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Movement disorders are neurological conditions in which patients manifest a diverse range of movement impairments. Distinct structures within the basal ganglia of the brain, an area involved in movement regulation, are differentially affected for every disease. Among the most studied movement disorder conditions are Parkinson's (PD) and Huntington's disease (HD), in which the deregulation of the movement circuitry due to the loss of specific neuronal populations in basal ganglia is the underlying cause of motor symptoms. These symptoms are due to the loss principally of dopaminergic neurons of the substantia nigra (SN) par compacta and the GABAergic neurons of the striatum in PD and HD, respectively. Although these diseases were described in the 19th century, no effective treatment can slow down, reverse, or stop disease progression. Available pharmacological therapies have been focused on preventing or alleviating motor symptoms to improve the quality of life of patients, but these drugs are not able to mitigate the progressive neurodegeneration. Currently, considerable therapeutic advances have been achieved seeking a more efficacious and durable therapeutic effect. Here, we will focus on the new advances of several therapeutic approaches for PD and HD, starting with the available pharmacological treatments to alleviate the motor symptoms in both diseases. Then, we describe therapeutic strategies that aim to restore specific neuronal populations or their activity. Among the discussed strategies, the use of Neurotrophic factors (NTFs) and genetic approaches to prevent the neuronal loss in these diseases will be described. We will highlight strategies that have been evaluated in both Parkinson's and Huntington's patients, and also the ones with strong preclinical evidence. These current therapeutic techniques represent the most promising tools for the safe treatment of both diseases, specifically those aimed to avoid neuronal loss during disease progression. [ABSTRACT FROM AUTHOR]

We undertook a retrospective study to evaluate minimal 8-year outcomes of 46 trapeziometacarpal joints (46 patients) treated with pyrocarbon implant arthroplasty after partial trapeziectomy for trapeziometacarpal joint osteoarthritis in two different hand surgery units. The mean follow-up interval was 9.5 years (average 113 months with a range 97–144 months). The study showed that pyrocarbon interpositional arthroplasty provided pain relief and high patient satisfaction. All patients experienced a reduction in the DASH score, with an average change of 30 points. The visual analogue scale score, the Kapandji score, and key pinch also showed remarkable improvement. The PyroDisk implant exhibited good longevity, with good implant survival. A review of the literature revealed that the functional outcomes after implant surgery are not superior to more common techniques, such as trapeziectomy with or without ligamentoplasty. Therefore, this is a reliable surgery but may not have added benefits over simpler surgical treatments. This implant could have a role, perhaps in a select group of young patients, as a time-procuring procedure. Level of evidence: IV [ABSTRACT FROM AUTHOR]

Objective: Although the assessment of expression of serotonin-related genes in experimental animals has become a common strategy to shed light on variations in brain serotonergic function, it remains largely unknown to what extent the manipulation of serotonin levels causes detectable changes in gene expression. We therefore chose to investigate how sub-acute depletion or elevation of brain serotonin influences the expression of a number of serotonin-related genes in six brain areas. Methods: Male Wistar rats were administered a serotonin synthesis inhibitor, para-chlorophenylalanine (p-CPA), or a serotonin reuptake inhibitor, paroxetine, for 3 days and then sacrificed. The expression of a number of serotonin-related genes in the raphe nuclei, hypothalamus, amygdala, striatum, hippocampus and prefrontal cortex was investigated using real-time quantitative PCR (rt-qPCR). Results: While most of the studied genes were uninfluenced by paroxetine treatment, we could observe a robust downregulation of tryptophan hydroxylase-2 in the brain region where the serotonergic cell bodies reside, that is, the raphe nuclei. p-CPA induced a significant increase in the expression of Htr1b and Htr2a in amygdala and of Htr2c in the striatum and a marked reduction in the expression of Htr6 in prefrontal cortex; it also enhanced the expression of the brain-derived neurotrophic factor (Bdnf) in raphe and hippocampus. Conclusion: With some notable exceptions, the expression of most of the studied genes is left unchanged by short-term modulation of extracellular levels of serotonin. [ABSTRACT FROM AUTHOR]

The ability of new neurons to promote repair of brain circuitry depends on their capacity to re-establish afferent and efferent connections with the host. In this review article, we give an overview of past and current efforts to restore damaged connectivity in the adult mammalian brain using implants of fetal neuroblasts or stem cell-derived neuronal precursors, with a focus on strategies aimed to repair damaged basal ganglia circuitry induced by lesions that mimic the pathology seen in humans affected by Parkinson's or Huntington's disease. Early work performed in rodents showed that neuroblasts obtained from striatal primordia or fetal ventral mesencephalon can become anatomically and functionally integrated into lesioned striatal and nigral circuitry, establish afferent and efferent connections with the lesioned host, and reverse the lesion-induced behavioral impairments. Recent progress in the generation of striatal and nigral progenitors from pluripotent stem cells have provided compelling evidence that they can survive and mature in the lesioned brain and re-establish afferent and efferent axonal connectivity with a remarkable degree of specificity. The studies of cell-based circuitry repair are now entering a new phase. The introduction of genetic and virus-based techniques for brain connectomics has opened entirely new possibilities for studies of graft-host integration and connectivity, and the access to more refined experimental techniques, such as chemo- and optogenetics, has provided new powerful tools to study the capacity of grafted neurons to impact the function of the host brain. Progress in this field will help to guide the efforts to develop therapeutic strategies for cell-based repair in Huntington's and Parkinson's disease and other neurodegenerative conditions involving damage to basal ganglia circuitry. [ABSTRACT FROM AUTHOR]

The brain has persistent internal states that can modulate every aspect of an animal's mental experience1–4. In complex tasks such as foraging, the internal state is dynamic5–8. Caenorhabditis elegans alternate between local search and global dispersal5. Rodents and primates exhibit trade-offs between exploitation and exploration6,7. However, fundamental questions remain about how persistent states are maintained in the brain, which upstream networks drive state transitions and how state-encoding neurons exert neuromodulatory effects on sensory perception and decision-making to govern appropriate behaviour. Here, using tracking microscopy to monitor whole-brain neuronal activity at cellular resolution in freely moving zebrafish larvae9, we show that zebrafish spontaneously alternate between two persistent internal states during foraging for live prey (Paramecia). In the exploitation state, the animal inhibits locomotion and promotes hunting, generating small, localized trajectories. In the exploration state, the animal promotes locomotion and suppresses hunting, generating long-ranging trajectories that enhance spatial dispersion. We uncover a dorsal raphe subpopulation with persistent activity that robustly encodes the exploitation state. The exploitation-state-encoding neurons, together with a multimodal trigger network that is associated with state transitions, form a stochastically activated nonlinear dynamical system. The activity of this oscillatory network correlates with a global retuning of sensorimotor transformations during foraging that leads to marked changes in both the motivation to hunt for prey and the accuracy of motor sequences during hunting. This work reveals an important hidden variable that shapes the temporal structure of motivation and decision-making. During foraging for live prey, zebrafish larvae alternate between persistent exploitation and exploration behavioural states that correlate with distinct patterns of neuronal activation. [ABSTRACT FROM AUTHOR]

The lateral habenula (LHb) has been shown to play critical roles in a variety of appetitive tasks (e.g., spatial memory and object recognition) that require animals to flexibly respond to changing task conditions. These types of tasks are known to be dependent on hippocampus (HPC) and/or medial prefrontal cortex (mPFC), suggesting that the LHb contributes to the limbic memory circuit. Here we provide new evidence that the LHb and HPC play distinct but complimentary roles in tasks that require flexible responding to changing task conditions. Experiment 1 tested whether the LHb is needed for the performance of a HPC-dependent maze-based spatial delayed alternation task. The importance of interactions between the LHb and HPC to accomplish the same spatial delayed alternation task was tested in Experiment 2 where the LHb and HPC were disconnected both ipsilaterally and contralaterally. Experiment 3 tested LHb's involvement in a standard behavioral economic task that requires flexible responding (maze-based delayed discounting), a task previously shown to rely on HPC. Results of Experiment 1, revealed that LHb inactivation impairs spatial delayed alternation during asymptotic performance but not during initial learning. Importantly, working memory did not appear to be affected as performance remained above chance levels both during initial learning and asymptotic testing. Experiment 2 showed that ipsilateral and contralateral disconnection of the LHb and HPC led to impaired performance on the spatial delayed alternation task. Impairments were not observed after unilateral inactivation of only one structure. Results of Experiment 3 were similar to our previous report of the effects of HPC inactivation: LHb inactivation impaired delayed discounting. All effects could not be accounted for by changes in reward magnitude discrimination, reward location per se , or sex of the animal. These findings, combined with other recent publications confirms and extends our working hypothesis that the LHb enables adaptive and flexible responding, particularly when established rules must be flexibly applied on a trial by trial basis. Since there are no known direct anatomical connections between LHb and HPC, future research is needed to understand how these structures communicate to enable flexible and rapid responding. [ABSTRACT FROM AUTHOR]

The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus that sends cholinergic, glutamatergic, and gamma‐aminobutyric acid (GABA)‐ergic projections to the ventral tegmental area (VTA), a key brain region associated with reward information processing and reinforcement learning, and thus, with addiction induced by drugs of abuse, including cocaine. Recent studies have revealed that the LDT, in addition to the VTA, plays important roles in the development and expression of cocaine‐induced addiction and stress‐induced enhancement of addictive behaviors. Additionally, neuroplasticity induced in LDT cholinergic neurons by repeated cocaine administration critically contributes to these behaviors. Elucidation of the underlying mechanisms of cocaine‐induced neuroplasticity in the LDT that influences reward circuit activity may lead to the development of therapeutic strategies to treat cocaine addiction and stress‐induced reinstatement of cocaine use. This review summarizes recent progress in the study of the LDT, specifically neuroplasticity in LDT cholinergic neurons induced by cocaine and its functional roles in the development and modulation of addictive behaviors associated with cocaine. [ABSTRACT FROM AUTHOR]

Effects of stress on the reward system are well established in the literature. Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry using a cocaine-induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30-minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non-stressed rats. Intra-laterodorsal tegmental nucleus (LDT) microinjection of a β or α2 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Consistent with this observation, intra-LDT microinjection of a β or α2 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra-ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress-induced enhancement of cocaine CPP. Finally, intra-medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress-induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine-induced reward value. [ABSTRACT FROM AUTHOR]

Background Although nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies. Methods Functional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16–21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18–25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers. Results Connectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal. Conclusions Relief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking. [ABSTRACT FROM AUTHOR]

Background Methamphetamine use is associated with a variety of negative health outcomes, including psychosis. The frontal cortex serotonin receptors are thought to contribute to psychosis-like behaviors. This study investigated changes in serotonergic markers in the frontal cortex following methamphetamine self-administration and hallucinogenic drug-induced behavior. Methods Consistent with previously published studies, freely cycling male and female rats were allowed to self-administer methamphetamine (males: 0.12 mg/infusion; females: 0.09 mg/infusion) or saline (10 µL) for 7 days. On the day following self-administration or following 10 days of extinction training, animals were given the serotonin 2A/2C agonist, 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (2 mg/kg, i.p.), and head twitches were analyzed. Autoradiography was also used to assess serotonin receptors and transporters in the frontal cortex following self-administration. Results Methamphetamine self-administration led to an increase in DOI-induced head-twitch behavior compared to saline only on the day following self-administration. Increases in serotonin receptors in the orbitofrontal cortex and decreases in serotonin transporters in the orbitofrontal cortex and infralimbic cortex were observed following methamphetamine self-administration as assessed by autoradiography. Conclusions Methamphetamine self-administration was associated with serotonergic alterations in the frontal cortex, which may underlie behavioral changes related to methamphetamine-associated psychosis. [ABSTRACT FROM AUTHOR]

There is currently no cure for Parkinson’s disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations including the occurrence of motor complications related to its particular pharmacokinetic and pharmacodynamic properties. Other therapeutic strategies have thus been developed to overcome these problems such as the use of dopamine receptor agonists, dopamine metabolism inhibitors and non-dopaminergic drugs. Here we review the pharmacology and molecular mechanisms of dopamine replacement therapy in Parkinson’s disease, both at the presynaptic and postsynaptic levels. The perspectives in terms of novel drug development and prediction of drug response for a more personalised medicine will be discussed. [ABSTRACT FROM AUTHOR]

Alcohol use disorders (AUDs) represent a severe, world-wide problem, and are usually comorbid with psychiatric disorders, comorbidity increases the risks associated with AUDs, and results in more serious consequences for patients. However, currently the underlying mechanisms of comorbid psychiatric disorders in AUDs are not clear. Studies investigating comorbidity could help us understand the neural mechanisms of AUDs. In this review, we explore three comorbidities in AUDs, including schizophrenia, major depressive disorder (MDD), and personality disorders (PDs). They are all co-morbidities of AUDs with rate of 33.7, 28, and 50-70%, respectively. The rate is significantly higher than other diseases. Therefore we review and analyze relevant literature to explore whether these three diseases are the risk factors of AUDs, focusing on studies assessing cognitive function and those using neural imaging. We found that memory deficits, impairment of cognitive control, negative emotion, and impulsivity may increase an individual's vulnerability to AUDs. This comorbidity may indicate the neural basis of AUDs and reveal characteristics associated with different types of comorbidity, leading to further development of new treatment approaches for AUDs. [ABSTRACT FROM AUTHOR]

The Stria medullaris (SM) Thalami is a discrete white matter tract that directly connects frontolimbic areas to the habenula, allowing the forebrain to influence midbrain monoaminergic output. Habenular dysfunction has been shown in various neuropsychiatric conditions. However, there exists a paucity of research into the habenula's principal afferent tract, the SM. Diffusion-weighted tractography may provide insights into the properties of the SM in vivo, opening up investigation of this tract in conditions of monoamine dysregulation such as depression, schizophrenia, addiction and pain. We present a reliable method for reconstructing the SM using diffusionweighted imaging, and examine the effects of age and gender on tract diffusion metrics. We also investigate reproducibility of the method through inter-rater comparisons. In consultation with neuroanatomists, a Boolean logic gate protocol was developed for use in ExploreDTI to extract the SM from constrained spherical deconvolution based whole brain tractography. Particular emphasis was placed on the reproducibility of the tract, attention to crossing white matter tract proximity and anatomical consistency of anterior and posterior boundaries. The anterior commissure, pineal gland and mid point of the thalamus were defined as anatomical fixed points used for reconstruction. Fifty subjects were scanned using High Angular Resolution Diffusion Imaging (HARDI; 61 directions, b-value 1500 mm3). Following constrained spherical deconvolution whole brain tractography, two independent raters isolated the SM. Each output was checked, examined and cleaned for extraneous streamlines inconsistent with known anatomy of the tract by the rater and a neuroanatomist. A second neuroanatomist assessed tracts for face validity. The SM was reconstructed with excellent inter-rater reliability for dimensions and diffusion metrics. Gender had no effect on the dimensions or diffusion metrics, however radial diffusivity (RD) showed a positive correlation with age. Reliable identification and quantification of diffusion metrics of the SM invites further exploration of this key habenula linked structure in neuropsychiatric disorders such as depression, anxiety, chronic pain and addiction. The accurate anatomical localization of the SM may also aid preoperative stereotactic localization of the tract for deep brain stimulation (DBS) treatment. [ABSTRACT FROM AUTHOR]

Abstract: Extensive loss of noradrenaline‐containing neurons and fibers is a nearly invariant feature of Alzheimer's Disease (AD). However, the exact noradrenergic contribution to cognitive and histopathological changes in AD is still unclear. Here, this issue was addressed following selective lesioning and intrahippocampal implantation of embryonic noradrenergic progenitors in developing rats. Starting from about 3 months and up to 12 months post‐surgery, animals underwent behavioral tests to evaluate sensory‐motor, as well as spatial learning and memory, followed by post‐mortem morphometric analyses. At 9 months, Control, Lesioned and Lesion + Transplant animals exhibited equally efficient sensory‐motor and reference memory performance. Interestingly, working memory abilities were seen severely impaired in Lesion‐only rats and fully recovered in Transplanted rats, and appeared partly lost again 2 months after ablation of the implanted neuroblasts. Morphological analyses confirmed the almost total lesion‐induced noradrenergic neuronal and terminal fiber loss, the near‐normal reinnervation of the hippocampus promoted by the transplants, and its complete removal by the second lesion. Notably, the noradrenergic‐rich transplants normalized also the nuclear expression of the transactive response DNA‐binding protein 43 (TDP‐43) in various hippocampal subregions, whose cytoplasmic (i.e., pathological) occurrence appeared dramatically increased as a result of the lesions. Thus, integrity of ascending noradrenergic inputs to the hippocampus may be required for the regulation of specific aspects of learning and memory and to prevent TDP‐43 tissue pathology. [ABSTRACT FROM AUTHOR]

Phasic activity of dopaminergic (DA) neurons in the ventral tegmental area or substantia nigra compacta (VTA/SNc) has been suggested to encode reward-prediction error signal for reinforcement learning. Recent studies have shown that the lateral habenula (LHb) neurons exhibit a similar response, but for nonrewarding or punishment signals. Hence, the transient signaling role of LHb neurons is opposite that of DA neurons and also that of several other brain nuclei such as the border region of the globus pallidus internal segment (GPb) and the rostral medial tegmentum (RMTg). Previous theoretical models have investigated the neural circuit mechanism underlying reward-based phasic activity of DA neurons, but the feasibility of a larger neural circuit model to account for the observed reward-based phasic activity in other brain nuclei such as the LHb has yet to be shown. Here, we propose a large-scale neural circuit model and show that parallel excitatory and inhibitory pathways underlie the learned neural responses across multiple brain regions. Specifically, the model can account for the phasic neural activity observed in the GPb, LHb, RMTg, and VTA/SNc. Based on sensitivity analysis, the model is found to be robust against changes in the overall neural connectivity strength. The model also predicts that striosomes play a key role in the phasic activity of VTA/SNc and LHb neurons by encoding previous and expected rewards. Taken together, our model identifies the important role of parallel neural circuit pathways in accounting for phasic activity across multiple brain areas during reward and punishment processing. [ABSTRACT FROM AUTHOR]

Purpose: To detect local cholinergic changes in human medial temporal lobe during configural working memory performance.Materials and Methods: Proton magnetic resonance spectroscopy (1 H-MRS) measurements were acquired at 3T from a 2 × 2 × 3 cm voxel in right medial temporal lobe from 36 subjects during performance of a configural visual working memory task (cWMT). In order to compensate for expected task-based blood oxygenation level-dependent (BOLD) T2 * effects, resonance signal changes of unbound choline-containing metabolites (Cho) were referenced to an internal standard of creatine + phosphocreatine metabolites (Cre) and compared between four task blocks: rest, memorization, active memory maintenance, and recognition. An unannounced memory retention test was conducted in 21 subjects. Quality assurance analyses examined task-based Cho and Cre individually as well as referenced to resonance signal from N-acetylaspartate (NAA).Results: Increases from a resting baseline in the Cho/Cre ratio were observed during 60-second blocks of active memory maintenance across the group (P = 0.0042). Behavioral accuracy during task performance correlated with memory retention (r = 0.48, P = 0.027). Quality assurance measures showed task-based changes in Cre resonance signal both individually (P = 0.00099) and when utilized as a noncholinergic internal reference (NAA/Cre, P = 0.00079).Conclusion: Increases in human medial temporal lobe 1 H-MRS Cho/Cre ratio occur during the maintenance of configural working memory information. However, interpretation of these results as driven by cholinergic activity cannot be assumed, as NAA, a noncholinergic metabolite, shows similar results when utilizing Cre as a reference. Caution is advised when considering Cre as an internal standard for task-based 1 H-MRS measurements.Level Of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:682-691. [ABSTRACT FROM AUTHOR]

Neurons in the periaqueductal gray (PAG) modulate threat responses and nociception. Activity in the ventral tegmental area (VTA) on the other hand can cause reinforcement and aversion. While in many situations these behaviors are related, the anatomical substrate of a crosstalk between the PAG and VTA remains poorly understood. Here we describe the anatomical and electrophysiological organization of the VTA-projecting PAG neurons. Using rabies-based, cell type-specific retrograde tracing, we observed that PAG to VTA projection neurons are evenly distributed along the rostro-caudal axis of the PAG, but concentrated in its posterior and ventrolateral segments. Optogenetic projection targeting demonstrated that the PAG-to-VTA pathway is predominantly excitatory and targets similar proportions of Ih-expressing VTA DA and GABA neurons. Taken together, these results set the framework for functional analysis of the interplay between PAG and VTA in the regulation of reward and aversion. [ABSTRACT FROM AUTHOR]

Psychiatric illnesses, including depression and anxiety, are highly comorbid with epilepsy (for review see Josephson and Jetté (Int Rev Psychiatry 29:409-424, 2017), Salpekar and Mula (Epilepsy Behav 98:293-297, 2019)). Psychiatric comorbidities negatively impact the quality of life of patients (Johnson et al., Epilepsia 45:544-550, 2004; Cramer et al., Epilepsy Behav 4:515-521, 2003) and present a significant challenge to treating patients with epilepsy (Hitiris et al., Epilepsy Res 75:192-196, 2007; Petrovski et al., Neurology 75:1015-1021, 2010; Fazel et al., Lancet 382:1646-1654, 2013) (for review see Kanner (Seizure 49:79-82, 2017)). It has long been acknowledged that there is an association between psychiatric illnesses and epilepsy. Hippocrates, in the fourth-fifth century B.C., considered epilepsy and melancholia to be closely related in which he writes that "melancholics ordinarily become epileptics, and epileptics, melancholics" (Lewis, J Ment Sci 80:1-42, 1934). The Babylonians also recognized the frequency of psychosis in patients with epilepsy (Reynolds and Kinnier Wilson, Epilepsia 49:1488-1490, 2008). Despite the fact that the relationship between psychiatric comorbidities and epilepsy has been recognized for thousands of years, psychiatric illnesses in people with epilepsy still commonly go undiagnosed and untreated (Hermann et al., Epilepsia 41(Suppl 2):S31-S41, 2000) and systematic research in this area is still lacking (Devinsky, Epilepsy Behav 4(Suppl 4):S2-S10, 2003). Thus, although it is clear that these are not new issues, there is a need for improvements in the screening and management of patients with psychiatric comorbidities in epilepsy (Lopez et al., Epilepsy Behav 98:302-305, 2019) and progress is needed to understand the underlying neurobiology contributing to these comorbid conditions. To that end, this chapter will raise awareness regarding the scope of the problem as it relates to comorbid psychiatric illnesses and epilepsy and review our current understanding of the potential mechanisms contributing to these comorbidities, focusing on both basic science and clinical research findings., (© 2020. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Several cortical and diencephalic limbic brain regions incorporate neurons that fire in correlation with the speed of whole-body motion, also known as linear velocity. Besides the field mapping and head-directional information, the linear velocity is among the major signals that guide animal's spatial navigation. Large neuronal populations in the same limbic regions oscillate with theta rhythm during spatial navigation or attention episodes; and the frequency of theta also correlates with linear velocity. A functional similarity between these brain areas is that their inactivation impairs the ability to form new spatial memories; whereas an anatomical similarity is that they all receive projections from medial septum-diagonal band of Broca complex. We review recent findings supporting the model that septal theta rhythm integrates different sensorimotor signals necessary for spatial navigation. The medial septal is described here as a circuitry that mediates experience-dependent balance of sustained attention and path integration during navigation. We discuss the hypothesis that theta rhythm serves as a key mechanism for the aligning of intrinsic spatial representation to: (1) rapid change of position in the spatial environment; (2) continuous alteration of sensory signals throughout navigation; and (3) adapting levels of attentional behavior. The synchronization of these spatial, somatosensory and neuromodulatory signals is proposed here to be anatomically and physiologically mediated by the medial septum. [ABSTRACT FROM AUTHOR]

The habenula is an epithalamic structure differentiated into two nuclear complexes, medial (MHb) and lateral habenula (LHb). Recently, MHb together with its primary target, the interpeduncular nucleus (IP), have been identified as major players in mediating the aversive effects of nicotine. However, structures downstream of the MHb-IP axis, including the median (MnR) and caudal dorsal raphe nucleus (DRC), may contribute to the behavioral effects of nicotine. The afferent and efferent connections of the IP have hitherto not been systematically investigated with sensitive tracers. Thus, we placed injections of retrograde or anterograde tracers into different IP subdivisions or the MnR and additionally examined the transmitter phenotype of major IP and MnR afferents by combining retrograde tract tracing with immunofluorescence and in situ hybridization techniques. Besides receiving inputs from MHb and also LHb, we found that IP is reciprocally interconnected mainly with midline structures, including the MnR/DRC, nucleus incertus, supramammillary nucleus, septum, and laterodorsal tegmental nucleus. The bidirectional connections between IP and MnR proved to be primarily GABAergic. Regarding a possible topography of IP outputs, all IP subnuclei gave rise to descending projections, whereas major ascending projections, including focal projections to ventral hippocampus, ventrolateral septum, and LHb originated from the dorsocaudal IP. Our findings indicate that IP is closely associated to a distributed network of midline structures that modulate hippocampal theta activity and forms a node linking MHb and LHb with this network, and the hippocampus. Moreover, they support a cardinal role of GABAergic IP/MnR interconnections in the behavioral response to nicotine. [ABSTRACT FROM AUTHOR]

Loss of large carnivore populations may lead to increased population densities of large herbivores, and subsequent cascading effects on the composition, structure, and function of ecosystems. Using a macroecological approach based on studies in multiple boreal forest landscapes in the Baltic Sea region and Russia, we tested the hypothesis that disrupted trophic interactions among large carnivores and large herbivores affect the recruitment of both ecologically and economically valuable tree species. We measured damage levels on young trees and large herbivore density in 10 local landscapes representing a gradient from extinct to extant populations of both large carnivores and large herbivores. We also tested the alternative hypothesis that forest management intensity is correlated to reduced recruitment of these tree species. At the macroecological scale there was an inverse relationship between the number of large carnivores and large herbivores. This coincided with a steep gradient in browsing damage on the ecologically important aspen, rowan and sallow as hosts for specialized species, as well as the economically important Scots pine. In one landscape hunting had replaced the presence of carnivores. Mean damage levels of these four tree species were correlated with large herbivore abundance, but not with forest management intensity. We discuss the pros and cons of this macroecological approach, as well as the challenge of governing and managing trophic interactions at multiple scales. [ABSTRACT FROM AUTHOR]

Corticospinal and corticobulbar descending pathways act in parallel with brainstem systems, such as the reticulospinal tract, to ensure the control of voluntary movements via direct or indirect influences onto spinal motoneurons. The aim of this study was to investigate the corticobulbar projections from distinct motor cortical areas onto different nuclei of the reticular formation. Seven adult macaque monkeys were analysed for the location of corticobulbar axonal boutons, and one monkey for reticulospinal neurons' location. The anterograde tracer BDA was injected in the premotor cortex ( PM), in the primary motor cortex (M1) or in the supplementary motor area ( SMA), in 3, 3 and 1 monkeys respectively. BDA anterograde labelling of corticobulbar axons were analysed on brainstem histological sections and overlapped with adjacent Nissl-stained sections for cytoarchitecture. One adult monkey was analysed for retrograde CB tracer injected in C5-C8 hemispinal cord to visualise reticulospinal neurons. The corticobulbar axons formed bilateral terminal fields with boutons terminaux and en passant, which were quantified in various nuclei belonging to the Ponto-Medullary Reticular Formation ( PMRF). The corticobulbar projections from both PM and SMA tended to end mainly ipsilaterally in PMRF, but contralaterally when originating from M1. Furthermore, the corticobulbar projection was less dense when originating from M1 than from non-primary motor areas ( PM, SMA). The main nuclei of bouton terminals corresponded to the regions where reticulospinal neurons were located with CB retrograde tracing. In conclusion, the corticobulbar projection differs according to the motor cortical area of origin in density and laterality. [ABSTRACT FROM AUTHOR]

Purpose: Trapeziometacarpal (TM) osteoarthritis is the most common type of arthritis of the hand. To date, among surgical alternatives proposed, no one type has been proven superior to others. In this prospective study we evaluated the efficacy of treating arthroplasty with a latest-generation pyrocarbon implant (Pyrocardan).Methods: Thirty-six patients with TM arthritis were treated using Pyrocardan implant arthroplasty. Results were evaluated through thumb radial and palmar abduction assessment, key pinch strength evaluation, thumb opposition assessment according to Kapandji classification, the visual analogue scale, the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and the Patient's Satisfaction Index.Results: There was substantial pain reduction and a satisfying increase in range of motion and strength (p < 0.01) and improvement in DASH score (p < 0.01). Average Patient's Satisfaction Index was 8 out of 10.Conclusions: TM arthroplasty with Pyrocardan implantation is a suitable option in treating Eaton-Littler grade II or III TM osteoarthritis. [ABSTRACT FROM AUTHOR]

The bioabsorbable poly-L-D-lactide joint scaffold arthroplasty is a recent attempt in the reconstruction of small joints in rheumatoid patients. In this study, we analysed the 1-year clinical, functional and radiologic results of partial trapeziectomy with the poly-L-D-lactide (96/4) joint scaffold in 23 patients with isolated trapeziometacarpal osteoarthritis. The results showed that the procedure provided pain relief and improvement in overall function according to the Quick Disabilities of the Arm, Shoulder and Hand score in most patients. However, radiographs demonstrated a high frequency of osteolysis around the implant. Seven patients developed clinically manifested foreign-body reactions 6 months to 1 year after surgery. The reason for the unexpected tissue reactions may relate to excessive mechanical cyclic loading of the implant. The outcomes of this implant in our patients have not been sufficiently beneficial and we have discontinued use of this implant in isolated trapeziometacarpal osteoarthritis. [ABSTRACT FROM AUTHOR]

One of the major symptoms of the neurodegenerative condition Parkinson's disease (PD) is a slowness or loss of voluntary movement, yet frustratingly therapeutic strategies designed to restore movement can result in the development of excessive abnormal movements known as dyskinesia. These dyskinesias commonly develop as a result of pharmacotherapy in the form of L-DOPA administration, but have also been identified following deep brain stimulation (DBS) and intrastriatal cell transplantation. In the case of L-DOPA these movements can be treatment limiting, and whilst they are not long lasting or troubling following DBS, recognition of their development had a near devastating effect on the field of cell transplantation for PD. Understanding the relationship between these therapeutic approaches and the development of dyskinesia may improve our ability to restore function without disabling side effects. Interestingly, despite the fact that dopaminergic cell transplantation repairs many of the changes induced by the disease process and through L-DOPA treatment, there appears to be a relationship between the two. In rodent models of the disease, the severity of dyskinesia induced by L-DOPA prior to the transplantation procedure correlated with post-transplantation, graft-induced dyskinesia. A review of clinical data also suggested that the worse preoperational dyskinesia causes worsened graft-induced dyskinesia (GID). Understanding how these aberrant behaviors come about has been of keen interest to open up these therapeutic options more widely and one major underlying theory is the effects of these approaches on the plasticity of synapses within the basal ganglia. This review uniquely brings together developments in understanding the role of striatal synaptic plasticity in both L-DOPA and GID to guide and stimulate further investigations on the important striatal plasticity. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominant inherited disorder leading to the loss inter alia of DARPP-32 positive medium spiny projection neurons ("MSNs") in the striatum. There is no known cure for HD but the relative specificity of cell loss early in the disease has made cell replacement by neural transplantation an attractive therapeutic possibility. Transplantation of human fetal striatal precursor cells has shown "proof-of-principle" in clinical trials; however, the practical and ethical difficulties associated with sourcing fetal tissues have stimulated the need to identify alternative source(s) of donor cells that are more readily available and more suitable for standardization.We now have available the first generation of protocols to generate DARPP-32 positive MSN-like neurons from pluripotent stem cells and these have been successfully grafted into animal models of HD. However, whether these grafts can provide stable functional recovery to the level that can regularly be achieved with primary fetal striatal grafts remains to be demonstrated. Of particular concern, primary fetal striatal grafts are not homogenous; they contain not only the MSN subpopulation of striatal projection neurons but also include all the different cell types that make up the mature striatum, such as the multiple populations of striatal interneurons and striatal glia, and which certainly contribute to normal striatal function. By contrast, present protocols for pluripotent stem cell differentiation are almost entirely targeted at specifying just neurons of an MSN lineage. So far, evidence for the functionality and integration of stem-cell derived grafts is correspondingly limited. Indeed, consideration of the features of full striatal reconstruction that is achieved with primary fetal striatal grafts suggests that optimal success of the next generations of stem cell-derived replacement therapy in HD will require that graft protocols be developed to allow inclusion of multiple striatal cell types, such as interneurons and/or glia. Almost certainly, therefore, more sophisticated differentiation protocols will be necessary, over and above replacement of a specific population of MSNs. A rational solution to this technical challenge requires that we readdress the underlying question-what constitutes a functional striatal graft? [ABSTRACT FROM AUTHOR]

Stuttering has been the subject of much research, nevertheless its etiology remains incompletely understood. This article presents a critical review of the literature on stuttering, with particular reference to the role of the basal ganglia (BG). Neuroimaging and lesion studies of developmental and acquired stuttering, as well as pharmacological and genetic studies are discussed. Evidence of structural and functional changes in the BG in those who stutter indicates that this motor speech disorder is due, at least in part, to abnormal BG cues for the initiation and termination of articulatory movements. Studies discussed provide evidence of a dysfunctional hyperdopaminergic state of the thalamocortical pathways underlying speech motor control in stuttering. Evidence that stuttering can improve, worsen or recur following deep brain stimulation for other indications is presented in order to emphasize the role of BG in stuttering. Further research is needed to fully elucidate the pathophysiology of this speech disorder, which is associated with significant social isolation. [ABSTRACT FROM AUTHOR]

The brain reward circuit has a central role in reinforcing behaviors that are rewarding and preventing behaviors that lead to punishment. Recent work has shown that the lateral habenula is an important part of the reward circuit by providing 'negative value' signals to the dopaminergic and serotonergic systems. Studies have also suggested that dysfunction of the lateral habenula is associated with psychiatric disorders, including major depression. Here, we discuss insights gained from neuronal recordings in monkeys regarding how the lateral habenula processes reward-related information. We then highlight recent optogenetic experiments in rodents addressing normal and abnormal functions of the habenula. Finally, we discuss how deregulation of the lateral habenula may be involved in depressive behaviors. [ABSTRACT FROM AUTHOR]

The dorsal raphe nucleus (DRN), representing the main source of brain's serotonin, is implicated in the pathophysiology and therapeutics of several mental disorders that can be debilitating and life-long including depression, anxiety and autism. The activity of DRN neurons is precisely regulated, both phasically and tonically, by excitatory glutamate and inhibitory GABAergic axons arising from extra-raphe areas as well as from local sources within the nucleus. Changes in serotonin neurotransmission associated with pathophysiology may be encoded by alterations within this network of regulatory afferents. However, the complex organization of the DRN circuitry remains still poorly understood. Using a recently developed high-resolution immunofluorescence technique called array tomography (AT) we quantitatively analyzed the relative contribution of different populations of glutamate axons originating from different brain regions to the excitatory drive of the DRN. Additionally, we examined the presence of GABA axons within the DRN and their possible association with glutamate axons. In this review, we summarize our findings on the architecture of the rodent DRN synaptic neuropil using high-resolution neuroanatomy, and discuss possible functional implications for the nucleus. Understanding of the synaptic architecture of neural circuits at high resolution will pave the way to understand how neural structure and function may be perturbed in pathological states. [ABSTRACT FROM AUTHOR]

Photo-cross-linkable physical hydrogels based on the coiled-coil region of the cartilage oligomeric matrix protein and polyethylene glycol diacrylate were designed and synthesized to mimic the natural extracellular matrix for three-dimensional cell culture. The engineered polypeptides (Pcys and RGDPcys) were modified with polyethylene glycol diacrylate to form photo-cross-linkable multifunctional macromers via the Michael-type addition reaction between the cysteine residues and acrylates. Gel formation was confirmed by rheological measurements. The swelling ratio and stability of 10% w/v RGDP-PEG-acrylate[sub 6k] hydrogel were 38% and 15 days, respectively. Spreading and migration of encapsulated fibroblast cells were observed in these physical hydrogels, while round cells were observed in a covalent control hydrogel. In addition, rapid self-healing of these physical hydrogels can provide a flexible way to build tissue by self-assembly and bottom-up approach. The results demonstrate that such physical hydrogels are expected to have great potential applications in tissue engineering. [ABSTRACT FROM AUTHOR]

A growing number of studies in humans demonstrate the involvement of vestibular information in tasks that are seemingly remote from well-known functions such as space constancy or postural control. In this review article we point out three emerging streams of research highlighting the importance of vestibular input: (1) Spatial Cognition: Modulation of vestibular signals can induce specific changes in spatial cognitive tasks like mental imagery and the processing of numbers. This has been shown in studies manipulating body orientation (changing the input from the otoliths), body rotation (changing the input from the semicircular canals), in clinical findings with vestibular patients, and in studies carried out in microgravity. There is also an effect in the reverse direction; top-down processes can affect perception of vestibular stimuli. (2) Body Representation: Numerous studies demonstrate that vestibular stimulation changes the representation of body parts, and sensitivity to tactile input or pain. Thus, the vestibular system plays an integral role in multisensory coordination of body representation. (3) Affective Processes and Disorders: Studies in psychiatric patients and patients with a vestibular disorder report a high comorbidity of vestibular dysfunctions and psychiatric symptoms. Recent studies investigated the beneficial effect of vestibular stimulation on psychiatric disorders, and how vestibular input can change mood and affect. These three emerging streams of research in vestibular science are-at least in part-associated with different neuronal core mechanisms. Spatial transformations draw on parietal areas, body representation is associated with somatosensory areas, and affective processes involve insular and cingulate cortices, all of which receive vestibular input. Even though a wide range of different vestibular cortical projection areas has been ascertained, their functionality still is scarcely understood. [ABSTRACT FROM AUTHOR]

During post-weaning development, a marked increase in peer-peer interactions is observed in mammals, including humans, which is signified by the abundance of social play behaviour. Social play is highly rewarding, and known to be modulated through monoaminergic neurotransmission. Recently, the habenula has received widespread attention because of its role in the regulation of monoaminergic neurotransmission as well as in a variety of emotional and cognitive functions. Therefore, in the present study, we investigated the involvement of the habenula in social play behaviour. Using the neuronal activity maker c-fos, we showed that the habenula was activated after 24 h of social isolation in adolescent rats, and that a subsequent social play interaction reduced c-fos activity in the medial part of the lateral habenula. This suggested that habenula activity modulated the aversive properties of social isolation, which was alleviated by the positive effects of social play. Furthermore, after functional inactivation of the habenula, using a mixture of the GABA receptor agonists baclofen and muscimol, social play behaviour was markedly reduced, whereby responsiveness to play solicitation was more sensitive to habenula inactivation than play solicitation itself. Together, our data indicate an important role for the habenula in the processing of positive (i.e. social play behaviour) and negative (i.e. social isolation) social information in adolescent rats. Altered habenula function might therefore be related to the social impairments in childhood and adolescent psychiatric disorders such as autism, attention deficit/hyperactivity disorder and early-onset schizophrenia. [ABSTRACT FROM AUTHOR]

Blood capillaries are crucial for the biological evaluation of drug diffusion to target tissues, and the penetration of cancer cells or viruses. Since most capillaries have a bilayered structure consisting of a monolayer of endothelial cells (ECs) and surrounding smooth muscle cells (SMCs), the in vitro reconstruction of this bilayered structure is a key challenge for pharmaceutical and biomedical applications. Here, a unique technology to construct size, length, orientation, and layer-number controllable blood capillary networks in biodegradable hydrogels is reported. Uniaxial microchannels are prepared inside biodegradable hydrogels by the simple extraction of silica capillary tubes. The channel size, length, and distance of the uniaxial channels are easily controlled by altering these parameters of the silica tubes. The inner surfaces of the channels are successfully covered by bilayered structures consisting of ECs and SMCs by a hierarchical cell manipulation technique. Notably, serum albumin, which has an approximately 8 nm size, cannot penetrate this capillary wall during several hours of incubation due to the high blood vessel wall barrier property. This suggests a successful reconstruction of multilayered blood capillary networks possessing similar barrier function as native blood capillaries. Moreover, these capillary networks can be completely collected by the selective degradation of the surrounding hydrogels. This technique will be an innovative and versatile approach for in vitro permeability assays of drugs, drug delivery carriers, and cancer cells. [ABSTRACT FROM AUTHOR]

Acetylcholine has been implicated in both the pathophysiology and treatment of a number of psychiatric disorders, with most of the data related to its role and therapeutic potential focusing on schizophrenia. However, there is little thought given to the consequences of the documented changes in the cholinergic system and how they may affect the functioning of the brain. This review looks at the cholinergic system and its interactions with the intrinsic neurotransmitters glutamate and gamma-amino butyric acid as well as those with the projection neurotransmitters most implicated in the pathophysiologies of psychiatric disorders; dopamine and serotonin. In addition, with the recent focus on the role of factors normally associated with inflammation in the pathophysiologies of psychiatric disorders, links between the cholinergic system and these factors will also be examined. These interfaces are put into context, primarily for schizophrenia, by looking at the changes in each of these systems in the disorder and exploring, theoretically, whether the changes are interconnected with those seen in the cholinergic system. Thus, this review will provide a comprehensive overview of the connectivity between the cholinergic system and some of the major areas of research into the pathophysiologies of psychiatric disorders, resulting in a critical appraisal of the potential outcomes of a dysregulated central cholinergic system. [ABSTRACT FROM AUTHOR]