Bradykinesia of posed smiling and voluntary movement of the lower face in Parkinson's disease

ObjectiveImpaired facial expression, including spontaneous and emotional movements such as smiling, has been often reported in Parkinson's disease (PD). There is a general consensus that spontaneous smiling is abnormal in PD. Investigations on posed smiling yield contrasting results. Moreover, no study has yet addressed the relationship between posed smiling and abnormalities of voluntary movements of the lower face, global motor impairment and the effects of dopaminergic medication.MethodsWe investigated the kinematics of posed smiling (mimicking a smile shown in a picture) and those of voluntary movements of the lower face (showing the teeth as fast as possible – voluntary grinning) in 15 patients with PD (ON and OFF therapy) and in 16 healthy controls. Facial movements were recorded using a 3D optoelectronic system and analyzed using dedicated software.ResultsSome kinematic parameters of both posed smiling and voluntary grinning were abnormally lower in PD patients in comparison to healthy subjects. The kinematics of posed smiling correlated with those of voluntary grinning in PD patients but not in healthy controls. Posed smiling and voluntary grinning abnormalities were related to global motor severity but did not significantly improve upon L-dopa administration.ConclusionsThese results suggest that posed smiling and voluntary grinning are both abnormal in PD patients and that they are likely mediated by a common pathophysiological mechanism.     

A systematic review of mirror neuron system function in developmental coordination disorder: Imitation,motor imagery,and neuroimaging evidence

PURPOSEThe aim of this systematic review was to investigate the evidence of abnormal functioning of the mirror neuron system (MNS) in children and adults with developmental coordination disorder (DCD), through examination of imitation, motor imagery, and neuroimaging literature.METHODSThe following databases were comprehensively searched for relevant articles: CINAHL Plus, Embase, MEDLINE, PsycINFO, Pubmed, and Web of Science. Full-text articles of all potentially relevant citations were obtained and assessed for eligibility by two authors. Outcome measures of interest at a motor behaviour level were any measures of imitation or motor imagery proficiency and, at a neurological level, were any measures of neural activity in MNS brain regions. Due to differences in outcome measures between studies and the variables reported, a narrative review was undertaken to synthesise findings from the studies.RESULTSOverall, 31 articles met the inclusion criteria. Children and adults with DCD display deficits imitating meaningful and novel gestures and demonstrate different response patterns to controls when undertaking complex motor imagery tasks. Children with DCD present reduced activation and connectivity of frontal, parietal, and temporal MNS regions.CONCLUSIONSPreliminary evidence indicates some deficit in the functioning of the MNS at a motor behaviour and neurological level. As no published neuroimaging studies have been designed specifically to explore MNS function, these results must be interpreted with caution. Further research to explore the MNS hypothesis in greater detail, particularly from a neuroimaging perspective, has the potential to provide information on the underlying mechanisms of DCD, inform future research into the aetiology of this disorder, and inform intervention approaches.     

Association between dopaminergic dysfunction and anxiety in de novo Parkinson's disease

ObjectivesTo explore the relationships between nigrostriatal dysfunction and neuropsychiatric symptoms (including anxiety, depression and apathy) in a large cohort of newly diagnosed, drug-naïve Parkinson disease (PD) patients compared to a cohort of healthy controls (HC).MethodsThis is a cross-sectional analysis of the Parkinson's Progression Markers Initiative (PPMI) cohort at baseline, including 405 PD patients and 187 HC. Nigrostriatal degeneration was evaluated by means of SPECT DAT scan. Relationships between neuropsychiatric symptoms and DAT uptakes were analysed by means of stepwise multiple regression analysis.ResultsIn the PD group, lower DAT uptake in the right caudate was associated with higher STAI trait subscore (β = −2.939, 95%CI: −4.634 to −1.254, p = 0.001). Depression and apathy scores were not related with DAT uptakes. No associations were found in the HC group.ConclusionsOur cross-sectional analysis of the PPMI data shows that lower caudate DAT uptake is associated with higher level of anxiety. The data strengthens the relationship between dopaminergic dysfunction and neuropsychiatric symptoms in early PD.     

Evidence for Pretreatment LICI Deficits Among Depressed Children and Adolescents With Nonresponse to Fluoxetine

BackgroundResearch suggests that alterations in gamma-aminobutyric acid receptor functioning have a role in depression. Paired-pulse transcranial magnetic stimulation (TMS) paradigms are noninvasive measures of cortical inhibitory and excitatory circuits.Objective/hypothesisThe present study examined pretreatment short-interval intracortical inhibition (SICI), long-interval cortical inhibition (LICI), and intracortical facilitation (ICF) in children and adolescents with major depressive disorder who were initiating fluoxetine treatment. The primary objective was to examine the relationship of these measures with subsequent treatment response. It was hypothesized that alterations in pretreatment GABA and glutamate mediated neurotransmission, would be associated with fluoxetine nonresponse.MethodsSixteen children and adolescents with major depressive disorder underwent paired-pulse TMS testing before beginning fluoxetine treatment. Response was prospectively characterized by scores of 1 or 2 on the Clinical Global Impression Scale and less than 40 on the Children's Depression Rating Scale-Revised after 6 weeks of fluoxetine treatment (20–40 mg/day).ResultsEight patients responded to treatment. Least-squares mean LICI values were consistently higher bilaterally for treatment nonresponders. Higher LICI values indicate less inhibition and impaired GABA_B functioning. There was no significant effect of treatment response on the measures of SICI and ICF.ConclusionsOur findings suggest that deficits in pretreatment GABA_B may be related to fluoxetine nonresponse in depressed youth. This is congruent with prior work demonstrating that GABA_B interneurons have serotonergic input and antidepressants modulate GABA_B receptors. These findings also show that TMS paradigms have utility in studying the neurophysiology and treatment of childhood mood disorders.RegistrationsCortical Excitability and Inhibition in Children and Adolescents With Major Depressive Disorder, http://www.clinicaltrials.gov/ct2/show/NCT00896090?term=cortical+excitability+and+inhibition&rank=2, NCT00896090; Sequential Treatment of Pediatric MDD to Increase Remission and Prevent Relapse, http://www.clinicaltrials.gov/ct2/show/NCT00612313?term=Sequential+Treatment+and+MDD&rank=1, NCT00612313.     

Increased methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of patients with generalized anxiety disorder

Previous findings on the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety disorder (GAD) are controversial, and the molecular mechanisms underlying such dysfunction remain unclear. We analyzed the methylation status of the NR3C1 1_F promoter and the expression of glucocorticoid receptor-α isoform (GRα) in peripheral blood mononuclear cells (PMBCs), the basal cortisol level in serum, and a functional neuroendocrine marker for GR sensitivity in the PMBCs in 64 patients with current GAD and 85 healthy controls. We found that patients with GAD had significantly elevated levels of morning basal serum cortisol (P < 0.0001) and diminished GR sensitivity in the PBMCs (P < 0.0001) compared with healthy controls. The overall methylation levels across NR3C1 1_F promoter (P < 0.0001) and percent methylation at each of the 5 CpG sites including CpG12, 21, 30, 31, and 32 (P < 0.001) significantly increased. Accordingly, the mRNA levels of GRα significantly decreased (P < 0.0001) in the PBMCs in patients with GAD compared with healthy controls, with the effects specific in patients without childhood traumatic experience. Moreover, both serum basal cortisol levels and GR sensitivity in the PBMCs were negatively correlated with the overall methylation levels of the NR3C1 1_F promoter (P < 0.0001) and positively correlated with GRα mRNA levels (P = 0.007) in the PBMCs. In sum, our study revealed the increased activity of the HPA axis and diminished peripheral glucocorticoid responsiveness of GR underlying episodes of GAD. Furthermore, such dysfunction of the HPA axis is associated with both increased DNA methylation of NR3C1 1_F promoter and decreased GRα expression.     

Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy

BackgroundSevere putamen dopamine depletion characterizes Parkinson's disease (PD) and multiple system atrophy (MSA). The extent of the depletion is greater than can be accounted for by loss of nigrostriatal dopaminergic terminals alone. We used putamen tissue levels and ratios of cysteinyl and parent catechols to explore possible denervation-independent abnormalities of dopamine synthesis and fate in PD and MSA. 5-S-Cysteinyldopa (Cys-DOPA) is produced from spontaneous oxidation of DOPA and 5-S-cysteinyldopamine (Cys-DA) from spontaneous oxidation of DA.MethodsPost-mortem putamen tissue samples from 17 PD and 25 MSA patients and 30 controls were assayed for endogenous catechols including DA, its cytoplasmic metabolites (Cys-DA, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethanol, and 3,4-dihydroxyphenylacetaldehyde), and tyrosine hydroxylation products proximal to DA (DOPA and Cys-DOPA).ResultsThe PD and MSA groups did not differ in mean values of parent or cysteinyl catechols, and the data for the two groups were lumped. In the patients an index of vesicular storage of DA (the ratio of DA to the sum of its cytoplasmic metabolites) averaged 54% of control (p = 0.001), and an index of L-aromatic-amino-acid decarboxylase (LAAAD) activity (the ratio of DA and the sum of its cytoplasmic metabolites to the sum of DOPA + Cys-DOPA) averaged 21% of control (p < 0.0001). An index of innervation (the sum of DOPA + Cys-DOPA) averaged 63% of control (p = 0.01).InterpretationBased on patterns of parent and cysteinyl catechols in putamen, PD and MSA involve decreased vesicular uptake and decreased LAAAD activity in the residual dopaminergic terminals. The combination seems to contribute importantly to dopamine depletion in these diseases.     

Smartphone-based tactile cueing improves motor performance in Parkinson's disease

IntroductionVisual and auditory cueing improve functional performance in Parkinson's disease (PD) patients. However, audiovisual processing shares many cognitive resources used for attention-dependent tasks such as communication, spatial orientation, and balance. Conversely, tactile cues (TC) may be processed faster, with minimal attentional demand, and may be more efficient means for modulating motor-cognitive performance. In this study we aimed to investigate the efficacy and limitations of TC for modulating simple (heel tapping) and more complex (walking) motor tasks (1) over a range of cueing intervals, (2) with/without a secondary motor task (holding tray with cups of water).MethodsTen PD patients (71 ± 9 years) and 10 healthy controls (69 ± 7 years) participated in the study. TCs was delivered through a smart phone attached to subjects' dominant arm and were controlled by a custom-developed Android application.ResultsPD patients and healthy controls were able to use TC to modulate heel tapping (F(3.8,1866.1) = 1008.1, p < 0.001), and partially modulate walking (F(3.5,1448.7) = 187.5, p < 0.001) tasks. In the walking task, PD patients modulated performance over a narrower range of cueing intervals (R² = 0.56) than healthy controls (R² = 0.84; group difference F(3.5,1448.7) = 8.6, p < 0.001). TC diminished synchronization error associated with performance of secondary motor task during walking in PD patients and healthy controls (main effect of Task (F(1,494) = 0.4; p = 0.527), Task X Group interaction (F(1,494) = 0.5; p = 0.493)).ConclusionThis study expands modalities of TC usage for movement modulation and motor-cognitive integration in PD patients. The smartphone TC application was validated as a user-friendly movement modulation aid.     

Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease

BackgroundThere is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.ObjectiveTo investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.MethodsCross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [¹¹C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.ResultsThere were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98 ± 1.01) compared to the non-diabetics (−0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).ConclusionDiabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.     

Mitochondrial DNA sequence data reveals association of haplogroup U with psychosis in bipolar disorder

Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged.     

Exploring risk factors for stuttering development in Parkinson disease after deep brain stimulation

BackgroundStuttering is a speech disorder with disruption of verbal fluency, occasionally present in Parkinson's disease (PD). PD co-incident stuttering may either worsen or improve after Deep Brain Stimulation (DBS).MethodsSixteen out of 453 PD patients (3.5%) exhibited stuttering after DBS (PD-S) and were compared with a group of patients without stuttering (PD-NS) using non-parametric statistics.ResultsAfter DBS, stuttering worsened in 3 out of 4 patients with co-incidental stuttering. Most PD-S underwent subthalamic (STN) DBS, but 4 were implanted in the globus pallidus (GPi). Nine out of 16 PD-S (56.3%) reported a positive familial history for stuttering compared to none of the PD-NS. PD-S were mainly male (81.3%) with slight worse motor features compared to PD-NS.ConclusionHerein, we describe a group of PD patients developing stuttering after DBS and report the presence of a positive familial history for stuttering as the most relevant risk factor, suggesting a possible underlying genetic cause. The fact that stuttering occurred after either STN or GPi DBS is an argument against the impact of medication reduction on stuttering.     

A genome-wide association study of suicide severity scores in bipolar disorder

BackgroundSuicide claims one million lives worldwide annually, making it a serious public health concern. The risk for suicidal behaviour can be partly explained by genetic factors, as suggested by twin and family studies (reviewed in (Zai et al. 2012)). Recently, genome-wide association studies (GWASs) of suicide attempt on large samples of bipolar disorder (BD) patients from multiple sites have identified a number of novel candidate genes. GWASs of suicide behaviour severity, from suicidal ideation to serious suicide attempt, have not been reported for BD.MethodsWe conducted a GWAS of suicide behaviour severity in three independent BD samples:212 small nuclear families with BD probands from Toronto, Canada, 428 BD cases from Toronto, and 483 BD cases from the UK. We carried out imputation with 1000 Genome Project data as reference using IMPUTE2. Quality control and data analysis was conducted using PLINK and R. We conducted the quantitative analyses of suicide behaviour severity in the three samples separately, and derived an overall significance by a meta-analysis using the METAL software.ResultsWe did not find genome-wide significant association of any tested markers in any of the BD samples, but we found a number of suggestive associations, including regions on chromosomes 8 and 10 (p < 1e-5).ConclusionsOur GWAS findings suggest that likely many gene variants of small effects contribute collectively to the risk for suicidal behaviour severity in BD. Larger independent replications are required to strengthen the findings from the GWAS presented here.     

Back to sleep or not: the effect of the supine position on pediatric OSA: Sleeping position in children with OSA

BackgroundIn both adults and children, obstructive sleep apnea (OSA) has significant adverse cardiovascular consequences. In adults, sleeping position has a marked effect on the severity of OSA; however, the limited number of studies conducted in children have reported conflicting findings. We aimed to evaluate the effect of sleeping position on OSA severity and the cardiovascular consequences in preschool-aged children.MethodsThis was a retrospective analysis of children (3–5 years of age) diagnosed with OSA (n = 75) and nonsnoring controls (n = 25). Sleeping position was classified as supine, semi-supine, left lateral, right lateral, prone, and semi-prone by using video recordings during one night of attended polysomnography. OSA severity and cardiovascular parameters were compared between the positions.ResultsAll children spent significantly more sleep time in the supine position than in any other position. The obstructive apnea-hypopnea index was higher in the supine position than in the other sleeping positions during NREM (p < 0.05), higher in the moderate/severe OSA group when sleeping in the supine position than when sleeping in the left and right lateral positions (p < 0.05 for both) and prone position (p = 0.007) during REM. Sympathovagal balance was decreased in children with OSA in the supine and lateral positions (p < 0.05).ConclusionsThis study identified that preschool-aged children, whether nonsnoring controls or children with OSA, predominately sleep in the supine position, and OSA was more severe in the supine position. We suggest that to avoid the supine sleep position, positional therapy has the potential to ameliorate OSA severity, and the known cardiovascular consequences.     

Impaired short-term plasticity in restless legs syndrome: a pilot rTMS study

BackgroundPrevious studies showed an impairment of the LTP-like plasticity to TMS in restless legs syndrome (RLS). Clinically, repetitive TMS (rTMS) was effective in alleviating the sensory-motor complaints of patients, although the effects induced by low-frequency (inhibitory) rTMS have not yet been investigated. An impaired LTD-like mechanism of cortical plasticity has been hypothesized, which we have directly assessed in this pilot study.MethodsMotor evoked potentials (MEPs) from the right first dorsal interosseus muscle were recorded at the stimulus intensity of 110% of the resting motor threshold (rMT) from 13 right-handed patients and ten age-matched right-handed healthy controls. Median peak-to-peak amplitudes were calculated in all participants at baseline (T₀), after the first train of a single evening session of low-frequency (1 Hz) rTMS over the left primary motor cortex (T₁), and after the whole rTMS procedure (T₂), which consists of 20 trains with 50 stimuli per train and intertrain interval of 30 s (1000 stimuli in total).ResultsNo differences were found for rMT and MEPs size between the two groups at T₀. Smaller MEPs amplitudes at both T₁ and T₂ were observed in all subjects, although this was significantly more pronounced in controls than in patients.ConclusionsCompared to normal individuals, patients exhibited an impairment of the LTD-like mechanisms induced by inhibitory rTMS, thus adding support to the involvement of GABA in RLS pathophysiology. Although future studies with a larger population are needed, TMS is confirmed to be effective in noninvasive probing of the neurophysiology and neurochemistry of RLS.     

Hearing loss mediates executive function impairment in sleep-disordered breathing

BackgroundSleep-disordered breathing (SDB) is often co-morbid with conductive hearing loss in early childhood due to a shared aetiology of adenotonsillar hypertrophy. Hearing loss is independently associated with impairment of executive function and behavioural difficulties. We hypothesised that these impairments in children with SDB may be mediated through hearing loss.MethodsFifty-eight children including 37 snorers awaiting adenotonsillectomy and 21 healthy non-snoring controls, aged 3–5 years, were assessed with pure tone audiometry, Strengths and Difficulties (SDQ), Behaviour Rating of Executive Function (BRIEF-P), and Childhood Middle Ear Disease and Hearing questionnaires. Polysomnography in snoring children generated an obstructive apnoea/hypopnea index (OAHI). Two regression models examined the effect of SDB and the mediating impact of hearing loss on BRIEF and SDQ.ResultsSnoring children had significantly poorer hearing, greater past exposure to hearing loss, and higher total SDQ and BRIEF-P scores than non-snoring controls. The first regression model, including all children, demonstrated that the impact of snoring on BRIEF_P, but not SDQ, was entirely mediated by a history of hearing loss exposure but not same-day audiometry. The second model examined snoring children only, categorising the group into 12 with obstructive sleep apnoea (OSA) (OAHI ≥ 5) and 25 without OSA. OSA had a direct effect on SDQ scores, but this was not mediated by a history of hearing loss.ConclusionIn early childhood, conductive hearing loss mediates the relationship between SDB, irrespective of severity, and parent report of executive function but not behaviour. Treatment of hearing loss in pre-school SDB might improve executive function.     

Catathrenia,a REM predominant disorder of arousal?

ObjectivesCatathrenia is an uncommon and poorly understood disorder, characterized by groaning during sleep occurring in tandem with prolonged expiration. Its classification, pathogenesis, and clinical relevance remain debated, substantially due to the limited number of cases reported to date. We report a series of consecutive cases of catathrenia, their clinical and polysomnographic characteristics, and their subsequent management.MethodsConsecutive patients with catathrenia who had undergone full polysomnography in our institution over a 5.5-year period were included. Catathrenia events (CEs) were examined in clusters, which formulated catathrenia periods (CPs). The relationships between CPs, sleep stage distribution, electroencephalogram (EEG) arousals, and other sleep parameters were assessed, along with the clinical presentation and management of catathrenic patients.ResultsA total of 427 CPs were identified in 38 patients, 81% arising from rapid eye movement (REM) sleep. EEG arousals preceded or coincided with the onset of 84% of CPs, which were of longer duration than those not associated with an arousal (57.3 ± 56.8 vs. 32.2 ± 29.4 s, p < 0.001). Each CE had a characteristic airflow signal, with inspiration preceding a protracted expiration and a brief more rapid exhalation, followed by deep inspiration. Although the majority of patients were referred on the basis of bed partner complaints, 44.7% complained of daytime sleepiness. Continuous positive airway pressure therapy and sleep-consolidating pharmacotherapy led to subjective improvement, but were limited by poor long-term adherence.ConclusionsIn the largest series of catathrenia patients reported to date, we found that this rare disorder is characterized by a distinct breathing pattern and arises predominantly from REM sleep, with arousals almost uniformly preceding or coinciding with the onset of CPs.     

Long term retention of retigabine in a cohort of people with drug resistant epilepsy

PurposeTo assess the utility of retigabine (RTG) for epilepsy in clinical practice at a single UK tertiary centre.MethodsWe identified all individuals who were offered RTG from April 2011 to May 2013. We collected demographics, seizure types, previous and current antiepileptic drugs (AEDs), starting and maximum attained daily dose of RTG, clinical benefits, side effects, and reason to discontinue RTG from in- and outpatient encounters until February 28, 2014.Results145 people who had failed a median of 11 AEDs took at least one dose of RTG. One year retention was 32% and decreased following the safety alert by the US Federal Drug Administration (FDA) in April 2013. None became seizure free. 34 people (24%) reported a benefit that was ongoing at last assessment in five (3%). The most relevant benefit was the significant reduction or cessation of drop attacks or seizure-related falls in four women, this persisted at last assessment in two. The presence of simple partial seizures was associated with longer retention, as was a higher attained dose of RTG. Adverse effects were seen in 74% and largely CNS-related or nonspecific and affected the genitourinary system in 13%.ConclusionRetention of RTG was less favourable compared to data from open label extension studies of the regulatory trials. In comparison with historical data on similar retention audits retention of RTG at one year appears to be less than lamotrigine, topiramate, levetiracetam, pregabalin, zonisamide, and lacosamide, and slightly higher than gabapentin.     

Associations between anxiety disorders,suicide ideation,and age in nationally representative samples of Canadian and American adults

Suicidal behaviors are of significant concern for the individuals displaying such behavior and for service providers who encounter them. Using nationally representative samples of Canadian and American adults, we aimed to examine: whether age moderates the relationship between having any anxiety disorder and suicide ideation (SI), the prevalence of SI among younger and older adults, and whether age and individual anxiety disorders were differentially associated with SI. Age moderated the relationship between any anxiety disorder and SI among Americans only. Past-year SI was less prevalent among older, compared to younger, adults; though, nearly every anxiety disorder was associated with increased odds of SI among younger and older Canadian and American adults after controlling for covariates. Effect sizes were particularly large for older American adults, but were coupled with large confidence intervals. Findings contribute to a growing literature suggesting that SI in the context of anxiety is a highly prevalent and complex mental health problem across the adult lifespan.     

Clinical correlates of graph theory findings in temporal lobe epilepsy

PurposeTemporal lobe epilepsy (TLE) is considered a brain network disorder, additionally representing the most common form of pharmaco-resistant epilepsy in adults. There is increasing evidence that seizures in TLE arise from abnormal epileptogenic networks, which extend beyond the clinico-radiologically determined epileptogenic zone and may contribute to the failure rate of 30–50% following epilepsy surgery. Graph theory allows for a network-based representation of TLE brain networks using several neuroimaging and electrophysiologic modalities, and has potential to provide clinicians with clinically useful biomarkers for diagnostic and prognostic purposes.MethodsWe performed a review of the current state of graph theory findings in TLE as they pertain to localization of the epileptogenic zone, prediction of pre- and post-surgical seizure frequency and cognitive performance, and monitoring cognitive decline in TLE.ResultsAlthough different neuroimaging and electrophysiologic modalities have yielded occasionally conflicting results, several potential biomarkers have been characterized for identifying the epileptogenic zone, pre-/post-surgical seizure prediction, and assessing cognitive performance. For localization, graph theory measures of centrality have shown the most potential, including betweenness centrality, outdegree, and graph index complexity, whereas for prediction of seizure frequency, measures of synchronizability have shown the most potential. The utility of clustering coefficient and characteristic path length for assessing cognitive performance in TLE is also discussed.ConclusionsFuture studies integrating data from multiple modalities and testing predictive models are needed to clarify findings and develop graph theory for its clinical utility.     

Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference

Background and objectivesThe orally active dual OX₁R and OX₂R antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults.Patients and methodsProspective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18–64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake time after sleep onset (WASO). Further sleep variables were also evaluated.ResultsFrom 709 randomized patients, 707 (mean age 45.4 years; 61.7% female) received treatment and 663 (93.8%) completed the study. A significant decrease versus placebo in median objective WASO was observed with almorexant 200 mg at the start and end of randomized treatment (−26.8 min and −19.5 min, respectively; both p < 0.0001); subjective WASO also decreased over the two-week treatment period (p = 0.0006). Objective and subjective total sleep time (TST) were increased with almorexant 200 mg (p < 0.0001). Almorexant 200 mg significantly reduced objective and subjective latency to persistent sleep and latency to sleep onset at initiation of therapy, and provided longer duration of sleep stages with no suppression of slow-wave sleep. No impaired next-day performance, rebound insomnia, or withdrawal effects were observed. Adverse events were similar with almorexant and placebo.ConclusionAlmorexant reduced time to sleep onset and maintained sleep without residual effects on next-day performance or safety concerns. This study provides further support for the role of the endogenous orexin system in insomnia disorder.ClinicalTrials.gov registrationNCT00608985.