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Neuroscience
Using transcranial magnetic stimulation of the undamaged brain to identify lesion sites that predict language outcome after stroke
Apr 21, 2017   Brain : A Journal Of Neurology
Lorca-Puls DL, Gajardo-Vidal A, Seghier ML, Leff AP, Sethi V, Prejawa S, Hope TMH, Devlin JT, Price CJ
Using transcranial magnetic stimulation of the undamaged brain to identify lesion sites that predict language outcome after stroke
Apr 21, 2017
Brain : A Journal Of Neurology
Transcranial magnetic stimulation focused on either the left anterior supramarginal gyrus or opercular part of the left inferior frontal gyrus has been reported to transiently impair the ability to perform phonological more than semantic tasks. Here we tested whether phonological processing abilities were also impaired following lesions to these regions in right-handed, English speaking adults, who were investigated at least 1 year after a left-hemisphere stroke. When our regions of interest were limited to 0.5 cm3 of grey matter centred around sites that had been identified with transcranial magnetic stimulation-based functional localization, phonological impairments were observed in 74% (40/54) of patients with damage to the regions and 21% (21/100) of patients sparing these regions. This classification accuracy was better than that observed when using regions of interest centred on activation sites in previous functional magnetic resonance imaging studies of phonological processing, or transcranial magnetic stimulation sites that did not use functional localization. New regions of interest were generated by redefining the borders of each of the transcranial magnetic stimulation sites to include areas that were consistently damaged in the patients with phonological impairments. This increased the incidence of phonological impairments in the presence of damage to 85% (46/54) and also reduced the incidence of phonological impairments in the absence of damage to 15% (15/100). The difference in phonological processing abilities between those with and without damage to these 'transcranial magnetic stimulation-guided' regions remained highly significant even after controlling for the effect of lesion size. The classification accuracy of the transcranial magnetic stimulation-guided regions was validated in a second sample of 108 patients and found to be better than that for (i) functional magnetic resonance imaging-guided regions; (ii) a region identified from an unguided lesion overlap map; and (iii) a region identified from voxel-based lesion-symptom mapping. Finally, consistent with prior findings from functional imaging and transcranial magnetic stimulation in healthy participants, we show how damage to our transcranial magnetic stimulation-guided regions affected performance on phonologically more than semantically demanding tasks. The observation that phonological processing abilities were impaired years after the stroke, suggests that other brain regions were not able to fully compensate for the contribution that the transcranial magnetic stimulation-guided regions make to language tasks. More generally, our novel transcranial magnetic stimulation-guided lesion-deficit mapping approach shows how non-invasive stimulation of the healthy brain can be used to guide the identification of regions where brain damage is likely to cause persistent behavioural effects. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.
Molecular Mechanisms of Sleep Homeostasis in Flies and Mammals
Apr 22, 2017   Cold Spring Harbor Perspectives In Biology
Allada R, Cirelli C, Sehgal A
Molecular Mechanisms of Sleep Homeostasis in Flies and Mammals
Apr 22, 2017
Cold Spring Harbor Perspectives In Biology
Sleep is homeostatically regulated with sleep pressure accumulating with the increasing duration of prior wakefulness. Yet, a clear understanding of the molecular components of the homeostat, as well as the molecular and cellular processes they sense and control to regulate sleep intensity and duration, remain a mystery. Here, we will discuss the cellular and molecular basis of sleep homeostasis, first focusing on the best homeostatic sleep marker in vertebrates, slow wave activity; second, moving to the molecular genetic analysis of sleep homeostasis in the fruit fly Drosophila; and, finally, discussing more systemic aspects of sleep homeostasis. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.
The comprehensive connectome of a neural substrate for 'ON' motion detection in Drosophila
Apr 22, 2017   ELife
Takemura SY, Nern A, Chklovskii DB, Scheffer LK, Rubin GM, Meinertzhagen IA
The comprehensive connectome of a neural substrate for 'ON' motion detection in Drosophila
Apr 22, 2017
ELife
Analysing computations in neural circuits often uses simplified models because the actual neuronal implementation is not known. For example, a problem in vision, how the eye detects image motion, has long been analysed using Hassenstein-Reichardt (HR) detector or Barlow-Levick (BL) models. These both simulate motion detection well, but the exact neuronal circuits undertaking these tasks remain elusive. We reconstructed a comprehensive connectome of the circuits of Drosophila's motion-sensing T4 cells using a novel EM technique. We uncover complex T4 inputs and reveal that putative excitatory inputs cluster at T4's dendrite shafts, while inhibitory inputs localize to the bases. Consistent with our previous study, we reveal that Mi1 and Tm3 cells provide most synaptic contacts onto T4. We are, however, unable to reproduce the spatial offset between these cells reported previously. Our comprehensive connectome reveals complex circuits that include candidate anatomical substrates for both HR and BL types of motion detectors.
The good lies: Altruistic goals modulate processing of deception in the anterior insula
Apr 22, 2017   Human Brain Mapping
Yin L, Hu Y, Dynowski D, Li J, Weber B
The good lies: Altruistic goals modulate processing of deception in the anterior insula
Apr 22, 2017
Human Brain Mapping
When it comes to lies, the beneficiaries of one's dishonesty play an important role in the decision-making process. Altruistic lies that are made with the intention of benefiting others are a specific type of lies and very common in real life. While it has been shown that altruistic goals influence (dis)honest behaviors, the neural substrates of this effect is still unknown. To reveal how the brain integrates altruistic goals into (dis)honest decisions, this study used functional magnetic resonance imaging to examine the neural activity of participants in a real incentivized context while they were making (dis)honest decisions. We manipulated the beneficiaries of individuals' decisions (self vs. a charity) and whether the choices of higher payoffs involved deception or not. While finding that participants lied more often to benefit charities than for themselves, we observed that the altruistic goal of benefiting a charity, compared with the self-serving goal, reduced the activity in the anterior insula (AI) when lying to achieve higher payoffs. Furthermore, the degree of altruistic goal-induced reduction of AI activity was positively correlated with the degree of altruistic goal-induced reduction of honesty concerns. These results suggest that the AI serves as a neural hub in modulating the effect of altruistic goals on deception, which shed light on the underlying neural mechanism of altruistic lies. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Cross-species studies of cognition relevant to drug discovery: A translational approach
Apr 22, 2017   British Journal Of Pharmacology
Robbins TW
Cross-species studies of cognition relevant to drug discovery: A translational approach
Apr 22, 2017
British Journal Of Pharmacology
This Review advances the case that bidirectional, cross-species translation of findings from experimental animals to and from humans is an important strategy for drug discovery. Animal models of mental disorders require appropriate behavioural or cognitive outcome variables that can be generalized cross-species. One example is the treatment of impulsive behaviour in attention deficit hyperactivity disorder (ADHD) with stimulant drugs. Performance on the stop signal reaction task as an index of impulsivity is improved both in healthy human volunteers and in patients with adult ADHD by stimulant drugs and also by the selective noradrenergic reuptake blocker atomoxetine. Functional neuroimaging evidence suggests a modulation of circuitry including the inferior prefrontal cortex by this drug. Parallel work in rats had shown that atomoxetine improves stop signal performance by affecting possibly homologous regions of the rodent prefrontal cortex. This parallel effect of atomoxetine in rodents and humans could potentially be exploited in other disorders in which impulsivity plays a role such as stimulant abuse and Parkinson's disease. A contrasting relative lack of involvement of 5-hydroxytryptamine mechanisms in the stop signal reaction time task will also be described. Research in humans and experimental animals that demonstrate effects of serotoninergic agents such as the selective serotonin reuptake inhibitor citalopram on probabilistic learning and reversal (upon which atomoxetine has little effect) will also be reviewed, possibly relevant to the treatment of clinical depression, Finally, other promising examples of parallel studies of behavioural effects of CNS-active drugs in animals and humans will also be described. This article is protected by copyright. All rights reserved.
Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants
Apr 22, 2017   Human Mutation
Tio M, Wen R, Lim YL, Zukifli ZHB, Xie S, Ho P, Zhou Z, Koh TW, Zhao Y, Tan EK
Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants
Apr 22, 2017
Human Mutation
Mutations and polymorphic risk variant of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) have been associated with late-onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction which could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress and impairment in synaptic transmission. However, both mutants showed more severe early motor dysfunction, dopaminergic neuronal loss and higher hydrogen peroxide production compared to risk variant. p.Thr61Ile (co-segregated in three independent PD families) displayed the most severe phenotype followed by p.Arg145Gln (present only in index patient). We treated the transgenic flies with Ebselen, a mitochondrial hydrogen peroxide scavenger compound and Ebselen appears to be more effective in ameliorating motor function in the mutant than the risk variant models. We provide the first in vivo evidence of the pathological effects associated with CHCHD2 mutations. There was a difference in the pathological and drug response effects between the pathogenic and the risk variants. Ebselen may be a useful neuroprotective drug for carriers of CHCHD2 mutations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
MDMA does not alter responses to the Trier Social Stress Test in humans
Apr 22, 2017   Psychopharmacology
Bershad AK, Miller MA, de Wit H
MDMA does not alter responses to the Trier Social Stress Test in humans
Apr 22, 2017
Psychopharmacology
±3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a stimulant-psychedelic drug with unique social effects. It may dampen reactivity to negative social stimuli such as social threat and rejection. Perhaps because of these effects, MDMA has shown promise as a treatment for post-traumatic stress disorder (PTSD). However, the effect of single doses of MDMA on responses to an acute psychosocial stressor has not been tested. In this study, we sought to test the effects of MDMA on responses to stress in healthy adults using a public speaking task. We hypothesized that the drug would reduce responses to the stressful task. Volunteers (N = 39) were randomly assigned to receive placebo (N = 13), 0.5 mg/kg MDMA (N = 13), or 1.0 mg/kg MDMA (N = 13) during a stress and a no-stress session. Dependent measures included subjective reports of drug effects and emotional responses to the task, as well as salivary cortisol, heart rate, and blood pressure. The stress task produced its expected increase in physiological responses (cortisol, heart rate) and subjective ratings of stress in all three groups, and MDMA produced its expected subjective and physiological effects. MDMA alone increased ratings of subjective stress, heart rate, and saliva cortisol concentrations, but contrary to our hypothesis, it did not moderate responses to the Trier Social Stress Test. Despite its efficacy in PTSD and anxiety, MDMA did not reduce either the subjective or objective responses to stress in this controlled study. The conditions under which MDMA relieves responses to negative events or memories remain to be determined.
How visual experience impacts the internal and external spatial mapping of sensorimotor functions
Apr 22, 2017   Scientific Reports
Crollen V, Albouy G, Lepore F, Collignon O
How visual experience impacts the internal and external spatial mapping of sensorimotor functions
Apr 22, 2017
Scientific Reports
Tactile perception and motor production share the use of internally- and externally-defined coordinates. In order to examine how visual experience affects the internal/external coding of space for touch and movement, early blind (EB) and sighted controls (SC) took part in two experiments. In experiment 1, participants were required to perform a Temporal Order Judgment task (TOJ), either with their hands in parallel or crossed over the body midline. Confirming previous demonstration, crossing the hands led to a significant decrement in performance in SC but did not affect EB. In experiment 2, participants were trained to perform a sequence of five-finger movements. They were tested on their ability to produce, with the same hand but with the keypad turned upside down, the learned (internal) or the mirror (external) sequence. We observed significant transfer of motor sequence knowledge in both EB and SC irrespective of whether the representation of the sequence was internal or external. Together, these results demonstrate that visual experience differentially impacts the automatic weight attributed to internal versus external coordinates depending on task-specific spatial requirements.
A microRNA-mRNA expression network during oral siphon regeneration in Ciona
Apr 22, 2017   Development (Cambridge, England)
Spina EJ, Guzman E, Zhou H, Kosik KS, Smith WC
A microRNA-mRNA expression network during oral siphon regeneration in Ciona
Apr 22, 2017
Development (Cambridge, England)
Here we present a parallel study of mRNA and microRNA expression during oral siphon (OS) regeneration in Ciona robusta, and the derived network of their interactions. In the process of identifying 248 mRNAs and 15 microRNAs as differentially expressed (DE), we also identified 57 novel microRNAs, several of which are among the most highly DE. Analysis of functional categories identified enriched transcripts related to stress responses and apoptosis at the wound healing stage, signaling pathways including Wnt and TGF-β during early regrowth, and negative regulation of extracellular proteases in late stage regeneration. Consistent with the expression results we found that inhibition of TGF-β signaling blocked OS regeneration. A correlation network was subsequently inferred for all predicted microRNA-mRNA target pairs expressed during regeneration. Network based clustering associated transcripts into 22 non-overlapping groups, functional analysis of which showed enrichment of stress response, signaling pathway and extracellular protease categories could be related to specific microRNAs. Finally, predicted targets of the miR-9 cluster suggest a role in regulating differentiation and proliferative state of neural progenitors through regulation of the cytoskeleton and cell cycle. © 2017. Published by The Company of Biologists Ltd.
Focal local field potential (LFP) signature of the single-axon monosynaptic thalamocortical connection
Apr 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Hagen E, Fossum JC, Pettersen KH, Alonso JM, Swadlow HA, Einevolla GT
Focal local field potential (LFP) signature of the single-axon monosynaptic thalamocortical connection
Apr 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Recent years have seen a resurgence in use of the extracellularly recorded local field potential (LFP) to investigate neural network activity. To probe monosynaptic thalamic activation of cortical postsynaptic target cells, so called spike-trigger-averaged LFP (stLFP) signatures have been measured. In these experiments the cortical LFP is measured by means of multielectrodes covering several cortical lamina and averaged on spontaneous spikes of thalamocortical (TC) cells. Using a well-established forward-modeling scheme, we investigate the biophysical origin of this stLFP signature with simultaneous synaptic activation of cortical layer 4 neurons, mimicking the effect of a single afferent spike from a single TC neuron. Constrained by previously measured intracellular responses of the main postsynaptic target cell types and with biologically plausible assumptions regarding the spatial distribution of thalamic synaptic inputs into layer 4, the model predicted characteristic contributions to monosynaptic stLFP signatures both for the regular spiking (RS) excitatory neurons and the fast spiking (FS) inhibitory interneurons. In particular, the FS cells generated stLFP signatures of shorter temporal duration than the RS cells. Added together, a sum of the stLFP signatures of these two principal synaptic targets of thalamocortical cells were observed to resemble experimentally measured stLFP signatures. Outside the volume targeted by TC afferents the resulting postsynaptic LFP signals were found to be sharply attenuated. This implies that such stLFP signatures provide a very local measure of thalamocortical synaptic activation, and that newly developed inverse CSD-estimation methods are needed for precise assessment of the underlying spatiotemporal current-source density (CSD) profiles.SIGNIFICANCE STATEMENTDespite its long history and prevalent use, the proper interpretation of the extracellularly recorded local field potential (LFP) is still not fully established. Here we investigate by means of biophysical modeling the origin of the focal LFP signature of the single-axon monosynaptic thalamocortical connection as measured by spike-trigger-averaging of cortical LFPs on spontaneous spikes of thalamocortical neurons. We find that this LFP signature is well accounted for by a model assuming thalamic projections to two cortical layer-4 cell populations: one excitatory (putatively regular-spiking cells) and one inhibitory (putatively fast-spiking cells). The LFP signature is observed to decay sharply outside the cortical region receiving the thalamocortical projection, implying that it indeed provides a very local measure of thalamocortical synaptic activation. Copyright © 2017 Hagen et al.
Visually-evoked 3-5 Hz membrane potential oscillations reduce the responsiveness of visual cortex neurons in awake behaving mice
Apr 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Einstein MC, Polack PO, Tran DT, Golshani P
Visually-evoked 3-5 Hz membrane potential oscillations reduce the responsiveness of visual cortex neurons in awake behaving mice
Apr 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Low frequency membrane potential (Vm) oscillations were once thought to only occur in sleeping and anesthetized states. Recently, low frequency Vm oscillations have been described in inactive awake animals, but it is unclear if they shape sensory processing in neurons and whether they occur during active awake behavioral states. To answer these questions, we performed two-photon guided whole-cell Vm recordings from primary visual cortex layer 2/3 excitatory and inhibitory neurons in awake mice during passive visual stimulation and performance of visual and auditory discrimination tasks. We recorded stereotyped 3-5 Hz Vm oscillations where the Vm baseline hyperpolarized as the Vm underwent high amplitude rhythmic fluctuations lasting 1-2 seconds in duration. When 3-5 Hz Vm oscillations coincided with visual cues, excitatory neuron responses to preferred cues were significantly reduced. Despite this disruption to sensory processing, visual cues were critical for evoking 3-5 Hz Vm oscillations when animals performed discrimination tasks and passively viewed drifting grating stimuli. Using pupilometry and animal locomotive speed as indicators of arousal, we found that 3-5 Hz oscillations were not restricted to unaroused states and that they occurred equally in aroused and unaroused states. Therefore, low frequency Vm oscillations play a role in shaping sensory processing in visual cortical neurons, even during active wakefulness and decision making.SIGNIFICANCE STATEMENTA neuron's membrane potential (Vm) strongly shapes how information is processed in sensory cortices of awake animals. Yet, very is little known about how low frequency Vm oscillations influence sensory processing and whether they occur in aroused awake animals. By performing 2-photon guided whole-cell recordings from layer 2/3 excitatory and inhibitory neurons in the visual cortex of awake behaving animals, we found visually-evoked stereotyped 3-5 Hz Vm oscillations that disrupt excitatory responsiveness to visual stimuli. Moreover, these oscillations occurred when animals were in high and low arousal states as measured by animal speed and pupilometry. These findings show for the first time that low frequency Vm oscillations can significantly modulate sensory signal processing even in awake active animals. Copyright © 2017 the authors.
Feature Selective Attention Adaptively Shifts Noise Correlations in Primary Auditory Cortex
Apr 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Downer J, Rapone B, Verhein J, O'Connor KN, Sutter ML
Feature Selective Attention Adaptively Shifts Noise Correlations in Primary Auditory Cortex
Apr 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Sensory environments often contain an overwhelming amount of information, with both relevant and irrelevant information competing for neural resources. Feature attention mediates this competition by selecting the sensory features needed to form a coherent percept. How attention affects the activity of populations of neurons to support this process is poorly understood because population coding is typically studied through simulations in which one sensory feature is encoded without competition. Therefore, to study the effects of feature attention on population-based neural coding, investigations must be extended to include stimuli with both relevant and irrelevant features. We measured noise correlations (rnoise) between small neural populations in primary auditory cortex while rhesus macaques performed a novel feature selective attention task. We found that the effect of feature selective attention on rnoise depended not only on the population tuning to the attended feature, but also on the tuning to the distractor feature. To attempt to explain how these observed effects might support enhanced perceptual performance, we propose an extension of a simple and influential model in which shifts in rnoise can simultaneously enhance the representation of the attended feature while suppressing the distractor. These findings present a novel mechanism by which attention modulates neural populations to support sensory processing in cluttered environments.SIGNIFICANCE STATEMENTThough feature selective attention constitutes one of the building blocks of listening in natural environments, its neural bases remain obscure. To address this, we developed a novel auditory feature selective attention task and measured noise correlations (rnoise) in rhesus macaque A1 during task performance. Unlike previous studies that have shown that the effect of attention on rnoise depends on population tuning to the attended feature, we show that the effect of attention depends on the tuning to the distractor feature as well. We suggest that these effects represent an efficient process by which sensory cortex simultaneously enhances relevant, and suppresses irrelevant information. Copyright © 2017 the authors.
Incidence of First Stroke in Pregnant and Nonpregnant Women of Childbearing Age: A Population-Based Cohort Study From England
Apr 22, 2017   Journal Of The American Heart Association
Ban L, Sprigg N, Abdul Sultan A, Nelson-Piercy C, Bath PM, Ludvigsson JF, Stephansson O, Tata LJ
Incidence of First Stroke in Pregnant and Nonpregnant Women of Childbearing Age: A Population-Based Cohort Study From England
Apr 22, 2017
Journal Of The American Heart Association
Pregnant women may have an increased risk of stroke compared with nonpregnant women of similar age, but the magnitude and the timing of such risk are unclear. We examined the risk of a first stroke event in women of childbearing age and compared the risk during pregnancy and in the early postpartum period with the background risk outside these periods. We conducted an open cohort study of 2 046 048 women aged 15 to 49 years between April 1, 1997, and March 31, 2014, using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care records in England. Risk of first stroke was assessed by calculating the incidence rate of stroke in antepartum, peripartum (2 days before until 1 day after delivery), and early (first 6 weeks) and late (second 6 weeks) postpartum periods compared with nonpregnant time using a Poisson regression model with adjustment for maternal age, socioeconomic group, and calendar time. A total of 2511 women had a first stroke. The incidence rate of stroke was 25.0 per 100 000 person-years (95% CI 24.0-26.0) in nonpregnant time. The rate was lower antepartum (10.7 per 100 000 person-years, 95% CI 7.6-15.1) but 9-fold higher peripartum (161.1 per 100 000 person-years, 95% CI 80.6-322.1) and 3-fold higher early postpartum (47.1 per 100 000 person-years, 95% CI 31.3-70.9). Rates of ischemic and hemorrhagic stroke both increased peripartum and early postpartum. Although the absolute risk of first stroke is low in women of childbearing age, healthcare professionals should be aware of a considerable increase in relative risk during the peripartum and early postpartum periods. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
Left Brain Asymmetry of the Planum Temporale in a Nonhominid Primate: Redefining the Origin of Brain Specialization for Language
Apr 21, 2017   Cerebral Cortex (New York, N.Y. : 1991)
Marie D, Roth M, Lacoste R, Nazarian B, Bertello A, Anton JL, Hopkins WD, Margiotoudi K, Love SA, Meguerditchian A
Left Brain Asymmetry of the Planum Temporale in a Nonhominid Primate: Redefining the Origin of Brain Specialization for Language
Apr 21, 2017
Cerebral Cortex (New York, N.Y. : 1991)
The planum temporale (PT) is a critical region of the language functional network in the human brain showing a striking size asymmetry toward the left hemisphere. Historically considered as a structural landmark of the left-brain specialization for language, a similar anatomical bias has been described in great apes but never in monkeys-indicating that this brain landmark might be unique to Hominidae evolution. In the present in vivo magnetic resonance imaging study, we show clearly for the first time in a nonhominid primate species, an Old World monkey, a left size predominance of the PT among 96 olive baboons (Papio anubis), using manual delineation of this region in each individual hemisphere. This asymmetric distribution was quasi-identical to that found originally in humans. Such a finding questions the relationship between PT asymmetry and the emergence of language, indicating that the origin of this cerebral specialization could be much older than previously thought, dating back, not to the Hominidae, but rather to the Catarrhini evolution at the common ancestor of humans, great apes and Old World monkeys, 30-40 million years ago. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Utility of the new Movement Disorder Society clinical diagnostic criteria for Parkinson's disease applied retrospectively in a large cohort study of recent onset cases
Apr 22, 2017   Parkinsonism & Related Disorders
Malek N, Lawton MA, Grosset KA, Bajaj N, Barker RA, Ben-Shlomo Y, Burn DJ, Foltynie T, Hardy J, Morris HR, Williams NM, Wood N, Grosset DG, PRoBaND clinical consortium
Utility of the new Movement Disorder Society clinical diagnostic criteria for Parkinson's disease applied retrospectively in a large cohort study of recent onset cases
Apr 22, 2017
Parkinsonism & Related Disorders
To examine the utility of the new Movement Disorder Society (MDS) diagnostic criteria in a large cohort of Parkinson's disease (PD) patients. Recently diagnosed (
The Sleeping Cerebellum
Apr 22, 2017   Trends In Neurosciences
Canto CB, Onuki Y, Bruinsma B, van der Werf YD, De Zeeuw CI
The Sleeping Cerebellum
Apr 22, 2017
Trends In Neurosciences
We sleep almost one-third of our lives and sleep plays an important role in critical brain functions like memory formation and consolidation. The role of sleep in cerebellar processing, however, constitutes an enigma in the field of neuroscience; we know little about cerebellar sleep-physiology, cerebro-cerebellar interactions during sleep, or the contributions of sleep to cerebellum-dependent memory consolidation. Likewise, we do not understand why cerebellar malfunction can lead to changes in the sleep-wake cycle and sleep disorders. In this review, we evaluate how sleep and cerebellar processing may influence one another and highlight which scientific routes and technical approaches could be taken to uncover the mechanisms underlying these interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.
Getting a grip on reality: Grasping movements directed to real objects and images rely on dissociable neural representations
Apr 22, 2017   Cortex; A Journal Devoted To The Study Of The Nervous System And Behavior
Freud E, Macdonald SN, Chen J, Quinlan DJ, Goodale MA, Culham JC
Getting a grip on reality: Grasping movements directed to real objects and images rely on dissociable neural representations
Apr 22, 2017
Cortex; A Journal Devoted To The Study Of The Nervous System And Behavior
In the current era of touchscreen technology, humans commonly execute visually guided actions directed to two-dimensional (2D) images of objects. Although real, three-dimensional (3D), objects and images of the same objects share high degree of visual similarity, they differ fundamentally in the actions that can be performed on them. Indeed, previous behavioral studies have suggested that simulated grasping of images relies on different representations than actual grasping of real 3D objects. Yet the neural underpinnings of this phenomena have not been investigated. Here we used functional magnetic resonance imaging (fMRI) to investigate how brain activation patterns differed for grasping and reaching actions directed toward real 3D objects compared to images. Multivoxel Pattern Analysis (MVPA) revealed that the left anterior intraparietal sulcus (aIPS), a key region for visually guided grasping, discriminates between both the format in which objects were presented (real/image) and the motor task performed on them (grasping/reaching). Interestingly, during action planning, the representations of real 3D objects versus images differed more for grasping movements than reaching movements, likely because grasping real 3D objects involves fine-grained planning and anticipation of the consequences of a real interaction. Importantly, this dissociation was evident in the planning phase, before movement initiation, and was not found in any other regions, including motor and somatosensory cortices. This suggests that the dissociable representations in the left aIPS were not based on haptic, motor or proprioceptive feedback. Together, these findings provide novel evidence that actions, particularly grasping, are affected by the realness of the target objects during planning, perhaps because real targets require a more elaborate forward model based on visual cues to predict the consequences of real manipulation. Copyright © 2017 Elsevier Ltd. All rights reserved.
Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene
Apr 22, 2017   Acta Neuropathologica Communications
Davidson YS, Flood L, Robinson AC, Nihei Y, Mori K, Rollinson S, Richardson A, Benson BC, Jones M, Snowden JS, Pickering-Brown S, Haass C, Lashley T, Mann DMA
Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene
Apr 22, 2017
Acta Neuropathologica Communications
Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups.Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.
Guided Internet-based versus face-to-face clinical care in the management of tinnitus: study protocol for a multi-centre randomised controlled trial
Apr 22, 2017   Trials
Beukes EW, Baguley DM, Allen PM, Manchaiah V, Andersson G
Guided Internet-based versus face-to-face clinical care in the management of tinnitus: study protocol for a multi-centre randomised controlled trial
Apr 22, 2017
Trials
Innovative strategies are required to improve access to evidence-based tinnitus interventions. A guided Internet-based cognitive behavioural therapy (iCBT) intervention for tinnitus was therefore developed for a U.K. Initial clinical trials indicated efficacy of iCBT at reducing tinnitus severity and associated comorbidities such as insomnia and depression. The aim of this phase III randomised controlled trial is to compare this new iCBT intervention with an established intervention, namely face-to-face clinical care for tinnitus. This will be a multi-centre study undertaken across three hospitals in the East of England. The design is a randomised, two-arm, parallel-group, non-inferiority trial with a 2-month follow-up. The experimental group will receive the guided iCBT intervention, whereas the active control group will receive the usual face-to-face clinical care. An independent researcher will randomly assign participants, using a computer-generated randomisation schedule, after stratification for tinnitus severity. There will be 46 participants in each group. The primary assessment measure will be the Tinnitus Functional Index. Data analysis will establish whether non-inferiority is achieved using a pre-defined non-inferiority margin. This protocol outlines phase III of a clinical trial comparing a new iCBT with established face-to-face care for tinnitus. If guided iCBT for tinnitus proves to be as effective as the usual tinnitus care, it may be a viable additional management route for individuals with tinnitus. This could increase access to evidence-based effective tinnitus care and reduce the pressures on existing health care systems. ClinicalTrials.gov identifier: NCT02665975 . Registered on 22 January 2016.
Recognition of depression by primary care clinicians in rural Ethiopia
Apr 22, 2017   BMC Family Practice
Fekadu A, Medhin G, Selamu M, Giorgis TW, Lund C, Alem A, Prince M, Hanlon C
Recognition of depression by primary care clinicians in rural Ethiopia
Apr 22, 2017
BMC Family Practice
Depression is a common health condition affecting up to a third of patients attending primary care, where most of the care for people with depression is provided. Adequate recognition of depression is the critical step in the path to effective care, particularly in low income countries. As part of the Programme for Improving Mental healthcare (PRIME), a project supporting the implementation of integrated mental healthcare in primary care, we evaluated the level of recognition of depression by clinicians working in primary care in rural Ethiopia prior to in service training. We hypothesised that the detection rate of depression will be under 10% and that detection would be affected by gender, education and severity of depression. Cross-sectional survey in eight health centres serving a population of over 160,000 people. A validated version of the 9-item patient health questionnaire (PHQ-9) was administered as an indicator of probable depression. In addition, primary care clinicians completed a clinician encounter form. Participants were consecutive primary care attendees aged 18 years and above. A total of 1014 participants were assessed. Primary care clinicians diagnosed 13 attendees (1.3%) with depression. The PHQ9 prevalence of depression at a cut-off score of ten was 11.5% (n = 117), of whom 5% (n = 6/117) had received a diagnosis of depression by primary care clinicians. Attendees with higher PHQ scores and suicidality were significantly more likely to receive a diagnosis of depression by clinicians. Women (n = 9/13) and participants with higher educational attainment were more likely to be diagnosed with depression, albeit non-significantly. All cases diagnosed with depression by the clinicians had presented with psychological symptoms. Although not based on a gold standard diagnosis, over 98% of cases with PHQ-9 depression were undetected. Failure of recognition of depression may pose a serious threat to the scale up of mental healthcare in low income countries. Addressing this threat should be an urgent priority, and requires a better understanding of the nature of depression and its presentation in rural low-income primary care settings.
Validation of the short version of the 10/66 dementia diagnosis in multiethnic Asian older adults in Singapore
Apr 22, 2017   BMC Geriatrics
Abdin E, Vaingankar JA, Picco L, Chua BY, Prince M, Chong SA, Subramaniam M
Validation of the short version of the 10/66 dementia diagnosis in multiethnic Asian older adults in Singapore
Apr 22, 2017
BMC Geriatrics
To validate the short version of the 10/66 dementia diagnosis against the standard version of the 10/66 dementia diagnosis and clinical diagnosis and examine concurrent validity with the World Health Organisation Disability Assessment schedule and care needs in a multiethnic Asian older adult population in Singapore. Data from the Well-being of the Singapore Elderly study, a nationally representative survey of the older Singapore Resident population aged 60 years and above was used. The validity of the short version of the 10/66 dementia diagnostic criteria derived from the Community Screening Instrument for Dementia, the modified Consortium to Establish a Registry of Alzheimer's Disease 10-word list delayed recall and the EURO-D depression screen were examined against the standard version of the 10/66 dementia diagnosis and clinician diagnosis as a gold standard. Concurrent validity was tested by examining the relationships between the short version 10/66 dementia diagnosis, disability and care needs. A total of 2373 respondents who had completed data on the short version diagnosis were included in this study. The majority (82.63%) of respondents were of Chinese descent, 9.86% were Malays, 6.12% were of Indian descent and 1.39% belonged to other ethnic group. We found the short version 10/66 dementia diagnosis showed almost perfect agreement with the standard version 10/66 dementia diagnosis (kappa = 0.90, AUC = 0.96) and substantial agreement with clinical diagnosis (kappa = 0.70, AUC = 0.87). The weighted prevalence of dementia in the population was slightly higher based on the short version diagnosis than the standard version diagnosis (10.74% vs. 10.04%). We also found that those with the short version 10/66 dementia were significantly associated with higher disability (β = 28.90, 95% CI = 23.62, 9.62) and needed care occasionally (OR =35.21, 95% CI = 18.08, 68.59) or much of the time (OR = 9.02, 95% CI = 5.21, 15.61). The study found that the short version 10/66 dementia diagnosis has excellent validity to diagnose dementia in a multiethnic Asian population in Singapore. Further research is required to determine the usefulness of this diagnosis in clinical practice or institutional settings to aid early detection and intervention for dementia.
Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease
Apr 21, 2017   Neurobiology Of Aging
Mak E, Su L, Williams GB, Firbank MJ, Lawson RA,   . . . . . .   , Brooks DJ, Rowe JB, Barker RA, Burn DJ, O'Brien JT
Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease
Apr 21, 2017
Neurobiology Of Aging
We investigated whole-brain atrophy and ventricular enlargement over 18 months in nondemented Parkinson's disease (PD) and examined their associations with clinical measures and baseline CSF markers. PD subjects (n = 100) were classified at baseline into those with mild cognitive impairment (MCI; PD-MCI, n = 36) and no cognitive impairment (PD-NC, n = 64). Percentage of whole-brain volume change (PBVC) and ventricular expansion over 18 months were assessed with FSL-SIENA and ventricular enlargement (VIENA) respectively. PD-MCI showed increased global atrophy (-1.1% ± 0.8%) and ventricular enlargement (6.9 % ± 5.2%) compared with both PD-NC (PBVC: -0.4 ± 0.5, p < 0.01; VIENA: 2.1% ± 4.3%, p < 0.01) and healthy controls. In a subset of 35 PD subjects, CSF levels of tau, and Aβ42/Aβ40 ratio were correlated with PBVC and ventricular enlargement respectively. The sample size required to demonstrate a 20% reduction in PBVC and VIENA was approximately 1/15th of that required to detect equivalent changes in cognitive decline. These findings suggest that longitudinal MRI measurements have potential to serve as surrogate markers to complement clinical assessments for future disease-modifying trials in PD. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Combining Human Epigenetics and Sleep Studies in C. elegans: A Cross-species Approach for Finding Conserved Genes Regulating Sleep
Apr 21, 2017   Sleep
Huang H, Zhu Y, Eliot MN, Knopik VS, McGeary JE, Carskadon MA, Hart AC
Combining Human Epigenetics and Sleep Studies in C. elegans: A Cross-species Approach for Finding Conserved Genes Regulating Sleep
Apr 21, 2017
Sleep
We aimed to test a combined approach to identify conserved genes regulating sleep and to explore the association between DNA methylation and sleep length. We identified candidate genes associated with shorter versus longer sleep duration in college students based on DNA methylation using Illumina Infinium HumanMethylation450 BeadChip arrays. Orthologous genes in Caenorhabditiselegans were identified and we examined whether their loss of function affected C. elegans sleep. For genes whose perturbation affected C. elegans sleep, we subsequently undertook a small pilot study to re-examine DNA methylation in an independent set of human subjects with shorter versus longer sleep durations. Eighty-seven out of 485,577 CpG sites had significant differential methylation in young adults with shorter versus longer sleep duration, corresponding to 52 candidate genes. We identified 34 C. elegans orthologs, including NPY/flp-18 and flp-21, which are known to affect sleep. Loss of 5 additional genes alter developmentally-timed C. elegans sleep (B4GALT6/bre-4, DOCK180/ced-5, GNB2L1/rack-1, PTPRN2/ida-1, ZFYVE28/lst-2). For one of these genes, ZFYVE28 (also known as hLst2), the pilot replication study again found decreased DNA methylation associated with shorter sleep duration at the same two CpG sites in the first intron of ZFYVE28. Using an approach that combines human epigenetics and C. elegans sleep studies, we identified 5 genes that play previously unidentified roles in C. elegans sleep. We suggest sleep duration in humans may be associated with differential DNA methylation at specific sites and that the conserved genes identified here likely play roles in C. elegans sleep and in other species.
Ontogeny and thermogenic role for sternal fat in female sheep
Apr 21, 2017   Endocrinology
Henry BA, Pope M, Birtwistle M, Loughnan R, Alagal R, Fuller-Jackson JP, Perry V, Budge H, Clarke IJ, Symonds ME
Ontogeny and thermogenic role for sternal fat in female sheep
Apr 21, 2017
Endocrinology
Brown adipose tissue acting through a unique uncoupling protein (UCP1) has a critical role in preventing hypothermia in new-born sheep but is then considered to rapidly disappear during postnatal life. The extent to which the anatomical location of fat influences postnatal development and thermogenic function, particularly following feeding, in adulthood, are not known and were both examined in our study. Changes in gene expression of functionally important pathways (i.e. thermogenesis, development, adipogenesis and metabolism) were compared between sternal and retroperitoneal fat depots together with a representative skeletal muscle over the first month of postnatal life, coincident with the loss of brown fat and accumulation of white fat. In adult sheep, implanted temperature probes were used to characterise the thermogenic response of fat and muscle to feeding and the effects of reduced or increased adiposity. UCP1 was more abundant within sternal than retroperitoneal fat and was only retained in the sternal depot of adults. Distinct differences in the abundance of gene pathway markers were apparent between tissues, with sternal fat exhibiting some similarities with muscle that were not apparent in the retroperitoneal depot. In adults, the post-prandial rise in temperature was greater and more prolonged in sternal than retroperitoneal fat and muscle, a difference that was maintained with altered adiposity. In conclusion, sternal adipose tissue retains UCP1 into adulthood when it shows a greater thermogenic response to feeding than muscle and retroperitoneal fat. Sternal fat may be more amenable to targeted interventions that promote thermogenesis in large mammals. Copyright © 2017 Endocrine Society.
Presynaptic morphology and vesicular composition determine vesicle dynamics in mouse central synapses
Apr 22, 2017   ELife
Guillaud L, Dimitrov D, Takahashi T
Presynaptic morphology and vesicular composition determine vesicle dynamics in mouse central synapses
Apr 22, 2017
ELife
Transport of synaptic vesicles (SVs) in nerve terminals is thought to play essential roles in maintenance of neurotransmission. To identify factors modulating SV movements, we performed real-time imaging analysis of fluorescently labeled SVs in giant calyceal and conventional hippocampal terminals. Compared with small hippocampal terminals, SV movements in giant calyceal terminals were faster, longer and kinetically more heterogeneous. Morphological maturation of giant calyceal terminals was associated with an overall reduction in SV mobility and displacement heterogeneity. At the molecular level, SVs over-expressing vesicular glutamate transporter 1 (VGLUT1) showed higher mobility than VGLUT2-expressing SVs. Pharmacological disruption of the presynaptic microtubule network preferentially reduced long directional movements of SVs between release sites. Functionally, synaptic stimulation appeared to recruit SVs to active zones without significantly altering their mobility. Hence, the morphological features of nerve terminals and the molecular signature of vesicles are key elements determining vesicular dynamics and movements in central synapses.

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