Output Station Research Articles

Dynamic activity model of movement disorders: a unified view to understand their pathophysiology

Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their underlying pathophysiology is still subject to debate. To understand their pathophysiology in a unified manner, we propose the "dynamic activity model", on the basis of alterations of cortically induced responses in individual nuclei of the basal ganglia. In the normal state, electric stimulation in the motor cortex, mimicking cortical activity during initiation of voluntary movements, evokes a triphasic response consisting of early excitation, inhibition, and late excitation in the output stations of the basal ganglia of monkeys, rodents, and humans. Among three components, cortically induced inhibition, which is mediated by the direct pathway, releases an appropriate movement at an appropriate time by disinhibiting thalamic and cortical activity, whereas early and late excitation, which is mediated by the hyperdirect and indirect pathways, resets on-going cortical activity and stops movements, respectively. Cortically induced triphasic response patterns are systematically altered in various movement disorder models and could well explain the pathophysiology of their motor symptoms. In monkey and mouse models of Parkinson's disease, cortically induced inhibition is reduced and prevents the release of movements, resulting in akinesia/bradykinesia. On the other hand, in a mouse model of dystonia, cortically induced inhibition is enhanced and releases unintended movements, inducing involuntary muscle contractions. Moreover, after blocking the subthalamic nucleus activity in a monkey model of Parkinson's disease, cortically induced inhibition is recovered and enables voluntary movements, explaining the underlying mechanism of stereotactic surgery to ameliorate parkinsonian motor signs. The "dynamic activity model" gives us a more comprehensive view of the pathophysiology underlying motor symptoms of movement disorders and clues for their novel therapies.

Anatomical Connectivity of the Intercalated Cells of the Amygdala.

The intercalated cells of the amygdala (ITCs) are a fundamental processing structure in the amygdala that remain relatively understudied. They are phylogenetically conserved from insectivores through primates, inhibitory, and project to several of the main processing and output stations of the amygdala and basal forebrain. Through these connections, the ITCs are best known for their role in conditioned fear, where they are required for fear extinction learning and recall. Prior work on ITC connectivity is limited, and thus holistic characterization of their afferent and efferent connectivity in a genetically defined manner is incomplete. The ITCs express the FoxP2 transcription factor, affording genetic access to these neurons for viral input-output mapping. To fully characterize the anatomic connectivity of the ITCs, we used cre-dependent viral strategies in FoxP2-cre mice to reveal the projections of the main (mITC), caudal (cITC), and lateral (lITC) clusters along with their presynaptic sources of innervation. Broadly, the results confirm many known pathways, reveal previously unknown ones, and demonstrate important novel insights about each nucleus's unique connectivity profile and relative distributions. We show that the ITCs receive information from a wide range of cortical, subcortical, basal, amygdalar, hippocampal, and thalamic structures, and project broadly to areas of the basal forebrain, hypothalamus, and entire extent of the amygdala. The results provide a comprehensive map of their connectivity and suggest that the ITCs could potentially influence a broad range of behaviors by integrating information from a wide array of sources throughout the brain.

Inverse pattern of GABAergic system impairment in the external versus internal globus pallidus in male heroin addicts

Opioid addiction is a global problem that has been exacerbated in the USA and Europe by the COVID-19 pandemic. The globus pallidus (GP) plays a prominent neurobiological role in the regulation of behaviour as an output station of the striato-pallidal system. GABAergic large projection neurons are the main neuronal type in the external (EGP) and internal (IGP) parts of the GP, where addiction-specific molecular and functional abnormalities occur. In these neurons, glutamate decarboxylase (GAD) with isoforms GAD 65 and 67 is a key enzyme in GABA synthesis, and experimental studies suggest GAD dysregulation in the GP of heroin addicts. Our study, which was performed on paraffin-embedded brains from the Magdeburg Brain Bank, aimed to investigate abnormalities in the GABAergic function of large GP neurons by densitometric evaluation of their GAD 65/67-immunostained thick dendrites. The study revealed a bilaterally decreased fibres density in the EGP paralleled by the increase in the IGP in 11 male heroin addicts versus 11 healthy controls (significant U-test P values). The analysis of confounding variables found no interference of age, brain volume, and duration of formalin fixation with the results. Our findings suggest a dysregulation of GABAergic activity in the GP of heroin addicts, which is consistent with experimental data from animal models and plays potentially a role in the disturbed function of basal ganglia circuit in opioid addiction.

Türkiye'nin nehirlerinde eksik akım verilerinin tamamlanması için çeşitli veri odaklı tekniklerin performans değerlendirmesi

Missing data with gaps is always an obstacle to effective planning and management of water resources. Complete and reliable hydrological time series are necessary for the optimal design of water resources. A study was conducted to fill in missing streamflow data of 54 observation stations across Turkey. This process was done with the aid of various statistical estimation methods. Estimations were performed by using Linear regression (LR), Artificial neural network (ANN), adaptive neuro-fuzzy inference system (ANFIS), Support vector machine (SVM), Multivariate Adaptive regression splines (MARS), and K-nearest neighbor (KNN) methods. Performances of infilling methods were evaluated based on four performance criteria; namely, root mean squared error (RMSE), coefficient of determination (R2), mean absolute error (MAE), and the Kling–Gupta efficiency (KGE) during training and test periods. Reliable and long streamflow data from surrounding stations were selected as input to fill in missing streamflow data for an output station. The results revealed that a single method cannot be specified as the best-fit method for the study area. During the test phase, the R2 ranged from 0.54 to 0.99, and the KGE range was between 0.62 and 0.98. This study showed that especially SVM and MARS methods are suitable for estimating missing streamflow data in Turkey’s rivers. These findings will provide reliable streamflow data that can be used in hydrological modeling and water resources planning and management.

A disynaptic basal ganglia connection to the inferior olive: potential for basal ganglia influence on cerebellar learning.

Recent studies have shown that the cerebellum and the basal ganglia are interconnected at subcortical levels. However, a subcortical basal ganglia connection to the inferior olive (IO), being the source of the olivocerebellar climbing fiber system, is not known. We have used classical tracing with CTb, retrograde transneuronal infection with wildtype rabies virus, conditional tracing with genetically modified rabies virus, and examination of material made available by the Allen Brain Institute, to study potential basal ganglia connections to the inferior olive in rats and mice. We show in both species that parvalbumin-positive, and therefore GABAergic, neurons in the entopeduncular nucleus, representing the rodent equivalent of the internal part of the globus pallidus, innervate a group of cells that surrounds the fasciculus retroflexus and that are collectively known as the area parafascicularis prerubralis. As these neurons supply a direct excitatory input to large parts of the inferior olivary complex, we propose that the entopeduncular nucleus, as a main output station of the basal ganglia, provides an inhibitory influence on olivary excitability. As such, this connection may influence olivary involvement in cerebellar learning and/or could be involved in transmission of reward properties that have recently been established for olivocerebellar signaling.

A review on integrated design and off-design operation of solar power tower system with S–CO2 Brayton cycle

The solar power tower (SPT) system integrated with supercritical CO2 (S–CO2) Brayton cycle is a potential flexible power output station to balance supply and demand in the future power system with high renewable energy penetration, so as to maintain the reliability of power supply. Reasonable design and accurate parameter adjustment are crucial to the efficient, low-cost, and reliable operation of the SPT system with S–CO2 Brayton cycle. Many works have studied the design optimization and operation control strategy of the system. But the research focuses and conclusions are various, and there is a lack of important summary in this field. This paper provides a review on the integrated design and off-design operation of SPT system with S–CO2 Brayton cycle. In terms of system integrated design, the performance criteria, subsystem selections, and key parameter optimizations are summarized. Furthermore, an improved system design method based on off-design operating performance is introduced and recommended. In terms of system off-design operation, the fluctuating factors, parameter control strategies, and the actual operation results are introduced. The conclusions and study prospects for this promising technology in the aspects of design and operation are presented.

Elimination of the Cortico-Subthalamic Hyperdirect Pathway Induces Motor Hyperactivity in Mice.

The substantia nigra pars reticulata (SNr) is the output station of the basal ganglia and receives cortical inputs by way of the following three basal ganglia pathways: the cortico-subthalamo (STN)-SNr hyperdirect, the cortico-striato-SNr direct, and the cortico-striato-external pallido-STN-SNr indirect pathways. Compared with the classical direct and indirect pathways via the striatum, the functions of the hyperdirect pathway remain to be fully elucidated. Here we used a photodynamic technique to selectively eliminate the cortico-STN projection in male mice and observed neuronal activity and motor behaviors in awake conditions. After cortico-STN elimination, cortically evoked early excitation in the SNr was diminished, while the cortically evoked inhibition and late excitation, which are delivered through the direct and indirect pathways, respectively, were unchanged. In addition, locomotor activity was significantly increased after bilateral cortico-STN elimination, and apomorphine-induced ipsilateral rotations were observed after unilateral cortico-STN elimination, suggesting that cortical activity was increased. These results are compatible with the notion that the cortico-STN-SNr hyperdirect pathway quickly conveys cortical excitation to the output station of the basal ganglia, resets or suppresses the cortical activity related to ongoing movements, and prepares for the forthcoming movement.SIGNIFICANCE STATEMENT The basal ganglia play a pivotal role in the control of voluntary movements, and their malfunctions lead to movement disorders, such as Parkinson's disease and dystonia. Understanding their functions is important to find better treatments for such diseases. Here we used a photodynamic technique to selectively eliminate the projection from the motor cortex to the subthalamic nucleus, the input station of the basal ganglia, and found greatly reduced early excitatory signals from the cortex to the output station of the basal ganglia and motor hyperactivity. These results suggest that the neuronal signals through the cortico-subthalamic hyperdirect pathway reset or suppress ongoing movements and that blockade of this pathway may be beneficial for Parkinson's disease, which is characterized by oversuppression of movements.

Stress-Induced Enhanced Long-Term Potentiation and Reduced Threshold for N-Methyl-D-Aspartate Receptor- and β-Adrenergic Receptor-Mediated Synaptic Plasticity in Rodent Ventral Subiculum.

Stress is a biologically relevant signal and can modulate hippocampal synaptic plasticity. The subiculum is the major output station of the hippocampus and serves as a critical hub in the stress response network. However, stress-associated synaptic plasticity in the ventral subiculum has not been adequately addressed. Therefore, we investigated the impact of a single exposure to an inherently stressful two-way active avoidance conditioning on the induction of long-term potentiation (LTP) at CA1—subiculum synapses in ventral hippocampal slices from young adult rats 1 day after stressor exposure. We found that acute stress enhanced LTP and lowered the induction threshold for a late-onset LTP at excitatory CA1 to subicular burst-spiking neuron synapses. This late-onset LTP was dependent on the activation of β-adrenergic and glutamatergic N-methyl-D-aspartate receptors and independent of D1/D5 dopamine receptor activation. Thereby, we present a cellular mechanism that might contribute to behavioral stress adaptation after acute stressor exposure.

Reducing Retrieval Time in Automated Storage and Retrieval System with a Gravitational Conveyor Based on Multi-Agent Systems

The main objective of this study is to reduce the retrieval time of a list of products by choosing the best combination of storage and retrieval rules at any time. This is why we start by implementing some storage rules in an Automated Storage/Retrieval System (Automated Storage and Retrieval System: AS/RS) fitted with a gravity conveyor while some of these rules are dedicated to storage and others to retrieval. The system is seen as a Multi-Agent System (MAS) where the produced agents are reactive agents that can interact to achieve a behavior (organizing the store). Our MAS is characterized by a decentralized control, which means that there is no preset plan. The produced agents exchange information such as their color, their distance from the output station, etc. Each product merely applies a set of behavioral rules. The aim is to choose the best product to be retrieved in the shortest possible time. The product-type agents have no cognitive ability, but still perform complex tasks.

Time minimization in flexible robotic cells considering intermediate input buffers: a comparative study of three well-known problems

ABSTRACTFlexible manufacturing cells are widely used in many real-life industries. These cells contain a group of highly automated machines, the input station, and the output station that are interconnected by a robot which handles the materials, automatically. The system repeats a cycle in its long run, and the cycle time depends on the order of the loading/unloading activities which are performed by the robot. To achieve the most efficient use of these cells, order of the robot activities must be determined. This study is motivated by such a real life system with intermediate machine buffers. First, a mathematical model is presented. Then, to decrease the solution time, a modification of the model is proposed. Additionally, another model is proposed to find the maximum processing time of the machines when the cycle time is known. An assignment problem method is utilized to optimize the cyclic production, and performances of all the proposed methods are examined using several numerical instances. Finally, the performance of the considered system is compared with no intermediate machine buffers system, and also it is compared with the system utilizing a dual-gripper robot. The results show that performances of the three robotic cells are non-identical in practice.

Presynaptic control of [3H]-glutamate release by dopamine receptor subtypes in the rat substantia nigra. Central role of D1 and D3 receptors

Substantia nigra pars reticulata is the output station in basal ganglia; its GABAergic neurons control the activity of thalamo-cortical premotor nuclei, thus controlling motor behavior. D1-like and D2-like presynaptic dopamine receptors on subthalamo-nigral afferents by modulation of glutamate release change the firing rate of nigral neurons; however, their relative contribution to the control of glutamate release and their pharmacological properties have not been studied. This is important since the prevalence of the inhibition or stimulation of release determines the firing rate of nigral neurons, therefore motor activity.Here we used depolarization induced [3H]-glutamate release in slices of rat substantia nigra from reserpinized and non-reserpinized rats to explore the relative contribution of the D1-like and D2-like receptor subtypes to the control of glutamate release. We found a significant control of release by D1-like and D3R, and a modest effect of D2R. D4R exerted no effect. Dopamine showed more potency for D3R than for D1-like receptors; however, these latter enhanced release to a greater degree, as shown by the Emax. We also co-activated these to test their interaction; an antagonist interaction of D1-like with D2 and D3R, and an additive between D2 and D3R were found. Pharmacological receptor antagonist effects in release from reserpinized vs. non-reserpinized slices were similar, suggesting that endogenous dopamine stimulates receptors in the same way. These findings suggest differences in the control of glutamate release by different dopamine receptors in the substantia nigra, which could contribute to explaining the effect of dopamine and its agonists on motor behavior.

Optimising two dwell point policies for AS/RSs with input and output point at opposite ends of the aisle

Automated storage and retrieval systems (AS/RSs) are widely used for storing and retrieving products in all types of warehouses. Dwell point policy is a vital control policy that can greatly affect the performance of AS/RSs. In this paper, we study dwell point policies in AS/RSs with input and output stations at opposite ends of the aisle. We first propose two dwell point policies. We find that five existing dwell point policies in the literature are special cases of exactly one of our policies. We then develop expected travel time models for the proposed policies, solve these models with the objective of minimising expected travel time, and obtain closed-form solutions for the optimal dwell location(s). We prove that one proposed policy dominates the other in terms of expected travel time. Numerical experiments are performed to quantify the percentage gap of expected travel time between the proposed policies and policies in the literature. We find that, in some situations, the better proposed policy can achieve up to 8%–10% reduction in expected travel time in comparison with the best literature policy. A real-data case study validates that these situations arise with high probability in typical daily warehouse operations.

Altered thalamic glucose metabolism in cerebellar projections in Parkinson’s disease

A pathological communication between the basal ganglia (BG) and the cerebellum (Cb) at the level of the thalamus has been proposed to be causative for the generation of parkinsonian tremor. Recent studies, however, indicated, that altered Cb-thalamic circuitry is not only underlying the genesis of tremor, but is involved in the generation of other parkinsonian symptoms like bradykinesia and rigor.Hence, we studied the glucose metabolism of akinetic-rigid parkinsonian patients in (i) anatomical (anterior, medial, lateral, posterior) and (ii) projection territory-based (Cb- and BG-thalamic) subdivision of the human thalamus and compared them with healthy controls in order to predict disease progression irrespective of the symptom tremor. The dentate nucleus was representatively chosen as output station for Cb regions, BG regions comprised the pallidum.Regarding (i) the anatomical subdivision we found no significant difference between patients and controls in the glucose metabolism for the anterior and medial group (p > 0.05), but an increase of glucose metabolism for the lateral and posterior group (p < 0.05). The glucose metabolism under (ii) the tractography-based subdivision revealed significant differences between patients and controls in the left (p < 0.05) and right (p < 0.01) Cb-thalamic, but not the BG-thalamic projection territory (p > 0.05). In order to test for disease specific alterations, we correlated bihemispherically averaged thalamic glucose metabolism for the anterior, medial, lateral and posterior thalamic group with disease progress (reflected by the Hoehn & Yahr score) and found a significant prediction of the glucose metabolism of the lateral thalamic group and the disease progression (p < 0.05; r = 0.4). A further subdivision into patients with right and left symptom onset evoked a group of 14 right- and 13 left affected patients. Again, we correlated clinical parameters of disease progression with the results of glucose metabolism and found a significant correlation of the right affected patients (p < 0.05) with the right Cb-thalamic region reflected by an up-regulation of glucose metabolism; right affected patients frequently show slower disease progression than left affected patients.Hence our results support a critical (maybe compensatory) role of the Cb-thalamic projections and forces a more straightforward thinking away from a pure “symptom-oriented” to a “dynamic-circuitry” approach due to functional changes in glucose metabolism with Cb and BG as one of the circuitry key elements defining the clinical parkinsonian phenotype.

Loop-based facility layout design under flexible bay structures

We develop heuristic procedures for concurrent design of block layout, material flow network, and input and output stations. Unlike the common practice in the flexible bay structure layout design, our objective function includes both loaded and empty flow between pairs of I/O stations. This measure of effectiveness is the main determinant of the fleet size of the vehicles, which in turn is the major driver of the total investment and operational costs in vehicle-based material handling. Our work is the first to design flexible bay structure layouts for loop-based material flow patterns. We first develop heuristic algorithms to configure the layout on the foundations of a unidirectional loop flow pattern. The loop and stations are then designed on the promising layouts. A set of improvement algorithms provide a better integration of the layout, loop, and stations.

Activation of 5-HT7 receptors reverses NMDA-R-dependent LTD by activating PKA in medial vestibular neurons

The medial vestibular nucleus (MVN) is a major output station for neurons that project to the vestibulo-spinal pathway. MVN neurons show capacity for long-term depression (LTD) during the juvenile period. We investigated LTD of MVN neurons using whole-cell patch-clamp recordings. High frequency stimulation (HFS) robustly induced LTD in 90% of type B neurons in the MVN, while only 10% of type A neurons were responsive, indicating that type B neurons are the major contributors to LTD in the MVN. The neuromodulator serotonin (5-HT) is known to modulate LTD in neural circuits of the cerebral cortex and the hippocampus. We therefore aim to determine the action of 5-HT on the LTD of type B MVN neurons and elucidate the relevant 5-HT receptor subtypes responsible for its action. Using specific agonists and antagonists of 5-HT receptors, we found that selective activation of 5-HT7 receptor in type B neurons in the MVN of juvenile (P13-16) rats completely abolished NMDA-receptor-mediated LTD in a protein kinase A (PKA)-dependent manner. Our finding that 5-HT restricts plasticity of type B MVN neurons via 5-HT7 receptors offers a mechanism whereby vestibular tuning contributes to the maturation of the vestibulo-spinal circuit and highlights the role of 5-HT in postural control.

P136 Investigating inhibitory processes within the motor cortex during conflict resolution using paired-pulse transcranial magnetic stimulation

Introduction In daily life, we often need to deal with situations in which multiple actions are possible, situations of so-called ‘response conflict’. Several brain regions have been identified as key nodes of a network involved in resolving response conflict. However, how and by which physiological mechanism those nodes finally affect the ‘output station’ of the brain, the primary motor cortex, is unknown. A potential mechanism is the involvement of inhibitory interneurons, which can be directly tested using paired-pulse transcranial magnetic stimulation (TMS). Question Here we test how inhibitory processes within the primary motor cortex change over time during the resolution of response conflict. Methods Participants performed an arrow version of the Flanker task. The arrows were arranged such that they either elicit one response with no conflict (e.g., all arrows point to the same direction) or two competing responses (e.g., the target arrow points towards the opposite direction as the flankers). To track the involvement of inhibitory processes over time short intra-cortical inhibition (SICI) was measured as the change in the amplitude of the motor-evoked potential over the left motor cortex elicited by a single supra-threshold pulse and by a supra-threshold pulse preceded by a sub-threshold pulse. This enabled the identification of time-specific physiological patterns of inhibitory processes at the level of primary motor cortex. Results Preliminary analyses show increased MEP amplitudes towards the response and specific changes in SICI over time dependent on the level of response conflict. Conclusion These results suggest involvement of primary motor cortex inhibitory interneurons when resolving situations of response conflict.

The role of the human globus pallidus in Huntington's disease

Huntington's disease (HD) is characterized by pronounced pathology of the basal ganglia, with numerous studies documenting the pattern of striatal neurodegeneration in the human brain. However, a principle target of striatal outflow, the globus pallidus (GP), has received limited attention in comparison, despite being a core component of the basal ganglia. The external segment (GPe) is a major output of the dorsal striatum, connecting widely to other basal ganglia nuclei via the indirect motor pathway. The internal segment (GPi) is a final output station of both the direct and indirect motor pathways of the basal ganglia. The ventral pallidum (VP), in contrast, is a primary output of the limbic ventral striatum. Currently, there is a lack of consensus in the literature regarding the extent of GPe and GPi neurodegeneration in HD, with a conflict between pallidal neurons being preserved, and pallidal neurons being lost. In addition, no current evidence considers the fate of the VP in HD, despite it being a key structure involved in reward and motivation. Understanding the involvement of these structures in HD will help to determine their involvement in basal ganglia pathway dysfunction in the disease. A clear understanding of the impact of striatal projection loss on the main neurons that receive striatal input, the pallidal neurons, will aid in the understanding of disease pathogenesis. In addition, a clearer picture of pallidal involvement in HD may contribute to providing a morphological basis to the considerable variability in the types of motor, behavioral, and cognitive symptoms in HD. This review aims to highlight the importance of the globus pallidus, a critical component of the cortical-basal ganglia circuits, and its role in the pathogenesis of HD. This review also summarizes the current literature relating to human studies of the globus pallidus in HD.

Listen to brain networks responding to placebos!

Growing evidence from several medical disorders proves that placebo and nocebo responses play a significant role in, and can thus contribute to, the outcome of medical therapies. Parkinson's disease (PD) is among these disorders, a neurodegenerative disorder comprising cardinal motor symptoms associated with a deficit in dopamine production and electrophysiological disbalance in the basal ganglia, some of which (such as the subthalamic nucleus; STN) can be targeted for chronic electrical stimulation (deep brain stimulation) for symptom relief by modulation of diseased neuronal rhythms. Expectations regarding the effect of a treatment and associative learning/behavioural conditioning processes have been identified as main mechanisms underlying placebo responses (for review see, for example, Enck et al. 2013). In recent years it was shown that administration of placebo drugs, which PD patients expect to be potent antiparkinsonian (dopaminergic) medication, induces a substantial dopamine release in the striatum (de la Fuente-Fernandez et al. 2001). Using the possibility of intraoperative recordings in deep brain stimulation surgery, Fabrizio Benedetti's group furthermore showed that alterations in the firing rate of single neurons in the STN were associated with improvement in a motor symptom (rigidity) (Benedetti et al. 2004). However, these different facets of placebo responses induced through expectation were only evident for some patients, so called ‘placebo responders’. Benedetti's group is now targeting learning mechanisms in PD in order to convert ‘placebo non-responders’ to ‘responders’ – mechanisms already investigated in pain and other disorders. On a physiological level, Benedetti et al. now report in this issue of The Journal of Physiology how conditioning can turn thalamic neurons that do not respond to placebos (placebo ‘non-responder’ neurons) into a placebo ‘responder’ (Benedetti et al. 2016). As a result these neurons respond to a placebo the same way as they would to a medically effective treatment. Conditioning was achieved in PD patients with the dopaminergic drug apomorphine, given up to four days in a row before the surgical implantation of electrodes for deep brain stimulation. Intraoperatively, apomorphine was replaced with a placebo (saline infusions) and single neurons in the thalamus were recorded. If apomorphine was repeatedly administered before placebo administration, the placebo induced increased neuronal activity associated with improvement in the motor symptom of rigidity. The authors found that magnitude of neuronal changes and clinical effect were correlated with the number of previous drug administrations. If a placebo was given after four previous administrations of apomorphine, the placebo response could be as strong as the drug response, and this effect lasted up to 24 h. These findings highlight some remarkable aspects in placebo research: (1) it is possible to maximize a placebo response by conditioned learning in PD, (2) it is possible to identify a neuronal correlate of this mechanism by listening to single neurons, and (3) there may be an impact on future therapy and a widening of the therapeutic window in PD by reducing drug intake while obtaining the same clinical benefit. As a limitation of the current work it should be briefly mentioned that the clinical effect reported here was limited to rigidity – which is (in contrast to akinesia) one but not the core cardinal motor symptom in PD. Furthermore, recordings in this study were not performed in the STN, the typical target for deep brain stimulation to improve akinesia and rigidity, but were rather performed in the motor thalamus – the output station of the basal ganglia. In the future, recordings from the STN would be desirable. Moreover, taking the current understanding of deep brain stimulation as a neuromodulation technique in pathological cortical–subcortical oscillatory networks into account, one should supplement single- or multi-unit recording techniques with an oscillatory network approach. In the framework of deep brain stimulation, the combination of invasive local field potential recordings and non-invasive electroencephalography or magnetoencephalography offers a unique network approach in humans allowing the disentangling of brain activity patterns and brain function, especially regarding barely accessible deep-seated areas (Trenado et al. 2016). As the behavioural data and technical gadgets are available now, let's move beyond single neurons to listen to neuronal network oscillations responding to placebos.

The pedunculopontine tegmental nucleus-A functional hypothesis from the comparative literature.

ABSTRACTWe present data from animal studies showing that the pedunculopontine tegmental nucleus—conserved through evolution, compartmentalized, and with a complex pattern of inputs and outputs—has functions that involve formation and updates of action–outcome associations, attention, and rapid decision making. This is in contrast to previous hypotheses about pedunculopontine function, which has served as a basis for clinical interest in the pedunculopontine in movement disorders. Current animal literature points to it being neither a specifically motor structure nor a master switch for sleep regulation. The pedunculopontine is connected to basal ganglia circuitry but also has primary sensory input across modalities and descending connections to pontomedullary, cerebellar, and spinal motor and autonomic control systems. Functional and anatomical studies in animals suggest strongly that, in addition to the pedunculopontine being an input and output station for the basal ganglia and key regulator of thalamic (and consequently cortical) activity, an additional major function is participation in the generation of actions on the basis of a first‐pass analysis of incoming sensory data. Such a function—rapid decision making—has very high adaptive value for any vertebrate. We argue that in developing clinical strategies for treating basal ganglia disorders, it is necessary to take an account of the normal functions of the pedunculopontine. We believe that it is possible to use our hypothesis to explain why pedunculopontine deep brain stimulation used clinically has had variable outcomes in the treatment of parkinsonism motor symptoms and effects on cognitive processing. © 2016 International Parkinson and Movement Disorder Society

The Physiology of Fear: Reconceptualizing the Role of the Central Amygdala in Fear Learning.

The historically understood role of the central amygdala (CeA) in fear learning is to serve as a passive output station for processing and plasticity that occurs elsewhere in the brain. However, recent research has suggested that the CeA may play a more dynamic role in fear learning. In particular, there is growing evidence that the CeA is a site of plasticity and memory formation, and that its activity is subject to tight regulation. The following review examines the evidence for these three main roles of the CeA as they relate to fear learning. The classical role of the CeA as a routing station to fear effector brain structures like the periaqueductal gray, the lateral hypothalamus, and paraventricular nucleus of the hypothalamus will be briefly reviewed, but specific emphasis is placed on recent literature suggesting that the CeA 1) has an important role in the plasticity underlying fear learning, 2) is involved in regulation of other amygdala subnuclei, and 3) is itself regulated by intra- and extra-amygdalar input. Finally, we discuss the parallels of human and mouse CeA involvement in fear disorders and fear conditioning, respectively.