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Joshua, M, Tokiyama S, Lisberger SG.  2015.  Interactions between target location and reward size modulate the rate of microsaccades in monkeys.. Journal of neurophysiology. :jn.00401.2015. Abstract
We have studied how rewards modulate the occurrence of microsaccades by manipulating the size of an expected reward and the location of the cue that sets the expectations for future reward. We found an interaction between the size of the reward and the location of the cue. When monkeys fixated on a cue that signaled the size of future reward, the frequency of microsaccades was higher if the monkey expected a large versus a small reward. When the cue was presented at a site in the visual field that was remote from the position of fixation, reward size had the opposite effect: the frequency of microsaccades was lower when the monkey was expecting a large reward. The strength of pursuit initiation also was affected by rewards size and by the presence of microsaccades just before the onset of target motion. The gain of pursuit initiation increased with reward size and decreased when microsaccades occurred just before or after the onset of target motion. The effect of the reward size on pursuit initiation was much larger than any indirect effects reward might cause through modulation of the rate of microsaccades. We found only a weak relationship between microsaccade direction and the location of the exogenous cue relative to fixation position, even in experiments where the location of the cue indicated the direction of target motion. Our results indicate that the expectation of reward is a powerful modulator of the occurrence of microsaccades, perhaps through attentional mechanisms.
McKyton, A, Ben-Zion I, Doron R, Zohary E.  2015.  The Limits of Shape Recognition following Late Emergence from Blindness.. Current biology : CB. Abstract
Visual object recognition develops during the first years of life [1]. But what if one is deprived of vision during early post-natal development? Shape information is extracted using both low-level cues (e.g., intensity- or color-based contours) and more complex algorithms that are largely based on inference assumptions (e.g., illumination is from above, objects are often partially occluded) [2]. Previous studies, testing visual acuity using a 2D shape-identification task (Lea symbols), indicate that contour-based shape recognition can improve with visual experience, even after years of visual deprivation from birth [3]. We hypothesized that this may generalize to other low-level cues (shape, size, and color), but not to mid-level functions (e.g., 3D shape from shading) that might require prior visual knowledge. To that end, we studied a unique group of subjects in Ethiopia that suffered from an early manifestation of dense bilateral cataracts and were surgically treated only years later. Our results suggest that the newly sighted rapidly acquire the ability to recognize an odd element within an array, on the basis of color, size, or shape differences. However, they are generally unable to find the odd shape on the basis of illusory contours, shading, or occlusion relationships. Little recovery of these mid-level functions is seen within 1 year post-operation. We find that visual performance using low-level cues is relatively robust to prolonged deprivation from birth. However, the use of pictorial depth cues to infer 3D structure from the 2D retinal image is highly susceptible to early and prolonged visual deprivation.
Roth, ZN, Zohary E.  2015.  Position and Identity Information Available in fMRI Patterns of Activity in Human Visual Cortex.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(33):11559-71. Abstract
Parietal cortex is often implicated in visual processing of actions. Action understanding is essentially abstract, specific to the type or goal of action, but greatly independent of variations in the perceived position of the action. If certain parietal regions are involved in action understanding, then we expect them to show these generalization and selectivity properties. However, additional functions of parietal cortex, such as self-action control, may impose other demands by requiring an accurate representation of the location of graspable objects. Therefore, the dimensions along which responses are modulated may indicate the functional role of specific parietal regions. Here, we studied the degree of position invariance and hand/object specificity during viewing of tool-grasping actions. To that end, we characterize the information available about location, hand, and tool identity in the patterns of fMRI activation in various cortical areas: early visual cortex, posterior intraparietal sulcus, anterior superior parietal lobule, and the ventral object-specific lateral occipital complex. Our results suggest a gradient within the human dorsal stream: along the posterior-anterior axis, position information is gradually lost, whereas hand and tool identity information is enhanced. This may reflect a gradual transformation of visual input from an initial retinotopic representation in early visual areas to an abstract, position-invariant representation of viewed action in anterior parietal cortex.
Duan, Y, Norcia AM, Yeatman JD, Mezer A.  2015.  The Structural Properties of Major White Matter Tracts in Strabismic Amblyopia.. Investigative ophthalmology & visual science. 56(9):5152-60. Abstract
In order to better understand whether white matter structural deficits are present in strabismic amblyopia, we performed a survey of the tissue properties of 28 major white matter tracts using diffusion and quantitative magnetic resonance imaging approaches.
Shofty, B, Mauda-Havakuk M, Weizman L, Constantini S, Ben-Bashat D, Dvir R, Pratt L-T, Joskowicz L, Kesler A, Yalon M et al..  2015.  The effect of chemotherapy on optic pathway gliomas and their sub-components: A volumetric MR analysis study.. Pediatric blood & cancer. 62(8):1353-9. Abstract
Optic pathway gliomas (OPG) represent 5% of pediatric brain tumors and compose a major therapeutic dilemma to the treating physicians. While chemotherapy is widely used for these tumors, our ability to predict radiological response is still lacking. In this study, we use volumetric imaging to examine in detail the long-term effect of chemotherapy on the tumor as well as its various sub-components.
Schechtman, E, Adler A, Deffains M, Gabbay H, Katabi S, Mizrahi A, Bergman H.  2015.  Coinciding decreases in discharge rate suggest that spontaneous pauses in firing of external pallidum neurons are network driven.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(17):6744-51. Abstract
The external segment of the globus pallidus (GPe) is one of the core nuclei of the basal ganglia, playing a major role in normal control of behavior and in the pathophysiology of basal ganglia-related disorders such as Parkinson's disease. In vivo, most neurons in the GPe are characterized by high firing rates (50-100 spikes/s), interspersed with long periods (∼0.6 s) of complete silence, which are termed GPe pauses. Previous physiological studies of single and pairs of GPe neurons have failed to fully disclose the physiological process by which these pauses originate. We examined 1001 simultaneously recorded pairs of high-frequency discharge GPe cells recorded from four monkeys during task-irrelevant periods, considering the activity in one cell while the other is pausing. We found that pauses (n = 137,278 pauses) coincide with a small yet significant reduction in firing rate (0.78 ± 0.136 spikes/s) in other GPe cells. Additionally, we found an increase in the probability of the simultaneously recorded cell to pause during the pause period of the "trigger" cell. Importantly, this increase in the probability to pause at the same time does not account for the reduction in firing rate by itself. Modeling of GPe cells as class 2 excitability neurons (Hodgkin, 1948) with common external inputs can explain our results. We suggest that common inputs decrease the GPe discharge rate and lead to a bifurcation phenomenon (pause) in some of the GPe neurons.
Tsuriel, S, Gudes S, Draft RW, Binshtok AM*, Lichtman JW*, corresponding authors *.  2015.  Multispectral labeling technique to map many neighboring axonal projections in the same tissue. Nature Methods. Abstract
We describe a method to map the location of axonal arbors of many individual neurons simultaneously via the spectral properties of retrogradely transported dye-labeled vesicles. We inject overlapping regions of an axon target area with three or more different colored retrograde tracers. On the basis of the combinations and intensities of the colors in the individual vesicles transported to neuronal somata, we calculate the projection sites of each neuron's axon. This neuronal positioning system (NPS) enables mapping of many axons in a simple automated way. In our experiments, NPS combined with spectral (Brainbow) labeling of the input to autonomic ganglion cells showed that the locations of ganglion cell projections to a mouse salivary gland related to the identities of their preganglionic axonal innervation. NPS could also delineate projections of many axons simultaneously in the mouse central nervous system.
Kfir, N, Lev-Maor G, Glaich O, Alajem A, Datta A, Sze SK, Meshorer E, Ast G.  2015.  SF3B1 Association with Chromatin Determines Splicing Outcomes.. Cell reports. Abstract
Much remains unknown concerning the mechanism by which the splicing machinery pinpoints short exons within intronic sequences and how splicing factors are directed to their pre-mRNA targets. One probable explanation lies in differences in chromatin organization between exons and introns. Proteomic, co-immunoprecipitation, and sedimentation analyses described here indicate that SF3B1, an essential splicing component of the U2 snRNP complex, is strongly associated with nucleosomes. ChIP-seq and RNA-seq analyses reveal that SF3B1 specifically binds nucleosomes located at exonic positions. SF3B1 binding is enriched at nucleosomes positioned over short exons flanked by long introns that are also characterized by differential GC content between exons and introns. Disruption of SF3B1 binding to such nucleosomes affects splicing of these exons similarly to SF3B1 knockdown. Our findings suggest that the association of SF3B1 with nucleosomes is functionally important for splice-site recognition and that SF3B1 conveys splicing-relevant information embedded in chromatin structure.
Travis, KE, Golden NH, Feldman HM, Solomon M, Nguyen J, Mezer A, Yeatman JD, Dougherty RF.  2015.  Abnormal white matter properties in adolescent girls with anorexia nervosa.. NeuroImage. Clinical. 9:648-59. Abstract
Anorexia nervosa (AN) is a serious eating disorder that typically emerges during adolescence and occurs most frequently in females. To date, very few studies have investigated the possible impact of AN on white matter tissue properties during adolescence, when white matter is still developing. The present study evaluated white matter tissue properties in adolescent girls with AN using diffusion MRI with tractography and T1 relaxometry to measure R1 (1/T1), an index of myelin content. Fifteen adolescent girls with AN (mean age = 16.6 years ± 1.4) were compared to fifteen age-matched girls with normal weight and eating behaviors (mean age = 17.1 years ± 1.3). We identified and segmented 9 bilateral cerebral tracts (18) and 8 callosal fiber tracts in each participant's brain (26 total). Tract profiles were generated by computing measures for fractional anisotropy (FA) and R1 along the trajectory of each tract. Compared to controls, FA in the AN group was significantly decreased in 4 of 26 white matter tracts and significantly increased in 2 of 26 white matter tracts. R1 was significantly decreased in the AN group compared to controls in 11 of 26 white matter tracts. Reduced FA in combination with reduced R1 suggests that the observed white matter differences in AN are likely due to reductions in myelin content. For the majority of tracts, group differences in FA and R1 did not occur within the same tract. The present findings have important implications for understanding the neurobiological factors underlying white matter changes associated with AN and invite further investigations examining associations between white matter properties and specific physiological, cognitive, social, or emotional functions affected in AN.
Barbash, S.  2015.  Dynamics of social network structure for Alzheimer and Lymphoma scientific communities.. Biology direct. 10(1):6. Abstract
It is generally assumed that sociology affects scientific progress but specific examples of this assumption are hard to find. We examined this hypothesis by comparing the social network structure and its dynamics over the last 16 years, for two common human diseases; Alzheimer's disease, for which there has been very little therapeutic progress, and Lymphoma, were there has been significant therapeutic progress. We found that the Alzheimer's research community is more interlinked ('dense') and more 'cliquish' than that of Lymphoma and suggest that this could affect its scientific progress.
Kalcheim, C.  2015.  Epithelial-Mesenchymal Transitions during Neural Crest and Somite Development.. Journal of clinical medicine. 5(1) Abstract
Epithelial-to-mesenchymal transition (EMT) is a central process during embryonic development that affects selected progenitor cells of all three germ layers. In addition to driving the onset of cellular migrations and subsequent tissue morphogenesis, the dynamic conversions of epithelium into mesenchyme and vice-versa are intimately associated with the segregation of homogeneous precursors into distinct fates. The neural crest and somites, progenitors of the peripheral nervous system and of skeletal tissues, respectively, beautifully illustrate the significance of EMT to the above processes. Ongoing studies progressively elucidate the gene networks underlying EMT in each system, highlighting the similarities and differences between them. Knowledge of the mechanistic logic of this normal ontogenetic process should provide important insights to the understanding of pathological conditions such as cancer metastasis, which shares some common molecular themes.
Rokem, A, Yeatman JD, Pestilli F, Kay KN, Mezer A, van der Walt S, Wandell BA.  2015.  Evaluating the accuracy of diffusion MRI models in white matter.. PloS one. 10(4):e0123272. Abstract
Models of diffusion MRI within a voxel are useful for making inferences about the properties of the tissue and inferring fiber orientation distribution used by tractography algorithms. A useful model must fit the data accurately. However, evaluations of model-accuracy of commonly used models have not been published before. Here, we evaluate model-accuracy of the two main classes of diffusion MRI models. The diffusion tensor model (DTM) summarizes diffusion as a 3-dimensional Gaussian distribution. Sparse fascicle models (SFM) summarize the signal as a sum of signals originating from a collection of fascicles oriented in different directions. We use cross-validation to assess model-accuracy at different gradient amplitudes (b-values) throughout the white matter. Specifically, we fit each model to all the white matter voxels in one data set and then use the model to predict a second, independent data set. This is the first evaluation of model-accuracy of these models. In most of the white matter the DTM predicts the data more accurately than test-retest reliability; SFM model-accuracy is higher than test-retest reliability and also higher than the DTM model-accuracy, particularly for measurements with (a) a b-value above 1000 in locations containing fiber crossings, and (b) in the regions of the brain surrounding the optic radiations. The SFM also has better parameter-validity: it more accurately estimates the fiber orientation distribution function (fODF) in each voxel, which is useful for fiber tracking.
Hochstein, S, Pavlovskaya M, Bonneh YS, Soroker N.  2015.  Global statistics are not neglected.. Journal of vision. 15(4):7. Abstract
In the framework of Reverse Hierarchy Theory it was suggested that initial vision at a glance brings the gist of the scene to conscious perception using explicit high cortical level representations, which are initially built by implicit bottom-up processing (Hochstein & Ahissar, 2002). Only later return to lower cortical level representations introduces local details to conscious perception. Global statistics of similar elements are perceived rapidly and accurately, suggesting they are included in the initial perception of the gist of the scene, not depending on prior conscious perception of local details. Patients with unilateral spatial neglect have difficulty responding to elements in their contralesional hemifield. However, this deficit is especially pronounced for tasks that require focused attention, i.e., are dependent on the reverse-hierarchy return. We review recent studies that indicate that perception of global statistics is among the spread attention tasks that are somewhat spared from this deficit. Combining these results, we suggest that perhaps the function of global statistics perception might include serving as a basic percept required for finding salient deviants from the mean, as in rapid odd element feature search paradigms, and perhaps subsequently focusing attention to them.
Mattout, A, Aaronson Y, Sailaja B S, Raghu Ram EV, Harikumar A, Mallm J-P, Sim K H, Nissim-Rafinia M, Supper E, Singh PB et al..  2015.  Heterochromatin Protein 1β (HP1β) has distinct functions and distinct nuclear distribution in pluripotent versus differentiated cells.. Genome biology. 16:213. Abstract
Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew. These characteristics correlate with a distinct nuclear architecture, epigenetic signatures enriched for active chromatin marks and hyperdynamic binding of structural chromatin proteins. Recently, several chromatin-related proteins have been shown to regulate ESC pluripotency and/or differentiation, yet the role of the major heterochromatin proteins in pluripotency is unknown.
Ramaswamy, S, et al.  2015.  The neocortical microcircuit collaboration portal: a resource for rat somatosensory cortex.. Frontiers in neural circuits. 9:44.
Ankri, L, Husson Z, Pietrajtis K, Proville R, Léna C, Yarom Y, Dieudonné S, Uusisaari M Y.  2015.  A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi cell activity.. eLife. 4 Abstract
The cerebellum, a crucial center for motor coordination, is composed of a cortex and several nuclei. The main mode of interaction between these two parts is considered to be formed by the inhibitory control of the nuclei by cortical Purkinje neurons. We now amend this view by showing that inhibitory GABA-glycinergic neurons of the cerebellar nuclei (CN) project profusely into the cerebellar cortex, where they make synaptic contacts on a GABAergic subpopulation of cerebellar Golgi cells. These spontaneously firing Golgi cells are inhibited by optogenetic activation of the inhibitory nucleo-cortical fibers both in vitro and in vivo. Our data suggest that the CN may contribute to the functional recruitment of the cerebellar cortex by decreasing Golgi cell inhibition onto granule cells.
Carmel, M S, Kahane N, Oberman F, Miloslavski R, Sela-Donenfeld D, Kalcheim C, Yisraeli JK.  2015.  A Novel Role for VICKZ Proteins in Maintaining Epithelial Integrity during Embryogenesis.. PloS one. 10(8):e0136408. Abstract
VICKZ (IGF2BP1,2,3/ZBP1/Vg1RBP/IMP1,2,3) proteins bind RNA and help regulate many RNA-mediated processes. In the midbrain region of early chick embryos, VICKZ is expressed in the neural folds and along the basal surface of the neural epithelium, but, upon neural tube closure, is down-regulated in prospective cranial neural crest (CNC) cells, concomitant with their emigration and epithelial-to-mesenchymal transition (EMT). Electroporation of constructs that modulate cVICKZ expression demonstrates that this down-regulation is both necessary and sufficient for CNC EMT. These results suggest that VICKZ down-regulation in CNC cell-autonomously promotes EMT and migration. Reduction of VICKZ throughout the embryo, however, inhibits CNC migration non-cell-autonomously, as judged by transplantation experiments in Xenopus embryos.
Busche, M A, Kekuš M, Adelsberger H, Noda T, Förstl H, Nelken I, Konnerth A.  2015.  Rescue of long-range circuit dysfunction in Alzheimer's disease models.. Nature Neuroscience. Abstract
Alzheimer's disease (AD) is associated with defects of synaptic connectivity. Such defects may not be restricted to local neuronal interactions but may extend to long-range brain activities, such as slow-wave oscillations that are particularly prominent during non-rapid eye movement (non-REM) sleep and are important for integration of information across distant brain regions involved in memory consolidation. There is increasing evidence that sleep is often impaired in AD, but it is unclear whether this impairment is directly related to amyloid-β (Aβ) pathology. Here we demonstrate that slow-wave activity is severely altered in the neocortex, thalamus and hippocampus in mouse models of AD amyloidosis. Most notably, our results reveal an Aβ-dependent impairment of slow-wave propagation, which causes a breakdown of the characteristic long-range coherence of slow-wave activity. The finding that the impairment can be rescued by enhancing GABAAergic inhibition identifies a synaptic mechanism underlying Aβ-dependent large-scale circuit dysfunction.
Jaffe-Dax, S, Raviv O, Jacoby N, Loewenstein Y, Ahissar M.  2015.  A Computational Model of Implicit Memory Captures Dyslexics' Perceptual Deficits. The Journal of Neuroscience. 35:12116–12126. AbstractPDF
Dyslexics are diagnosed for their poor reading skills, yet they characteristically also suffer from poor verbal memory and often from poor auditory skills. To date, this combined profile has been accounted for in broad cognitive terms. Here we hypothesize that the perceptual deficits associated with dyslexia can be understood computationally as a deficit in integrating prior information with noisy observations. To test this hypothesis we analyzed the performance of human participants in an auditory discrimination task using a two-parameter computational model. One parameter captures the internal noise in representing the current event, and the other captures the impact of recently acquired prior information. Our findings show that dyslexics' perceptual deficit can be accounted for by inadequate adjustment of these components; namely, low weighting of their implicit memory of past trials relative to their internal noise. Underweighting the stimulus statistics decreased dyslexics' ability to compensate for noisy observations. ERP measurements (P2 component) while participants watched a silent movie indicated that dyslexics' perceptual deficiency may stem from poor automatic integration of stimulus statistics. This study provides the first description of a specific computational deficit associated with dyslexia. SIGNIFICANCE STATEMENT This study presents the first attempt to specify the mechanisms underlying dyslexics' perceptual difficulties computationally by applying a specific model, inspired by the Bayesian framework. This model dissociates between the contribution of sensory noise and that of the prior statistics in an auditory perceptual decision task. We show that dyslexics cannot compensate for their perceptual noise by incorporating prior information. By contrast, adequately reading controls' usage of previous information is often close to optimal. We used ERP measurements to assess the neuronal stage of this deficit. We found that unlike their peers, dyslexics' ERP responses are not sensitive to the relations between the current observation and the prior observation, indicating that they cannot establish a reliable prior.
Loewenstein, Y, Yanover U, Rumpel S.  2015.  Predicting the Dynamics of Network Connectivity in the Neocortex. The Journal of Neuroscience. 35(36):12535–12544. AbstractPDF
Dynamic remodeling of connectivity is a fundamental feature of neocortical circuits. Unraveling the principles underlying these dynamics is essential for the understanding of how neuronal circuits give rise to computations. Moreover, as complete descriptions of the wiring diagram in cortical tissues are becoming available, deciphering the dynamic elements in these diagrams is crucial for relating them to cortical function. Here, we used chronic in vivo two-photon imaging to longitudinally follow a few thousand dendritic spines in the mouse auditory cortex to study the determinants of these spines' lifetimes. We applied nonlinear regression to quantify the independent contribution of spine age and several morphological parameters to the prediction of the future survival of a spine. We show that spine age, size, and geometry are parameters that can provide independent contributions to the prediction of the longevity of a synaptic connection. In addition, we use this framework to emulate a serial sectioning electron microscopy experiment and demonstrate how incorporation of morphological information of dendritic spines from a single time-point allows estimation of future connectivity states. The distinction between predictable and nonpredictable connectivity changes may be used in the future to identify the specific adaptations of neuronal circuits to environmental changes. The full dataset is publicly available for further analysis. SIGNIFICANCE STATEMENT The neural architecture in the neocortex exhibits constant remodeling. The functional consequences of these modifications are poorly understood, in particular because the determinants of these changes are largely unknown. Here, we aimed to identify those modifications that are predictable from current network state. To that goal, we repeatedly imaged thousands of dendritic spines in the auditory cortex of mice to assess the morphology and lifetimes of synaptic connections. We developed models based on morphological features of dendritic spines that allow predicting future turnover of synaptic connections. The dynamic models presented in this paper provide a quantitative framework for adding putative temporal dynamics to the static description of a neuronal circuit from single time-point connectomics experiments.
Mohan H, et al.  2015.  Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex. Cerebral Cortex. Abstract
The size and shape of dendrites and axons are strong determinants of neuronal information processing. Our knowledge on neuronal structure and function is primarily based on brains of laboratory animals. Whether it translates to human is not known since quantitative data on "full" human neuronal morphologies are lacking. Here, we obtained human brain tissue during resection surgery and reconstructed basal and apical dendrites and axons of individual neurons across all cortical layers in temporal cortex (Brodmann area 21). Importantly, morphologies did not correlate to etiology, disease severity, or disease duration. Next, we show that human L(ayer) 2 and L3 pyramidal neurons have 3-fold larger dendritic length and increased branch complexity with longer segments compared with temporal cortex neurons from macaque and mouse. Unsupervised cluster analysis classified 88% of human L2 and L3 neurons into human-specific clusters distinct from mouse and macaque neurons. Computational modeling of passive electrical properties to assess the functional impact of large dendrites indicates stronger signal attenuation of electrical inputs compared with mouse. We thus provide a quantitative analysis of "full" human neuron morphologies and present direct evidence that human neurons are not "scaled-up" versions of rodent or macaque neurons, but have unique structural and functional properties.
Deschamps, I, Agmon G, Loewenstein Y, Grodzinsky Y.  2015.  The processing of polar quantifiers, and numerosity perception. Cognition. 143:115-128. AbstractPDF
We investigated the course of language processing in the context of a verification task that required numerical estimation and comparison. Participants listened to sentences with complex quantifiers that contrasted in Polarity, a logical property (e.g., more-than-half, less-than-half), and then performed speeded verification on visual scenarios that displayed a proportion between 2 discrete quantities. We varied systematically not only the sentences, but also the visual materials, in order to study their effect on the verification process. Next, we used the same visual scenarios with analogous non-verbal probes that featured arithmetical inequality symbols (<, >). This manipulation enabled us to measure not only Polarity effects, but also, to compare the effect of different probe types (linguistic, non-linguistic) on processing. Like many previous studies, our results demonstrate that perceptual difficulty affects error rate and reaction time in keeping with Weber’s Law. Interestingly, these performance parameters are also affected by the Polarity of the quantifiers used, despite the fact that sentences had the exact same meaning, sentence structure, number of words, syllables, and temporal structure. Moreover, an analogous contrast between the non-linguistic probes (<, >) had no effect on performance. Finally, we observed no interaction between performance parameters governed by Weber’s Law and those affected by Polarity. We consider 4 possible accounts of the results (syntactic, semantic, pragmatic, frequency-based), and discuss their relative merit.
Marc, D, Hagai B.  2015.  Striatal cholinergic interneurons and cortico-striatal synaptic plasticity in health and disease. Movement Disorder. 3(no 8):1014-1025. Abstract
Basal ganglia disorders such as Parkinson's disease, dystonia, and Huntington's disease are characterized by a dysregulation of the basal ganglia neuromodulators (dopamine, acetylcholine, and others), which impacts cortico-striatal transmission. Basal ganglia disorders are often associated with an imbalance between the midbrain dopaminergic and striatal cholinergic systems. In contrast to the extensive research and literature on the consequences of a malfunction of midbrain dopaminergic signaling on the plasticity of the cortico-striatal synapse, very little is known about the role of striatal cholinergic interneurons in normal and pathological control of cortico-striatal transmission. In this review, we address the functional role of striatal cholinergic interneurons, also known as tonically active neurons and attempt to understand how the alteration of their functional properties in basal ganglia disorders leads to abnormal cortico-striatal synaptic plasticity. Specifically, we suggest that striatal cholinergic interneurons provide a permissive signal, which enables long-term changes in the efficacy of the cortico-striatal synapse. We further discuss how modifications in the striatal cholinergic activity pattern alter or prohibit plastic changes of the cortico-striatal synapse. Long-term cortico-striatal synaptic plasticity is the cellular substrate of procedural learning and adaptive control behavior. Hence, abnormal changes in this plasticity may underlie the inability of patients with basal ganglia disorders to adjust their behavior to situational demands. Normalization of the cholinergic modulation of cortico-striatal synaptic plasticity may be considered as a critical feature in future treatments of basal ganglia disorders.
Shteingart, H, Loewenstein Y.  2015.  The Effect of Sample Size and Cognitive Strategy on Probability Estimation Bias. Decison. 2(2):107-117. AbstractPDF
Probability estimation is an essential cognitive function in perception, motor control, and decision making. Many studies have shown that when making decisions in a stochastic operant conditioning task, people and animals behave as if they underesti- mate the probability of rare events. It is commonly assumed that this behavior is a natural consequence of estimating a probability from a small sample, also known as sampling bias. The objective of this article is to challenge this common lore. We show that, in fact, probabilities estimated from a small sample can lead to behaviors that will be interpreted as underestimating or as overestimating the probability of rare events, depending on the cognitive strategy used. Moreover, this sampling bias hypothesis makes an implausible prediction that minute differences in the values of the sample size or the underlying probability will determine whether rare events will be underweighted or overweighed. We discuss the implications of this sensitivity for the design and interpretation of experiments. Finally, we propose an alternative sequential learning model with a resetting of initial conditions for probability estimation and show that this model predicts the experimentally observed robust underweighting of rare events.
Ramirez de Noriega Fernando, Renana E, Odeya M, Lavi A, Eduard L, Hagai B, Zvi I.  2015.  Constant Current versus Constant Voltage Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Deisease. Stereotactic Functional Neurosurgry. 18(93(2)):114-121. Abstract
Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established therapy for advanced Parkinson's disease (PD). Motor efficacy and safety have been established for constant voltage (CV) devices and more recently for constant current (CC) devices. CC devices adjust output voltage to provide CC stimulation irrespective of impedance fluctuation, while the current applied by CV stimulation depends on the impedance that may change over time. No study has directly compared the clinical effects of these two stimulation modalities. Objective: To compare the safety and clinical impact of CC STN DBS to CV STN DBS in patients with advanced PD 2 years after surgery. Methods: Patients were eligible for inclusion if they had undergone STN DBS surgery for idiopathic PD, had been implanted with a Medtronic Activa PC and if their stimulation program and medication had been stable for at least 1 year. This single-center trial was designed as a double-blind, randomized, prospective study with crossover after 2 weeks. Motor equivalence of the 2 modalities was confirmed utilizing part III of the Unified Parkinson's Disease Rating Scale (UPDRS). PD diaries and multiple subjective and objective evaluations of quality of life, depression, cognition and emotional processing were evaluated on both CV and on CC stimulation. Analysis using the paired t test with Bonferroni correction for multiple comparisons was performed to identify any significant difference between the stimulation modalities. Results: 8 patients were recruited (6 men, 2 women); 1 patient did not complete the study. The average age at surgery was 56.7 years (range 47-63). Disease duration at the time of surgery was 7.5 years (range 3-12). Patients were recruited 23.8 months (range 22.5-24) after surgery. At the postoperative study baseline, this patient group showed an average motor improvement of 69% (range 51-97) as measured by the change in UPDRS part III with stimulation alone. Levodopa equivalent medication was reduced on average by 67% (range 15-88). Patients were poorly compliant with PD diaries, and these did not yield useful information. The minor deterioration in quality-of-life scores (Parkinson's Disease Questionnaire-39, Quality of Life Enjoyment and Satisfaction Questionnaire) with CC stimulation were not statistically significant. Two measures of depression (Hamilton Rating Scale D17, Quick Inventory of Depressive Symptomatology - Self-Report) showed a nonsignificant lower score (less depression) with CC stimulation, but a third (Beck Depression Inventory) showed equivalence. Cognitive testing (Mini Mental State Examination) and emotional processing (Montreal Affective Voices) were equivalent for CC and CV. Conclusion: CC STN DBS is safe. For equivalent motor efficacy, no significant difference could be identified between CC and CV stimulation for nonmotor evaluations in PD patients 2 years after surgery.