associations between anxiety symptomatology and antidepressant and anxiolytic use with any of the cognitive domains. CONCLUSION: Depressive symptomatology and anticonvulsant use were associated with lower cognitive function. Understanding the underlying mechanisms involved in these relationships can advance knowledge on the heterogeneity in cognitive ageing and aid in prevention initiatives.

The effects of pramipexole on motivational vigour during a saccade task: a placebo-controlled study in healthy adults.

Motivation allows us to energise actions when we expect reward and is reduced in depression. This effect, termed motivational vigour, has been proposed to rely on central dopamine, with dopaminergic agents showing promise in the treatment of depression. This suggests that dopaminergic agents might act to reduce depression by increasing the effects of reward or by helping energise actions. The aim of the current study was to investigate whether the dopamine agonist pramipexole enhanced motivational vigour during a rewarded saccade task. In addition, we asked whether the effects of pramipexole on vigour differ between reward contingent on performance and guaranteed reward. Healthy adult participants were randomised to receive either pramipexole (n = 19) or placebo (controls n = 18) for 18 days. The vigour of saccades was measured twice, once before the administration of study medication (Time 1) and after taking it for 12-15 days (Time 2). To separate motivation by contingency vs. reward, saccadic vigour was separately measured when (1) rewards were contingent on performance (2) delivered randomly with matched frequency, (3) when reward was guaranteed, (4) when reward was not present at all. Motivation increased response vigour, as expected. Relative to placebo, pramipexole also increased response vigour. However, there was no interaction, meaning that the effects of reward were not modulated by drug, and there was no differential drug effect on contingent vs. guaranteed rewards. The effect of pramipexole on vigour could not be explained by a speed/accuracy trade-off, nor by autonomic arousal as indexed by pupillary dilation. Chronic D2 stimulation increases general vigour, energising movements in healthy adults irrespective of extrinsic reward.

Does acute cannabidiol (CBD) use impair performance? A meta-analysis and comparison with placebo and delta-9-tetrahydrocannabinol (THC).

Cannabidiol (CBD) is widely used and believed to be non-intoxicating, lacking acute performance effects (e.g., non-impairing). However, a synthesis of data has not evaluated this. This meta-analysis synthesized data from controlled human laboratory studies that evaluated if acute CBD use impairs performance. Performance on objective and subjective measures of cognitive and psychomotor function were used as markers for potential performance changes and impairment. Studies were identified through systematic database searches. Adult clinical trials measuring acute CBD effects (within 0-8 h of administration) were included. The primary outcome was the peak mean difference in performance measures between CBD and placebo. A secondary analysis utilizing delta-9-tetrahydrocannabinol (Δ9-THC) as a positive control for comparison to CBD was completed. Pooled Hedges' g estimates were calculated using robust variance estimation (RVE) meta-regression. The omnibus RVE meta-analysis indicated a statistically significant, but small effect size (Hedge's g < 0.2) for impaired performance following acute CBD consumption compared to placebo (N = 16 trials, Hedges' g = 0.122, 95% CI: 0.023-0.221, p = 0.019). Measure type was a significant moderator with larger mean differences between CBD and placebo when subjective measures, specifically self-reported sedation, were used versus objective performance tasks (Hedges' gSubjective = 0.288 versus Hedges' gObjective = 0.048). Δ9-THC had a significantly greater magnitude of impairment compared to CBD (N = 8, Hedges' g = 0.416, 95% CI: 0.017-0.816, p = 0.043). In summary, acute CBD consumption was associated with a small increase in subjective ratings of sedation, but no difference from placebo was observed across multiple domains of objectively assessed cognitive or psychomotor performance. These findings suggest that acute CBD alone is unlikely to significantly impair daily functioning or workplace performance.

Residual effects of medications for sleep disorders on driving performance: A systematic review and network meta-analysis of randomized controlled trials: NMA driving and hypnotics.

Sleep medications often carry residual effects potentially affecting driving safety, warranting network meta-analysis (NMA). PubMed/EMBASE/TRID/Clinicaltrials.gov/WHO-ICTRP/WebOfScience were inquired for randomized controlled trials of hypnotic driving studies in persons with insomnia and healthy subjects up to 05/28/2023, considering the vehicle's standard deviation of lateral position - SDLP (Standardized Mean Difference/SMD) and driving impairment rates on the first morning (co-primary outcomes) and endpoint. Risk-of-bias, global/local inconsistencies were measured, and CINeMA was used to assess the confidence in the evidence. Of 4,805 identified records, 26 cross-over RCTs were included in the systematic review, of which 22 entered the NMA, focusing on healthy subjects only. After a single administration, most molecules paralleled the placebo, outperforming zopiclone regarding SDLP. In contrast, ramelteon 8 mg, daridorexant 100 mg, zolpidem 10 mg bedtime, zolpidem middle-of-the-night 10 mg and 20 mg, mirtazapine 15-30 mg, and triazolam 0.5 mg performed significantly worse than placebo. Lemborexant 2.5-5 mg, suvorexant 15-20 mg, and zolpidem 3.5 mg middle-of-the-night associated with lower impairment than zopiclone. Repeated administration (maximum follow-up time of ten days) caused fewer residual effects than acute ones, except for flurazepam. Heterogeneity and inconsistency were negligible. Confidence in the evidence was low/very low. Sensitivity analyses confirmed the main analyses. Most FDA-approved hypnotics overlapped placebo at in-label doses, outperforming zopiclone. Repeated administration for 15 days or less reduced residual effects, warranting further research on the matter.

Influence of cannabis use history on the impact of acute cannabis smoking on simulated driving performance during a distraction task.

Objective: This research explores the driving performance of people who use cannabis daily or occasionally during distraction tasks performed following acute cannabis use.Methods: Healthy adults aged 25 to 45 years with different cannabis usage histories were recruited to participate in a within-subjects controlled experiment using a car-based driving simulator. Participants were classified as having daily use (n = 31), occasional use (1 or 2 times per week; n = 24), or no-use (n = 30). Participants completed a practice drive followed by four 5-10 minute driving scenarios during the baseline period. Participants then smoked self-procured cannabis flower ad libitum for up to 15 minutes. Thirty minutes later, they completed four additional 5-10 minute scenarios. Scenarios were paired according to difficulty and randomized across the baseline and post-use periods. Each scenario contained between 0 and 3 repetitions of a distraction task where the participant was prompted by an audio message to select an app from a 4 × 5 grid displayed on a mounted tablet, a step that would require briefly looking away from the roadway. Measures of driving performance (lane departures, standard deviation of lateral position) were assessed during the five-second period following the audio trigger and analyzed using generalized linear mixed models.Results: Those with a pattern of occasional use were significantly more likely to experience a lane departure during distraction periods after acute cannabis use relative to baseline (OR = 3.71, p = 0.04, CI = 1.04, 13.17), while those with daily use did not exhibit a similar increase (OR = 1.56, p = 0.43, CI = 0.52, 4.64). Changes in departure risk were significantly greater for the occasional use group compared to no-use (p = 0.02), but not for the daily use group compared to no-use (p = 0.18). However, following acute use, those who use daily exhibited decreases in speed relative to baseline in comparison to the changes observed in the no-use group (p = 0.02), while differences between occasional and no-use did not reach statistical significance (p = 0.052). Differences in standard deviation of lateral position were not statistically significant, likely due to the short duration of tasks.Conclusions: These results find the largest potential safety concerns associated with a pattern of occasional use, who displayed an increase in lane departures after acute cannabis smoking. Those in the daily use group decreased their speed, which may be interpreted as compensation for drug effects. Further research is needed to understand the effects during longer and more complex secondary tasks.

Intranasal oxytocin attenuates the effects of monetary feedback on procedural learning.

Procedural learning is a vital brain function that allows us to acquire motor skills during development or re-learn them after lesions affecting the motor system. Procedural learning can be improved by feedback of different valence, e.g., monetary or social, mediated by dopaminergic circuits. While processing motivationally relevant stimuli, dopamine interacts closely with oxytocin, whose effects on procedural learning, particularly feedback-based approaches, remain poorly understood. In a randomized, double-blind, placebo-controlled trial, we investigated whether oxytocin modulates the differential effects of monetary and social feedback on procedural learning. Sixty-one healthy male participants were randomized to receive a placebo or oxytocin intranasally. The participants then performed a modified serial reaction time task. Oxytocin plasma concentrations were measured before and after applying the placebo or verum. Groups did not differ regarding general reaction times or measures of procedural learning. For the placebo group, monetary feedback improved procedural learning compared to a neutral control condition. In contrast, the oxytocin group did not show a differential effect of monetary or social feedback despite a significant increase in oxytocin plasma levels after intranasal application. The data suggest that oxytocin does not influence procedural learning per se. Instead, oxytocin seems to attenuate the effects of monetary feedback on procedural learning specifically.

Metabolic syndrome is associated with poor response to rifaximin in minimal hepatic encephalopathy.

Patients with cirrhosis may show minimal hepatic encephalopathy (MHE), for which rifaximin is effective. Metabolic syndrome may be associated with cognitive impairment. Our aims were to evaluate the influence of metabolic syndrome features on response to rifaximin for neurological and inflammatory alterations in MHE. A prospective cohort study was conducted in 63 cirrhotic patients and 30 controls from two tertiary centres recruited between 2015 and 2019. Metabolic syndrome was defined according to the Adult Treatment Panel-III. Patients were classified into 31 without and 32 with MHE according to the Psychometric Hepatic Encephalopathy Score (PHES). All participants performed specific psychometric tests, and inflammatory parameters were studied. Patients with MHE received rifaximin (400 mg/8 h). Response was evaluated by PHES at 3 and 6 months. Response according to metabolic syndrome manifestations was compared. The response rate was 66%. Older age (p = 0.012) and all metabolic syndrome diseases (p < 0.05) were associated with non-response, plus an increase in risk as the number of manifestations rose (p < 0.001). Patients with metabolic manifestations exhibited worse processing speed (p = 0.011), working memory (p = 0.005), visual coordination (p = 0.013) and lower proportion of activated CD4+ lymphocytes (p = 0.039) at baseline, as well as worse concentration (p = 0.030), bimanual coordination (p = 0.004) and higher levels of intermediate monocytes (p = 0.026), CX3CL1 (p < 0.05), IL-17 (p = 0.022), AHR (p = 0.010) and IgG (p < 0.05) at 3 and/or 6 months of rifaximin. Patients with clinical signs of metabolic syndrome have poor response to rifaximin for MHE, with a higher proportion of neurological alterations associated with a pro-inflammatory environment.

Clinical impacts of frailty, poor performance status, and advanced age in carfilzomib-containing treatment for relapsed/refractory multiple myeloma: post hoc investigation of the KOTOSG multicenter pilot prospective observational study.

We conducted a post hoc analysis of our previous pilot observational study on the efficacy and safety of carfilzomib (CFZ)-containing therapy in 50 patients with relapsed/refractory multiple myeloma in routine practice to clarify the relationships between three major criteria for vulnerability (frailty, poor performance status [PS], and advanced age [≥ 75 years]) and their clinical impact on efficacy and adverse events (AEs). Sixteen patients fulfilled at least one and five patients fulfilled all three criteria. The overall response rate was not significantly affected by frailty, poor PS, and/or advanced age; however, frailty and advanced age were significantly associated with shorter progression-free survival (PFS). In contrast, no significant difference in PFS was observed between patients with PS0-1 or PS2-4. The three criteria for vulnerability were associated with more frequent hematologic AEs: frailty, poor PS, and/or advanced age significantly increased the risk of grade 3-4 anemia and lymphopenia. However, these criteria were not associated with increased risk of other non-hematologic AEs except infection. Collectively, these results demonstrate the need to carefully manage severe hematologic AEs in vulnerable patients and perform disease-specific assessment of frailty to predict prognosis.

Boys with attention-deficit/hyperactivity disorder perform wider and fewer finger tapping than typically developing boys - Peer comparisons and the effects of methylphenidate from an exploratory perspective.

AIM: This study aimed to investigate the differences in fine motor and coordination skills between boys with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) boys and the effect of methylphenidate (MPH) in boys with ADHD. METHODS: Fourteen boys aged 7-12 years who were diagnosed with ADHD and previously treated with MPH were instructed to tap their thumbs and index fingers together repetitively for 10 s after attaching magnetic sensors. The participants executed "in-phase" and "anti-phase" tapping. A two-way analysis of variance for comparing boys with ADHD and TD boys and the paired t-test to investigate the effect of MPH between sessions with and without MPH were performed. RESULTS: Boys with ADHD showed a significantly lower "number of taps" and a significantly higher "average of local maximum distance" than TD boys. "Energy balance" was significantly lower in ADHD boys than in TD boys. MPH caused a significant difference in the "standard deviation (SD) of phase difference" in "anti-phase tapping." CONCLUSION: Our studies indicated that finger-tapping movements in boys with ADHD tended to be significantly wider and fewer than those in TD boys, and MPH may improve the phase difference of bimanual fine motor coordination skills in boys with ADHD who are above 1.0 SD. The results should be interpreted with caution because we conducted statistical tests for many outcomes and groups without considering the multiplicity factor from an exploratory perspective.

Long-term increase in sensitivity to ketamine's behavioral effects in mice exposed to mild blast induced traumatic brain injury.

Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic/analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe. This series of studies examined male C57BL/6 J mice exposed to a mild single blast overpressure (mbTBI) for indications of altered sensitivity to ketamine at varying times after injury. Dystaxia (altered gait), diminished sensorimotor gating (reduced prepulse inhibition) and impaired working memory (step-down inhibitory avoidance) were examined in mbTBI and sham animals 15 min following intraperitoneal injections of saline or R,S-ketamine hydrochloride, from day 7-16 post injury and again from day 35-43 post injury. Behavioral performance in the forced swim test and sucrose preference test were evaluated on day 28 and day 74 post injury respectively, 24 h following drug administration. Dynamic gait stability was compromised in mbTBI mice on day 7 and 35 post injury and further exacerbated following ketamine administration. On day 14 and 42 post injury, prepulse inhibition was robustly decreased by mbTBI, which ketamine further reduced. Ketamine-associated memory impairment was apparent selectively in mbTBI animals 1 h, 24 h and day 28 post shock (tested on day 15/16/43 post injury). Ketamine selectively reduced immobility scores in the FST in mbTBI animals (day 28) and reversed mbTBI induced decreases in sucrose consumption (Day 74). These results demonstrate increased sensitivity to ketamine in mice when tested for extended periods after TBI. The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical practice for enhanced sensitivity to its side effects in this patient population.

The neurotoxic effect of lactational PFOS exposure on cerebellar functional development in male mice.

Recent studies showed a possible association between perfluorooctane sulfonate (PFOS) and developmental disabilities. We previously found the specific effects of PFOS exposure on learning and memory, however, its effect on the other developmental disabilities such as motor and social deficits remains unclear. We examined the effect of early lactational PFOS exposure on motor coordination, social activity, and anxiety in male mice. We orally administered a PFOS solution to dams from postnatal day 1-14. At 10 weeks old, we conducted a behavior test battery to evaluate motor performance, social activity, and anxiety, followed by electrophysiology and Western blot analysis. PFOS-exposed mice displayed impaired motor coordination. Whole-cell patch-clamp recordings from Purkinje cells revealed that the short-term and long-term plasticity at parallel fiber-Purkinje cell synapses are affected by PFOS exposure. Western blot analysis indicated that PFOS exposure increased syntaxin binding protein 1 (Munc18-1) and glutamate metabotropic receptor 1 (mGluR1) protein levels, which may be associated with the change in neurotransmitter release from parallel fibers and the level of long-term depression, respectively. The present study demonstrates that lactational PFOS exposure may have disrupted the pre- and postsynaptic plasticity at parallel fiber-Purkinje cell synapses, causing profound, long-lasting abnormal effects on the cerebellar function.