Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes

BackgroundGlycogen synthase kinase-3 β (GSK3β) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3β is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3β becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3β (phospho-GSK3β) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3β has never been studied in humans.MethodsIn 27 patients with bipolar depression, total GSK3β and phospho-GSK3β were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group.ResultsNo differences in phospho-GSK3β or total GSK3β were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho-GSK3β and total GSK3β levels. From baseline to endpoint, lithium treatment inactivated GSK3β by significantly increasing phospho-GSK3β levels (p = 0.010). Clinical improvement (baseline HAM-D — endpoint HAM-D) negatively correlated with the increase in phospho-GSK3β (p = 0.03).ConclusionThe present results show that lithium inactivates platelet GSK3β in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3β as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3β in other neuropsychiatric disorders and as a new therapeutic target per se.     

Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice

Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001–0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237–258% of control), protein kinase B/Akt (Ser⁴⁷³) (116–127% of control), glycogen synthase kinase-3β (Ser⁹) (110–113% of control), extracellular signal-regulated kinases 1/2 (119–137% and 121–138% of control, respectively) and cAMP response elements (Ser¹³³) (127–152% of control), and brain-derived-neurotrophic factor (137–175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001–0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38^MAPK phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus.     

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.     

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.     

The short and long of adolescent sleep: the unique impact of day length

Study objectivesVariation in day length is proposed to impact sleep, yet it is unknown whether this is above the influence of behavioural factors. Day length, sleep hygiene, and parent-set bedtime were simultaneously explored, to investigate the relative importance of each on adolescents’ sleep.MethodsAn online survey was distributed in four countries at varying latitudes/longitudes (Australia, The Netherlands, Canada, Norway).ResultsOverall, 711 (242 male; age M = 15.7 ± 1.6, range = 12–19 yrs) adolescents contributed data. Hierarchical regression analyses showed good sleep hygiene was associated with earlier bedtime, shorter sleep latency, and longer sleep (β = −0.34; −0.30; 0.32, p < 0.05, respectively). Shorter day length predicted later bedtime (β = 0.11, p = 0.009), decreased sleep latency (β = −0.21, p < 0.001), and total sleep (β = −0.14, p = 0.001). Longer day length predicted earlier bedtimes (β = −0.11, p = 0.004), and longer sleep (β = 0.10, p = 0.011).ConclusionsSleep hygiene had the most clinical relevance for improving sleep, thus should be considered when implementing adolescent sleep interventions, particularly as small negative effects of shorter day length may be minimised through sleep hygiene techniques.     

Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function

Zinc transporter 3 (ZnT3) is the sole mechanism responsible for concentrating zinc ions within synaptic vesicles in a subset of the brain’s glutamatergic neurons. This vesicular zinc can then be released into the synaptic cleft in an activity-dependent fashion, where it can exert many signaling functions. This review provides a comprehensive discussion of the localization and function of ZnT3 and vesicular zinc in the central nervous system. We begin by reviewing the fundamentals of zinc homeostasis and transport, and the discovery of ZnT3. We then focus on four main topics. I) The anatomy of the zincergic system, including its development and its modulation through experience-dependent plasticity. II) The role of zinc in intracellular signaling, with a focus on how zinc affects neurotransmitter receptors and synaptic plasticity. III) The behavioural characterization of the ZnT3 KO mouse, which lacks ZnT3 and, therefore, vesicular zinc. IV) The roles of ZnT3 and vesicular zinc in health and disease.     

Responses to voluntary hyperventilation in children with separation anxiety disorder: Implications for the link to panic disorder

BackgroundBiological theories on respiratory regulation have linked separation anxiety disorder (SAD) to panic disorder (PD). We tested if SAD children show similarly increased anxious and psychophysiological responding to voluntary hyperventilation and compromised recovery thereafter as has been observed in PD patients.MethodsParticipants were 49 children (5–14 years old) with SAD, 21 clinical controls with other anxiety disorders, and 39 healthy controls. We assessed cardiac sympathetic and parasympathetic, respiratory (including pCO₂), electrodermal, electromyographic, and self-report variables during baseline, paced hyperventilation, and recovery.ResultsSAD children did not react with increased anxiety or panic symptoms and did not show signs of slowed recovery. However, during hyperventilation they exhibited elevated reactivity in respiratory variability, heart rate, and musculus corrugator supercilii activity indicating difficulty with respiratory regulation.ConclusionsReactions to hyperventilation are much less pronounced in children with SAD than in PD patients. SAD children showed voluntary breathing regulation deficits.     

Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

BackgroundDysregulation of extracellular signal-related kinase (ERK) activity has been potentially implicated in the pathophysiology of autistic disorder (autism). ERK is part of a central intracellular signaling cascade responsible for a myriad of cellular functions. ERK is expressed in peripheral blood lymphocytes, and measurement of activated (phosphorylated) lymphocytic ERK is commonly executed in many areas of medicine. We sought to conduct the first study of ERK activation in humans with autism by utilizing a lymphocytic ERK activation assay. We hypothesized that ERK activation would be enhanced in peripheral blood lymphocytes from persons with autism compared to those of neurotypical control subjects.MethodWe conducted an initial study of peripheral lymphocyte ERK activation in 45 subjects with autism and 26 age- and gender-matched control subjects (total n = 71). ERK activation was measured using a lymphocyte counting method (primary outcome expressed as lymphocytes staining positive for cytosolic phosphorylated ERK divided by total cells counted) and additional Western blot analysis of whole cell phosphorylated ERK adjusted for total ERK present in the lymphocyte lysate sample.ResultsCytosolic/nuclear localization of pERK activated cells were increased by almost two-fold in the autism subject group compared to matched neurotypical control subjects (cell count ratio of 0.064 ± 0.044 versus 0.034 ± 0.031; p = 0.002). Elevated phosphorylated ERK levels in whole cell lysates also showed increased activated ERK in the autism group compared to controls (n = 54 total) in Western blot analysis.ConclusionsThe results of this first in human ERK activation study are consistent with enhanced peripheral lymphocytic ERK activation in autism, as well as suggesting that cellular compartmentalization of activated ERK may be altered in this disorder. Future work will be required to explore the impact of concomitant medication use and other subject characteristics such as level of cognitive functioning on ERK activation.Trial RegistrationNot applicable.     

Characterizing the Mechanisms of Central and Peripheral Forms of Neurostimulation in Chronic Dysphagic Stroke Patients

BackgroundSwallowing problems following stroke may result in increased risk of aspiration pneumonia, malnutrition, and dehydration.Objective/hypothesisOur hypothesis was that three neurostimulation techniques would produce beneficial effects on chronic dysphagia following stroke through a common brain mechanism that would predict behavioral response.MethodsIn 18 dysphagic stroke patients (mean age: 66 ± 3 years, 3 female, time-post-stroke: 63 ± 15 weeks [±SD]), pharyngeal electromyographic responses were recorded after single-pulse transcranial magnetic stimulation (TMS) over the pharyngeal motor cortex, to measure corticobulbar excitability before, immediately, and 30 min, after real and sham applications of neurostimulation. Patients were randomized to a single session of either: pharyngeal electrical stimulation (PES), paired associative stimulation (PAS) or repetitive TMS (rTMS). Penetration-aspiration scores and bolus transfer timings were assessed before and after both real and sham interventions using videofluoroscopy.ResultsCorticobulbar excitability of pharyngeal motor cortex was beneficially modulated by PES, PAS and to a lesser extent by rTMS, with functionally relevant changes in the unaffected hemisphere. Following combining the results of real neurostimulation, an overall increase in corticobulbar excitability in the unaffected hemisphere (P = .005, F_1,17 = 10.6, ANOVA) with an associated 15% reduction in aspiration (P = .005, z = −2.79) was observed compared to sham.ConclusionsIn this mechanistic study, an increase in corticobulbar excitability the unaffected projection was correlated with the improvement in swallowing safety (P = .001, rho = −.732), but modality-specific differences were observed. Paradigms providing peripheral input favored change in neurophysiological and behavioral outcome measures in chronic dysphagia patients. Further larger cohort studies of neurostimulation in chronic dysphagic stroke are imperative.     

Effects of methylmercury on spinal cord afferents and efferents—A review

Methylmercury (MeHg) is an environmental neurotoxicant of public health concern. It readily accumulates in exposed humans, primarily in neuronal tissue. Exposure to MeHg, either acutely or chronically, causes severe neuronal dysfunction in the central nervous system and spinal neurons; dysfunction of susceptible neuronal populations results in neurodegeneration, at least in part through Ca²⁺-mediated pathways. Biochemical and morphologic changes in peripheral neurons precede those in central brain regions, despite the fact that MeHg readily crosses the blood-brain barrier. Consequently, it is suggested that unique characteristics of spinal cord afferents and efferents could heighten their susceptibility to MeHg toxicity. Transient receptor potential (TRP) ion channels are a class of Ca²⁺-permeable cation channels that are highly expressed in spinal afferents, among other sensory and visceral organs. These channels can be activated in numerous ways, including directly via chemical irritants or indirectly via Ca²⁺ release from intracellular storage organelles. Early studies demonstrated that MeHg interacts with heterologous TRP channels, though definitive mechanisms of MeHg toxicity on sensory neurons may involve more complex interaction with, and among, differentially-expressed TRP populations. In spinal efferents, glutamate receptors of the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and possibly kainic acid (KA) classes are thought to play a major role in MeHg-induced neurotoxicity. Specifically, the Ca²⁺-permeable AMPA receptors, which are abundant in motor neurons, have been identified as being involved in MeHg-induced neurotoxicity. In this review, we will describe the mechanisms that could contribute to MeHg-induced spinal cord afferent and efferent neuronal degeneration, including the possible mediators, such as uniquely expressed Ca²⁺-permeable ion channels.     

The clinimetric properties of aerobic and anaerobic fitness measures in adults with cerebral palsy: A systematic review of the literature

ObjectiveTo analyze the clinimetric properties of maximal aerobic and anaerobic fitness measurement protocols in adults with cerebral palsy (CP).Data SourcesA systematic search through March 2015 of databases PubMed, Embase, SPORTDiscus and PsycINFO was performed with medical subject heading terms for ‘cerebral palsy’ combined with search terms adults or adolescents and multiple text words for fitness and exercise tests that yielded 864 articles.Study SelectionAbstracts were screened by two reviewers to identify use of maximal fitness measurements in adolescents (14–18 yrs) or adults (>18 yrs) with CP of all abilities. Ninety-four articles were reviewed. No studies of adolescent (14–18 yrs) qualified. Eight articles reported clinimetric properties for adults with CP who walk or propel a wheelchair independently. Five articles reported on aerobic capacity, one reported on anaerobic capacity and two reported on both.Data ExtractionMethodological quality of the studies was rated using portions of the COSMIN (COnsensus-based Standards for the selection of health status Measurement INstruments) checklist. Quality of the measurement protocols was evaluated based on statistical strength of the clinimetrics. Synthesis of the overall evidence was based on the Cochrane review group guidelines which combine methodological quality and statistical strength.Data SynthesisEight articles reported on 4 aerobic and 1 anaerobic protocols. Overall synthesis revealed that for ambulatory adults with CP there is (i) moderate evidence for good reliability and good construct validity of maximal aerobic and anaerobic cycle tests, (ii) moderate evidence for good criterion validity of sub-maximal aerobic cycle tests, and (iii) strong evidence for poor criterion validity of the six-minute walk test as a maximal aerobic test. And for adults who propel a wheelchair there is limited evidence of good reliability for maximal aerobic wheelchair ergometer tests.ConclusionsLimited quality research exists on the clinimetric properties of aerobic and anaerobic capacity measures for adults with CP who have independent mobility. Quality aerobic and anaerobic measures for adults with more severe mobility impairments are absent.     

Comparative efficacy of CPAP,MADs, exercise-training,and dietary weight loss for sleep apnea: a network meta-analysis

Study objectiveTo synthesize evidence from available studies on the relative efficacies of continuous positive airway pressure (CPAP), mandibular advancement device (MAD), supervised aerobic exercise training, and dietary weight loss in patients with obstructive sleep apnea (OSA).DesignNetwork meta-analysis of 80 randomized controlled trials (RCTs) short-listed from PubMed, SCOPUS, Web of science, and Cochrane register (inception – September 8, 2015).PatientsIndividuals with OSA.InterventionsCPAP, MADs, exercise training, and dietary weight loss.ResultsCPAP decreased apnea–hypopnea index (AHI) the most [by 25.27 events/hour (22.03–28.52)] followed by exercise training, MADs, and dietary weight loss. While the difference between exercise training and CPAP was non-significant [−8.04 (−17.00 to 0.92), a significant difference was found between CPAP and MADs on AHI and oxygen desaturation index (ODI) [−10.06 (−14.21 to −5.91) and −7.82 (−13.04 to −2.59), respectively]. Exercise training significantly improved Epworth sleepiness scores (ESS) [by 3.08 (0.68–5.48)], albeit with a non-significant difference compared to MADs and CPAP.ConclusionsCPAP is the most efficacious in complete resolution of sleep apnea and in improving the indices of saturation during sleep. While MADs offer a reasonable alternative to CPAP, exercise training which significantly improved daytime sleepiness (ESS) could be used as adjunctive to the former two.     

Levetiracetam but not valproate inhibits function of CD8+ T lymphocytes

PurposeTo further elucidate possible immune-modulatory effects of valproate (VPA) or levetiracetam (LEV), we investigated their influence on apoptosis and cytotoxic function of CD8⁺ T lymphocytes in humans.MethodsIn 15 healthy subjects (9 female (60%), 35.7 ± 12.1 years), apoptosis and cytotoxic function of CD8⁺ T lymphocytes were measured using flow cytometry following in vitro exposure to LEV (5 mg/L and 50 mg/L) and VPA (10 mg/L and 100 mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1 h or 24 h. Cytotoxic function was assessed following 2 h stimulation with mixed virus peptides, using perforin release, CD107a/b expression and proliferation. The presence of synaptic vesicle protein 2A (SV2A) was investigated in human CD8⁺ T lymphocytes by flow cytometry analysis, Western blot and real time polymerase chain reaction (rtPCR).ResultsHigh concentration of LEV decreased perforin release of CD8⁺ T lymphocytes (LEV 50 mg/L vs. CEF only: 21.4% (interquartile range (IQR) 16.5–35.9%) vs. 16.6% (IQR 12–24.9%), p = 0.002). LEV had no influence on apoptosis and proliferation (p > 0.05). VPA (100 mg/L) slowed apoptosis of CD8⁺ T lymphocytes after 24 h (VPA 100 mg/L vs. control: 7.3% (IQR 5.4–9.5%) vs. 11.3% (IQR 8.2–15.1%), p < 0.001), but had no effects on perforin release (p > 0.05). SV2A protein was detected in CD8⁺ T lymphocytes.ConclusionLEV decreased degranulation of CD8⁺ T lymphocytes which may contribute to the increased incidence of upper respiratory tract infections in LEV treated patients. Inhibition of SV2A may be responsible for this effect.     

Activation of ER stress and apoptosis by α- and β-zearalenol in HCT116 cells,protective role of Quercetin

Zearalenone (ZEN) and its metabolites are found in many food products and are known to induce many toxic effects. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). The mechanisms by which they mediate their cytotoxic effects are not well known and seem to differ depending on the type of cells. We investigated the possible underlying mechanism in α-ZOL and β-ZOL-induced toxicity in HCT116 cells. We showed that cell treatment with α-ZOL/β-ZOL generated endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing and up-regulation of GADD34, GRP78, ATF4 and CHOP. Apoptosis was triggered by ZEN metabolites-induced ER stress, and executed through a mitochondria-dependent pathway, characterized by a loss of mitochondrial transmembrane potential (ΔΨ_m), a downstream generation of O₂•⁻ and caspase 3 activation. Cellular deficiency of the pro-apoptotic proteins Bax and Bak protected cells against α/β-ZOL-induced toxicity. However, treatment with α-ZOL or β-ZOL combined with Quercetin (QUER), a common dietary flavonoid with well-known antioxidant activity, significantly reduced damage induced by α and β-ZOL in all tested markers. We concluded that QUER protects against the cellular toxicity of α and β-ZOL.×     

The effects of preweaning manganese exposure on spatial learning ability and p-CaMKIIα level in the hippocampus

BackgroundThe effects and mechanisms of preweaning Manganese (Mn) exposure on cognitive dysfunction remain unclear.ObjectiveThis study evaluated the effects of preweaning Mn exposure on spatial learning and memory as well as the protein expression of CaMKIIα and p-CaMKIIα.MethodsWe treated neonate rats with Mn²⁺ doses of 0 (control group), 10, 20 and 30 mg of Mn²⁺ per kg body weight (Mn-exposed groups) over postnatal day (PND) 1–21 by intraperitoneal injection. The ability of spatial learning and memory was tested on PND 22 using the Morris water maze (MWM), while the protein expressions of CaMKIIα and p-CaMKIIα in the hippocampus were evaluated by Western blotting. The levels of Mn in the blood and hippocampus were measured by inductively coupled plasma-mass spectrometry (ICP-MS).ResultsThe rats in Mn-exposed groups showed a significant delay in spatial learning ability on the third day of the MWM without dose-dependent differences, but there was no effect on the spatial memory ability. p-CaMKIIα, but not CaMKIIα protein expression significantly reduced in the Mn-exposed group.ConclusionThese findings suggested that the inhibition of p-CaMKIIα could be one of the mechanisms involved in the occurrence of Mn-induced cognitive impairments.     

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.     

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.     

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.     

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.     

Focused Ultrasound-mediated Non-invasive Brain Stimulation: Examination of Sonication Parameters

BackgroundTranscranial focused ultrasound (FUS) has emerged as a new brain stimulation modality. The range of sonication parameters for successful brain stimulation warrants further investigation.ObjectiveThe objective of this study was to examine the range of FUS sonication parameters that minimize the acoustic intensity/energy deposition while successfully stimulating the motor brain area in Sprague–Dawley rats.MethodsWe transcranially administered FUS to the somatomotor area of the rat brain and measured the acoustic intensity that caused excitatory effects with respect to different pulsing parameters (tone-burst duration, pulse-repetition frequency, duty cycle, and sonication duration) at 350 and 650 kHz of fundamental frequency.ResultsWe observed that motor responses were elicited at minimum threshold acoustic intensities (4.9–5.6 W/cm² in spatial-peak pulse-average intensity; 2.5–2.8 W/cm² in spatial-peak temporal-average intensity) in a limited range of sonication parameters, i.e. 1–5 ms of tone-burst duration, 50% of duty cycle, and 300 ms of sonication duration, at 350 kHz fundamental frequency. We also found that the pulsed sonication elicited motor responses at lower acoustic intensities than its equivalent continuous sonication.ConclusionOur results suggest that the pulsed application of FUS selectively stimulates specific brain areas-of-interest at an acoustic intensity that is compatible with regulatory safety limits on biological tissue, thus allowing for potential applications in neurotherapeutics.