Brain Sciences

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Open AccessArticle

Using “Functional” Target Coordinates of the Subthalamic Nucleus to Assess the Indirect and Direct Methods of the Preoperative Planning: Do the Anatomical and Functional Targets Coincide?

by Ahmed Rabie, Leo Verhagen Metman and Konstantin V. Slavin

Brain Sci. 2016, 6(4), 65; https://doi.org/10.3390/brainsci6040065 - 21 Dec 2016

Cited by 20 | Viewed by 18329

Abstract

Objective: To answer the question of whether the anatomical center of the subthalamic nucleus (STN), as calculated indirectly from stereotactic atlases or by direct visualization on magnetic resonance imaging (MRI), corresponds to the best functional target. Since the neighboring red nucleus (RN) is [...] Read more.

Objective: To answer the question of whether the anatomical center of the subthalamic nucleus (STN), as calculated indirectly from stereotactic atlases or by direct visualization on magnetic resonance imaging (MRI), corresponds to the best functional target. Since the neighboring red nucleus (RN) is well visualized on MRI, we studied the relationships of the final target to its different borders. Methods: We analyzed the data of 23 PD patients (46 targets) who underwent bilateral frame-based STN deep brain stimulation (DBS) procedure with microelectrode recording guidance. We calculated coordinates of the active contact on DBS electrode on postoperative MRI, which we referred to as the final “functional/optimal” target. The coordinates calculated by the atlas-based “indirect” and “direct” methods, as well as the coordinates of the different RN borders were compared to these final coordinates. Results: The mean ± SD of the final target coordinates was 11.7 ± 1.5 mm lateral (X), 2.4 ± 1.5 mm posterior (Y), and 6.1 ± 1.7 mm inferior to the mid-commissural point (Z). No significant differences were found between the “indirect” X, Z coordinates and those of the final targets. The “indirect” Y coordinate was significantly posterior to Y of the final target, with mean difference of 0.6 mm (p = 0.014). No significant differences were found between the “direct” X, Y, and Z coordinates and those of the final targets. Conclusions: The functional STN target is located in direct proximity to its anatomical center. During preoperative targeting, we recommend using the “direct” method, and taking into consideration the relationships of the final target to the mid-commissural point (MCP) and the different RN borders. Full article

(This article belongs to the Special Issue Deep Brain Stimulation (DBS) Applications)

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Open AccessReview

Genetic Pathways to Insomnia

by Mackenzie J. Lind and Philip R. Gehrman

Brain Sci. 2016, 6(4), 64; https://doi.org/10.3390/brainsci6040064 - 20 Dec 2016

Cited by 47 | Viewed by 9012

Abstract

This review summarizes current research on the genetics of insomnia, as genetic contributions are thought to be important for insomnia etiology. We begin by providing an overview of genetic methods (both quantitative and measured gene), followed by a discussion of the insomnia genetics [...] Read more.

This review summarizes current research on the genetics of insomnia, as genetic contributions are thought to be important for insomnia etiology. We begin by providing an overview of genetic methods (both quantitative and measured gene), followed by a discussion of the insomnia genetics literature with regard to each of the following common methodologies: twin and family studies, candidate gene studies, and genome-wide association studies (GWAS). Next, we summarize the most recent gene identification efforts (primarily GWAS results) and propose several potential mechanisms through which identified genes may contribute to the disorder. Finally, we discuss new genetic approaches and how these may prove useful for insomnia, proposing an agenda for future insomnia genetics research. Full article

(This article belongs to the Special Issue New Research in Insomnia)

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Open AccessArticle

Evaluation of Teaching Signals for Motor Control in the Cerebellum during Real-World Robot Application

by Ruben Dario Pinzon Morales and Yutaka Hirata

Brain Sci. 2016, 6(4), 62; https://doi.org/10.3390/brainsci6040062 - 20 Dec 2016

Cited by 1 | Viewed by 6215

Abstract

Motor learning in the cerebellum is believed to entail plastic changes at synapses between parallel fibers and Purkinje cells, induced by the teaching signal conveyed in the climbing fiber (CF) input. Despite the abundant research on the cerebellum, the nature of this signal [...] Read more.

Motor learning in the cerebellum is believed to entail plastic changes at synapses between parallel fibers and Purkinje cells, induced by the teaching signal conveyed in the climbing fiber (CF) input. Despite the abundant research on the cerebellum, the nature of this signal is still a matter of debate. Two types of movement error information have been proposed to be plausible teaching signals: sensory error (SE) and motor command error (ME); however, their plausibility has not been tested in the real world. Here, we conducted a comparison of different types of CF teaching signals in real-world engineering applications by using a realistic neuronal network model of the cerebellum. We employed a direct current motor (simple task) and a two-wheeled balancing robot (difficult task). We demonstrate that SE, ME or a linear combination of the two is sufficient to yield comparable performance in a simple task. When the task is more difficult, although SE slightly outperformed ME, these types of error information are all able to adequately control the robot. We categorize granular cells according to their inputs and the error signal revealing that different granule cells are preferably engaged for SE, ME or their combination. Thus, unlike previous theoretical and simulation studies that support either SE or ME, it is demonstrated for the first time in a real-world engineering application that both SE and ME are adequate as the CF teaching signal in a realistic computational cerebellar model, even when the control task is as difficult as stabilizing a two-wheeled balancing robot. Full article

(This article belongs to the Special Issue Motor Control and Brain Plasticity)

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Open AccessArticle

Preconditioning of Spatial and Auditory Cues: Roles of the Hippocampus, Frontal Cortex, and Cue-Directed Attention

by Andrew C. Talk, Katrina L. Grasby, Tim Rawson and Jane L. Ebejer

Brain Sci. 2016, 6(4), 63; https://doi.org/10.3390/brainsci6040063 - 19 Dec 2016

Cited by 4 | Viewed by 5555

Abstract

Loss of function of the hippocampus or frontal cortex is associated with reduced performance on memory tasks, in which subjects are incidentally exposed to cues at specific places in the environment and are subsequently asked to recollect the location at which the cue [...] Read more.

Loss of function of the hippocampus or frontal cortex is associated with reduced performance on memory tasks, in which subjects are incidentally exposed to cues at specific places in the environment and are subsequently asked to recollect the location at which the cue was experienced. Here, we examined the roles of the rodent hippocampus and frontal cortex in cue-directed attention during encoding of memory for the location of a single incidentally experienced cue. During a spatial sensory preconditioning task, rats explored an elevated platform while an auditory cue was incidentally presented at one corner. The opposite corner acted as an unpaired control location. The rats demonstrated recollection of location by avoiding the paired corner after the auditory cue was in turn paired with shock. Damage to either the dorsal hippocampus or the frontal cortex impaired this memory ability. However, we also found that hippocampal lesions enhanced attention directed towards the cue during the encoding phase, while frontal cortical lesions reduced cue-directed attention. These results suggest that the deficit in spatial sensory preconditioning caused by frontal cortical damage may be mediated by inattention to the location of cues during the latent encoding phase, while deficits following hippocampal damage must be related to other mechanisms such as generation of neural plasticity. Full article

(This article belongs to the Special Issue Interaction Between the Prefrontal Cortex and Hippocampus in Memory Storage and Retrieval)

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Open AccessArticle

Body-Machine Interfaces after Spinal Cord Injury: Rehabilitation and Brain Plasticity

by Ismael Seáñez-González, Camilla Pierella, Ali Farshchiansadegh, Elias B. Thorp, Xue Wang, Todd Parrish and Ferdinando A. Mussa-Ivaldi

Brain Sci. 2016, 6(4), 61; https://doi.org/10.3390/brainsci6040061 - 19 Dec 2016

Cited by 17 | Viewed by 7529

Abstract

The purpose of this study was to identify rehabilitative effects and changes in white matter microstructure in people with high-level spinal cord injury following bilateral upper-extremity motor skill training. Five subjects with high-level (C5–C6) spinal cord injury (SCI) performed five visuo-spatial motor training [...] Read more.

The purpose of this study was to identify rehabilitative effects and changes in white matter microstructure in people with high-level spinal cord injury following bilateral upper-extremity motor skill training. Five subjects with high-level (C5–C6) spinal cord injury (SCI) performed five visuo-spatial motor training tasks over 12 sessions (2–3 sessions per week). Subjects controlled a two-dimensional cursor with bilateral simultaneous movements of the shoulders using a non-invasive inertial measurement unit-based body-machine interface. Subjects’ upper-body ability was evaluated before the start, in the middle and a day after the completion of training. MR imaging data were acquired before the start and within two days of the completion of training. Subjects learned to use upper-body movements that survived the injury to control the body-machine interface and improved their performance with practice. Motor training increased Manual Muscle Test scores and the isometric force of subjects’ shoulders and upper arms. Moreover, motor training increased fractional anisotropy (FA) values in the cingulum of the left hemisphere by 6.02% on average, indicating localized white matter microstructure changes induced by activity-dependent modulation of axon diameter, myelin thickness or axon number. This body-machine interface may serve as a platform to develop a new generation of assistive-rehabilitative devices that promote the use of, and that re-strengthen, the motor and sensory functions that survived the injury. Full article

(This article belongs to the Special Issue Motor Control and Brain Plasticity)

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Open AccessArticle

Phase- and Workload-Dependent Changes in Corticospinal Excitability to the Biceps and Triceps Brachii during Arm Cycling

by Alyssa-Joy Spence, Lynsey R. Alcock, Evan J. Lockyer, Duane C. Button and Kevin E. Power

Brain Sci. 2016, 6(4), 60; https://doi.org/10.3390/brainsci6040060 - 15 Dec 2016

Cited by 21 | Viewed by 6208

Abstract

This is the first study to examine corticospinal excitability (CSE) to antagonistic muscle groups during arm cycling. Transcranial magnetic stimulation (TMS) of the motor cortex and transmastoid electrical stimulation (TMES) of the corticospinal tract were used to assess changes in supraspinal and spinal [...] Read more.

This is the first study to examine corticospinal excitability (CSE) to antagonistic muscle groups during arm cycling. Transcranial magnetic stimulation (TMS) of the motor cortex and transmastoid electrical stimulation (TMES) of the corticospinal tract were used to assess changes in supraspinal and spinal excitability, respectively. TMS induced motor evoked potentials (MEPs) and TMES induced cervicomedullary evoked potentials (CMEPs) were recorded from the biceps and triceps brachii at two positions, mid-elbow flexion and extension, while cycling at 5% and 15% of peak power output. While phase-dependent modulation of MEP and CMEP amplitudes occurred in the biceps brachii, there was no difference between flexion and extension for MEP amplitudes in the triceps brachii and CMEP amplitudes were higher during flexion than extension. Furthermore, MEP amplitudes in both biceps and triceps brachii increased with increased workload. CMEP amplitudes increased with higher workloads in the triceps brachii, but not biceps brachii, though the pattern of change in CMEPs was similar to MEPs. Differences between changes in CSE between the biceps and triceps brachii suggest that these antagonistic muscles may be under different neural control during arm cycling. Putative mechanisms are discussed. Full article

(This article belongs to the Special Issue Motor Control and Brain Plasticity)

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Open AccessArticle

Insomnia Phenotypes Based on Objective Sleep Duration in Adolescents: Depression Risk and Differential Behavioral Profiles

by Julio Fernandez-Mendoza, Susan L. Calhoun, Alexandros N. Vgontzas, Yun Li, Jordan Gaines, Duanping Liao and Edward O. Bixler

Brain Sci. 2016, 6(4), 59; https://doi.org/10.3390/brainsci6040059 - 13 Dec 2016

Cited by 34 | Viewed by 6771

Abstract

Based on previous studies on the role of objective sleep duration in predicting morbidity in individuals with insomnia, we examined the role of objective sleep duration in differentiating behavioral profiles in adolescents with insomnia symptoms. Adolescents from the Penn State Child Cohort ( [...] Read more.

Based on previous studies on the role of objective sleep duration in predicting morbidity in individuals with insomnia, we examined the role of objective sleep duration in differentiating behavioral profiles in adolescents with insomnia symptoms. Adolescents from the Penn State Child Cohort (n = 397, ages 12–23, 54.7% male) underwent a nine-hour polysomnography (PSG), clinical history, physical examination and psychometric testing, including the Child or Adult Behavior Checklist and Pediatric Behavior Scale. Insomnia symptoms were defined as a self-report of difficulty falling and/or staying asleep and objective “short” sleep duration as a PSG total sleep time ≤7 h. A significant interaction showed that objective short sleep duration modified the association of insomnia symptoms with internalizing problems. Consistently, adolescents with insomnia symptoms and short sleep duration were characterized by depression, rumination, mood dysregulation and social isolation, while adolescents with insomnia symptoms and normal sleep duration were characterized by rule-breaking and aggressive behaviors and, to a lesser extent, rumination. These findings indicate that objective sleep duration is useful in differentiating behavioral profiles among adolescents with insomnia symptoms. The insomnia with objective short sleep duration phenotype is associated with an increased risk of depression earlier in the lifespan than previously believed. Full article

(This article belongs to the Special Issue New Research in Insomnia)

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Open AccessArticle

Improvement of Advanced Parkinson’s Disease Manifestations with Deep Brain Stimulation of the Subthalamic Nucleus: A Single Institution Experience

by Ahmed Rabie, Leo Verhagen Metman, Mazen Fakhry, Ayman Youssef Ezeldin Eassa, Wael Fouad, Ahmed Shakal and Konstantin V. Slavin

Brain Sci. 2016, 6(4), 58; https://doi.org/10.3390/brainsci6040058 - 13 Dec 2016

Cited by 14 | Viewed by 8711

Abstract

We present our experience at the University of Illinois at Chicago (UIC) in deep brain stimulation (DBS) of the subthalamic nucleus (STN), describing our surgical technique, and reporting our clinical results, and morbidities. Twenty patients with advanced Parkinson’s disease (PD) who underwent bilateral [...] Read more.

We present our experience at the University of Illinois at Chicago (UIC) in deep brain stimulation (DBS) of the subthalamic nucleus (STN), describing our surgical technique, and reporting our clinical results, and morbidities. Twenty patients with advanced Parkinson’s disease (PD) who underwent bilateral STN-DBS were studied. Patients were assessed preoperatively and followed up for one year using the Unified Parkinson’s Disease Rating Scale (UPDRS) in “on” and “off” medication and “on” and “off” stimulation conditions. At one-year follow-up, we calculated significant improvement in all the motor aspects of PD (UPDRS III) and in activities of daily living (UPDRS II) in the “off” medication state. The “off” medication UPDRS improved by 49.3%, tremors improved by 81.6%, rigidity improved by 50.0%, and bradykinesia improved by 39.3%. The “off” medication UPDRS II scores improved by 73.8%. The Levodopa equivalent daily dose was reduced by 54.1%. The UPDRS IVa score (dyskinesia) was reduced by 65.1%. The UPDRS IVb score (motor fluctuation) was reduced by 48.6%. Deep brain stimulation of the STN improves the cardinal motor manifestations of the idiopathic PD. It also improves activities of daily living, and reduces medication-induced complications. Full article

(This article belongs to the Special Issue Deep Brain Stimulation (DBS) Applications)

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Open AccessArticle

Long-Term Task- and Dopamine-Dependent Dynamics of Subthalamic Local Field Potentials in Parkinson’s Disease

by Sara J. Hanrahan, Joshua J. Nedrud, Bradley S. Davidson, Sierra Farris, Monique Giroux, Aaron Haug, Mohammad H. Mahoor, Anne K. Silverman, Jun Jason Zhang and Adam Olding Hebb

Brain Sci. 2016, 6(4), 57; https://doi.org/10.3390/brainsci6040057 - 29 Nov 2016

Cited by 11 | Viewed by 6712

Abstract

Subthalamic nucleus (STN) local field potentials (LFP) are neural signals that have been shown to reveal motor and language behavior, as well as pathological parkinsonian states. We use a research-grade implantable neurostimulator (INS) with data collection capabilities to record STN-LFP outside the operating [...] Read more.

Subthalamic nucleus (STN) local field potentials (LFP) are neural signals that have been shown to reveal motor and language behavior, as well as pathological parkinsonian states. We use a research-grade implantable neurostimulator (INS) with data collection capabilities to record STN-LFP outside the operating room to determine the reliability of the signals over time and assess their dynamics with respect to behavior and dopaminergic medication. Seven subjects were implanted with the recording augmented deep brain stimulation (DBS) system, and bilateral STN-LFP recordings were collected in the clinic over twelve months. Subjects were cued to perform voluntary motor and language behaviors in on and off medication states. The STN-LFP recorded with the INS demonstrated behavior-modulated desynchronization of beta frequency (13–30 Hz) and synchronization of low gamma frequency (35–70 Hz) oscillations. Dopaminergic medication did not diminish the relative beta frequency oscillatory desynchronization with movement. However, movement-related gamma frequency oscillatory synchronization was only observed in the medication on state. We observed significant inter-subject variability, but observed consistent STN-LFP activity across recording systems and over a one-year period for each subject. These findings demonstrate that an INS system can provide robust STN-LFP recordings in ambulatory patients, allowing for these signals to be recorded in settings that better represent natural environments in which patients are in a variety of medication states. Full article

(This article belongs to the Special Issue Deep Brain Stimulation (DBS) Applications)

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Open AccessArticle

Cerebellar Intermittent Theta-Burst Stimulation and Motor Control Training in Individuals with Cervical Dystonia

by Lynley V. Bradnam, Michelle N. McDonnell and Michael C. Ridding

Brain Sci. 2016, 6(4), 56; https://doi.org/10.3390/brainsci6040056 - 23 Nov 2016

Cited by 36 | Viewed by 6423

Abstract

Background: There is emerging evidence that cervical dystonia is a neural network disorder with the cerebellum as a key node. The cerebellum may provide a target for neuromodulation as a therapeutic intervention in cervical dystonia. Objective: This study aimed to assess effects of [...] Read more.

Background: There is emerging evidence that cervical dystonia is a neural network disorder with the cerebellum as a key node. The cerebellum may provide a target for neuromodulation as a therapeutic intervention in cervical dystonia. Objective: This study aimed to assess effects of intermittent theta-burst stimulation of the cerebellum on dystonia symptoms, quality of life, hand motor dexterity and cortical neurophysiology using transcranial magnetic stimulation. Methods: Sixteen participants with cervical dystonia were randomised into real or sham stimulation groups. Cerebellar neuromodulation was combined with motor training for the neck and an implicit learning task. The intervention was delivered over 10 working days. Outcome measures included dystonia severity and pain, quality of life, hand dexterity, and motor-evoked potentials and cortical silent periods recorded from upper trapezius muscles. Assessments were taken at baseline and after 5 and 10 days, with quality of life also measured 4 and 12 weeks later. Results: Intermittent theta-burst stimulation improved dystonia severity (Day 5, −5.44 points; p = 0.012; Day 10, −4.6 points; p = 0.025), however, effect sizes were small. Quality of life also improved (Day 5, −10.6 points, p = 0.012; Day 10, −8.6 points, p = 0.036; Week 4, −12.5 points, p = 0.036; Week 12, −12.4 points, p = 0.025), with medium or large effect sizes. There was a reduction in time to complete the pegboard task pre to post intervention (both p < 0.008). Cortical neurophysiology was unchanged by cerebellar neuromodulation. Conclusion: Intermittent theta-burst stimulation of the cerebellum may improve cervical dystonia symptoms, upper limb motor control and quality of life. The mechanism likely involves promoting neuroplasticity in the cerebellum although the neurophysiology remains to be elucidated. Cerebellar neuromodulation may have potential as a novel treatment intervention for cervical dystonia, although larger confirmatory studies are required. Full article

(This article belongs to the Special Issue Motor Control and Brain Plasticity)

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Open AccessArticle

No Effect of Cathodal Transcranial Direct Current Stimulation on Fear Memory in Healthy Human Subjects

by Aditya Mungee, Max Burger and Malek Bajbouj

Brain Sci. 2016, 6(4), 55; https://doi.org/10.3390/brainsci6040055 - 4 Nov 2016

Cited by 22 | Viewed by 5389

Abstract

Background: Studies have demonstrated that fear memories can be modified using non-invasive methods. Recently, we demonstrated that anodal transcranial direct current stimulation (tDCS) of the right dorsolateral prefrontal cortex is capable of enhancing fear memories. Here, we examined the effects of cathodal tDCS [...] Read more.

Background: Studies have demonstrated that fear memories can be modified using non-invasive methods. Recently, we demonstrated that anodal transcranial direct current stimulation (tDCS) of the right dorsolateral prefrontal cortex is capable of enhancing fear memories. Here, we examined the effects of cathodal tDCS of the right dorsolateral prefrontal cortex during fear reconsolidation in humans. Methods: Seventeen young, healthy subjects were randomly assigned to two groups, which underwent fear conditioning with mild electric stimuli paired with a visual stimulus. Twenty-four hours later, both groups were shown a reminder of the conditioned fearful stimulus. Shortly thereafter, they received either tDCS (right prefrontal—cathodal, left supraorbital—anodal) for 20 min at 1 mA, or sham stimulation. A day later, fear responses of both groups were compared. Results: On Day 3, during fear response assessment, there were no significant differences between the tDCS and sham group (p > 0.05). Conclusion: We conclude that cathodal tDCS of the right dorsolateral prefrontal cortex (right prefrontal—cathodal, left supraorbital—anodal) did not influence fear memories. Full article

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Open AccessArticle

Long-Term Plasticity in Reflex Excitability Induced by Five Weeks of Arm and Leg Cycling Training after Stroke

by Taryn Klarner, Trevor S. Barss, Yao Sun, Chelsea Kaupp, Pamela M. Loadman and E. Paul Zehr

Brain Sci. 2016, 6(4), 54; https://doi.org/10.3390/brainsci6040054 - 3 Nov 2016

Cited by 23 | Viewed by 6505

Abstract

Neural connections remain partially viable after stroke, and access to these residual connections provides a substrate for training-induced plasticity. The objective of this project was to test if reflex excitability could be modified with arm and leg (A & L) cycling training. Nineteen [...] Read more.

Neural connections remain partially viable after stroke, and access to these residual connections provides a substrate for training-induced plasticity. The objective of this project was to test if reflex excitability could be modified with arm and leg (A & L) cycling training. Nineteen individuals with chronic stroke (more than six months postlesion) performed 30 min of A & L cycling training three times a week for five weeks. Changes in reflex excitability were inferred from modulation of cutaneous and stretch reflexes. A multiple baseline (three pretests) within-subject control design was used. Plasticity in reflex excitability was determined as an increase in the conditioning effect of arm cycling on soleus stretch reflex amplitude on the more affected side, by the index of modulation, and by the modulation ratio between sides for cutaneous reflexes. In general, A & L cycling training induces plasticity and modifies reflex excitability after stroke. Full article

(This article belongs to the Special Issue Functional Recovery after Stroke)

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Open AccessReview

Prediction of Walking and Arm Recovery after Stroke: A Critical Review

by Li Khim Kwah and Robert D. Herbert

Brain Sci. 2016, 6(4), 53; https://doi.org/10.3390/brainsci6040053 - 2 Nov 2016

Cited by 41 | Viewed by 9142

Abstract

Clinicians often base their predictions of walking and arm recovery on multiple predictors. Multivariate prediction models may assist clinicians to make accurate predictions. Several reviews have been published on the prediction of motor recovery after stroke, but none have critically appraised development and [...] Read more.

Clinicians often base their predictions of walking and arm recovery on multiple predictors. Multivariate prediction models may assist clinicians to make accurate predictions. Several reviews have been published on the prediction of motor recovery after stroke, but none have critically appraised development and validation studies of models for predicting walking and arm recovery. In this review, we highlight some common methodological limitations of models that have been developed and validated. Notable models include the proportional recovery model and the PREP algorithm. We also identify five other models based on clinical predictors that might be ready for further validation. It has been suggested that neurophysiological and neuroimaging data may be used to predict arm recovery. Current evidence suggests, but does not show conclusively, that the addition of neurophysiological and neuroimaging data to models containing clinical predictors yields clinically important increases in predictive accuracy. Full article

(This article belongs to the Special Issue Functional Recovery after Stroke)

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Open AccessArticle

Prenatal Alcohol Exposure Affects Progenitor Cell Numbers in Olfactory Bulbs and Dentate Gyrus of Vervet Monkeys

by Mark W. Burke, Alexey Inyatkin, Maurice Ptito, Frank R. Ervin and Roberta M. Palmour

Brain Sci. 2016, 6(4), 52; https://doi.org/10.3390/brainsci6040052 - 27 Oct 2016

Cited by 7 | Viewed by 5614

Abstract

Fetal alcohol exposure (FAE) alters hippocampal cell numbers in rodents and primates, and this may be due, in part, to a reduction in the number or migration of neuronal progenitor cells. The olfactory bulb exhibits substantial postnatal cellular proliferation and a rapid turnover [...] Read more.

Fetal alcohol exposure (FAE) alters hippocampal cell numbers in rodents and primates, and this may be due, in part, to a reduction in the number or migration of neuronal progenitor cells. The olfactory bulb exhibits substantial postnatal cellular proliferation and a rapid turnover of newly formed cells in the rostral migratory pathway, while production and migration of postnatal neurons into the dentate gyrus may be more complex. The relatively small size of the olfactory bulb, compared to the hippocampus, potentially makes this structure ideal for a rapid analysis. This study used the St. Kitts vervet monkey (Chlorocebus sabeus) to (1) investigate the normal developmental sequence of post-natal proliferation in the olfactory bulb and dentate gyrus and (2) determine the effects of naturalistic prenatal ethanol exposure on proliferation at three different ages (neonate, five months and two years). Using design-based stereology, we found an age-related decrease of actively proliferating cells in the olfactory bulb and dentate gyrus for both control and FAE groups. Furthermore, at the neonatal time point, the FAE group had fewer actively proliferating cells as compared to the control group. These data are unique with respect to fetal ethanol effects on progenitor proliferation in the primate brain and suggest that the olfactory bulb may be a useful structure for studies of cellular proliferation. Full article

(This article belongs to the Special Issue Neurodegeneration in Developmental and Neoplastic Disorders of the Nervous System)

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Open AccessArticle

The Relationship between Estrogen and Nitric Oxide in the Prevention of Cardiac and Vascular Anomalies in the Developing Zebrafish (Danio Rerio)

by Benjamin G. Sykes, Peter M. Van Steyn, Jonathan D. Vignali, John Winalski, Julie Lozier, Wade E. Bell and James E. Turner

Brain Sci. 2016, 6(4), 51; https://doi.org/10.3390/brainsci6040051 - 26 Oct 2016

Cited by 13 | Viewed by 5172

Abstract

It has been known that both estrogen (E2) and nitric oxide (NO) are critical for proper cardiovascular system (CVS) function. It has also been demonstrated that E2 acts as an upstream effector in the nitric oxide (NO) pathway. Results from this study indicate [...] Read more.

It has been known that both estrogen (E2) and nitric oxide (NO) are critical for proper cardiovascular system (CVS) function. It has also been demonstrated that E2 acts as an upstream effector in the nitric oxide (NO) pathway. Results from this study indicate that the use of a nitric oxide synthase (NOS) inhibitor (NOSI) which targets specifically neuronal NOS (nNOS or NOS1), proadifen hydrochloride, caused a significant depression of fish heart rates (HR) accompanied by increased arrhythmic behavior. However, none of these phenotypes were evident with either the inhibition of endothelial NOS (eNOS) or inducible NOS (iNOS) isoforms. These cardiac arrhythmias could also be mimicked by inhibition of E2 synthesis with the aromatase inhibitor (AI), 4-OH-A, in a manner similar to that of nNOSI. In both scenarios, by using an NO donor (DETA-NO) in either NO + nNOSI or E2 + AI co-treatments, fish could be significantly rescued from decreased HR and increased arrhythmias. However, the addition of an NOS inhibitor (L-NAME) to the E2 + AI co-treatment fish prevented the rescue of low heart rates and arrhythmias, which strongly implicates the NO pathway as a downstream E2 targeted molecule for the maintenance of healthy cardiomyocyte contractile conditions in the developing zebrafish. Cardiac arrhythmias could be mimicked by the S-nitrosylation pathway inhibitor DTT (1,4-dithiothreitol) but not by ODQ (1H-[1–3]oxadiazolo[4,3-a]quinoxalin-1-one), the inhibitor of the NO receptor molecule sGC in the cGMP-dependent pathway. In both the nNOSI and AI-induced arrhythmic conditions, 100% of the fish expressed the phenotype, but could be rapidly rescued with maximum survival by a washout with dantrolene, a ryanodine Ca²⁺ channel receptor blocker, compared to the time it took for rescue using a control salt solution. In addition, of the three NOS isoforms, eNOS was the one most implicated in the maintenance of an intact developing fish vascular system. In conclusion, results from this study have shown that nNOS is the prominent isoform that is responsible, in part, for maintaining normal heart rates and prevention of arrhythmias in the developing zebrafish heart failure model. These phenomena are related to the upstream stimulatory regulation by E2. On the other hand, eNOS has a minimal effect and iNOS has little to no influence on this phenomenon. Data also suggests that nNOS acts on the zebrafish cardiomyocytes through the S-nitrosylation pathway to influence the SR ryanidine Ca²⁺ channels in the excitation-coupling phenomena. In contrast, eNOS is the prominent isoform that influences blood vessel development in this model. Full article

(This article belongs to the Special Issue Sex Differences in Brain Development)

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Open AccessArticle

Language Problems and ADHD Symptoms: How Specific Are the Links?

by Erin Hawkins, Susan Gathercole, Duncan Astle, The CALM Team and Joni Holmes

Brain Sci. 2016, 6(4), 50; https://doi.org/10.3390/brainsci6040050 - 21 Oct 2016

Cited by 46 | Viewed by 17157

Abstract

Symptoms of inattention and hyperactivity frequently co-occur with language difficulties in both clinical and community samples. We explore the specificity and strength of these associations in a heterogeneous sample of 254 children aged 5 to 15 years identified by education and health professionals [...] Read more.

Symptoms of inattention and hyperactivity frequently co-occur with language difficulties in both clinical and community samples. We explore the specificity and strength of these associations in a heterogeneous sample of 254 children aged 5 to 15 years identified by education and health professionals as having problems with attention, learning and/or memory. Parents/carers rated pragmatic and structural communication skills and behaviour, and children completed standardised assessments of reading, spelling, vocabulary, and phonological awareness. A single dimension of behavioural difficulties including both hyperactivity and inattention captured behaviour problems. This was strongly and negatively associated with pragmatic communication skills. There was less evidence for a relationship between behaviour and language structure: behaviour ratings were more weakly associated with the use of structural language in communication, and there were no links with direct measures of literacy. These behaviour problems and pragmatic communication difficulties co-occur in this sample, but impairments in the more formal use of language that impact on literacy and structural communication skills are tied less strongly to behavioural difficulties. One interpretation is that impairments in executive function give rise to both behavioural and social communication problems, and additional or alternative deficits in other cognitive abilities impact on the development of structural language skills. Full article

(This article belongs to the Special Issue Language Issues in Attention-Deficit Hyperactivity Disorder (ADHD): Etiological Pathways and Comorbidities)

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Open AccessCommunication

Corticospinal Excitability in Children with Congenital Hemiparesis

by Chao-Ying Chen, Tonya L. Rich, Jessica M. Cassidy and Bernadette T. Gillick

Brain Sci. 2016, 6(4), 49; https://doi.org/10.3390/brainsci6040049 - 20 Oct 2016

Cited by 7 | Viewed by 5054

Abstract

Transcranial magnetic stimulation (TMS) can be used as an assessment or intervention to evaluate or influence brain activity in children with hemiparetic cerebral palsy (CP) commonly caused by perinatal stroke. This communication report analyzed data from two clinical trials using TMS to assess [...] Read more.

Transcranial magnetic stimulation (TMS) can be used as an assessment or intervention to evaluate or influence brain activity in children with hemiparetic cerebral palsy (CP) commonly caused by perinatal stroke. This communication report analyzed data from two clinical trials using TMS to assess corticospinal excitability in children and young adults with hemiparetic CP. The results of this communication revealed a higher probability of finding a motor evoked potential (MEP) on the non-lesioned hemisphere compared to the lesioned hemisphere (p = 0.005). The resting motor threshold (RMT) was lower on the non-lesioned hemisphere than the lesioned hemisphere (p = 0.013). There was a significantly negative correlation between age and RMT (r_s = −0.65, p = 0.003). This communication provides information regarding MEP responses, motor thresholds (MTs) and the association with age during TMS assessment in children with hemiparetic CP. Such findings contribute to the development of future pediatric studies in neuroplasticity and neuromodulation to influence motor function and recovery after perinatal stroke. Full article

(This article belongs to the Special Issue Functional Recovery after Stroke)

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Open AccessArticle

Vocal Tremor: Novel Therapeutic Target for Deep Brain Stimulation

by Vinod K. Ravikumar, Allen L. Ho, Jonathon J. Parker, Elizabeth Erickson-DiRenzo and Casey H. Halpern

Brain Sci. 2016, 6(4), 48; https://doi.org/10.3390/brainsci6040048 - 10 Oct 2016

Cited by 11 | Viewed by 5003

Abstract

Tremulous voice is characteristically associated with essential tremor, and is referred to as essential vocal tremor (EVT). Current estimates suggest that up to 40% of individuals diagnosed with essential tremor also present with EVT, which is associated with an impaired quality of life. [...] Read more.

Tremulous voice is characteristically associated with essential tremor, and is referred to as essential vocal tremor (EVT). Current estimates suggest that up to 40% of individuals diagnosed with essential tremor also present with EVT, which is associated with an impaired quality of life. Traditional EVT treatments have demonstrated limited success in long-term management of symptoms. However, voice tremor has been noted to decrease in patients receiving deep brain stimulation (DBS) with the targeting of thalamic nuclei. In this study, we describe our multidisciplinary procedure for awake, frameless DBS with optimal stimulation targets as well as acoustic analysis and laryngoscopic assessment to quantify tremor reduction. Finally, we investigate the most recent clinical evidence regarding the procedure. Full article

(This article belongs to the Special Issue Deep Brain Stimulation (DBS) Applications)

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Open AccessReview

Disorders of Consciousness: Painless or Painful Conditions?—Evidence from Neuroimaging Studies

by Francesca Pistoia, Simona Sacco, Janet Stewart, Marco Sarà and Antonio Carolei

Brain Sci. 2016, 6(4), 47; https://doi.org/10.3390/brainsci6040047 - 8 Oct 2016

Cited by 23 | Viewed by 7696

Abstract

The experience of pain in disorders of consciousness is still debated. Neuroimaging studies, using functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET), multichannel electroencephalography (EEG) and laser-evoked potentials, suggest that the perception of pain increases with the level of consciousness. Brain activation [...] Read more.

The experience of pain in disorders of consciousness is still debated. Neuroimaging studies, using functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET), multichannel electroencephalography (EEG) and laser-evoked potentials, suggest that the perception of pain increases with the level of consciousness. Brain activation in response to noxious stimuli has been observed in patients with unresponsive wakefulness syndrome (UWS), which is also referred to as a vegetative state (VS), as well as those in a minimally conscious state (MCS). However, all of these techniques suggest that pain-related brain activation patterns of patients in MCS more closely resemble those of healthy subjects. This is further supported by fMRI findings showing a much greater functional connectivity within the structures of the so-called pain matrix in MCS as compared to UWS/VS patients. Nonetheless, when interpreting the results, a distinction is necessary between autonomic responses to potentially harmful stimuli and conscious experience of the unpleasantness of pain. Even more so if we consider that the degree of residual functioning and cortical connectivity necessary for the somatosensory, affective and cognitive-evaluative components of pain processing are not yet clear. Although procedurally challenging, the particular value of the aforementioned techniques in the assessment of pain in disorders of consciousness has been clearly demonstrated. The study of pain-related brain activation and functioning can contribute to a better understanding of the networks underlying pain perception while addressing clinical and ethical questions concerning patient care. Further development of technology and methods should aim to increase the availability of neuroimaging, objective assessment of functional connectivity and analysis at the level of individual cases as well as group comparisons. This will enable neuroimaging to truly become a clinical tool to reliably investigate pain in severely brain-injured patients as well as an asset for research. Full article

(This article belongs to the Special Issue Functional Neuroimaging of Pain)

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Open AccessReview

Rescue Procedures after Suboptimal Deep Brain Stimulation Outcomes in Common Movement Disorders

by Adam M. Nagy and Christopher M. Tolleson

Brain Sci. 2016, 6(4), 46; https://doi.org/10.3390/brainsci6040046 - 8 Oct 2016

Cited by 10 | Viewed by 5158

Abstract

Deep brain stimulation (DBS) is a unique, functional neurosurgical therapy indicated for medication refractory movement disorders as well as some psychiatric diseases. Multicontact electrodes are placed in “deep” structures within the brain with targets varying depending on the surgical indication. An implanted programmable [...] Read more.

Deep brain stimulation (DBS) is a unique, functional neurosurgical therapy indicated for medication refractory movement disorders as well as some psychiatric diseases. Multicontact electrodes are placed in “deep” structures within the brain with targets varying depending on the surgical indication. An implanted programmable pulse generator supplies the electrodes with a chronic, high frequency electrical current that clinically mimics the effects of ablative lesioning techniques. DBS’s efficacy has been well established for its movement disorder indications (Parkinson’s disease, essential tremor, and dystonia). However, clinical outcomes are sometimes suboptimal, even in the absence of common, potentially reversible complications such as hardware complications, infection, poor electrode placement, and poor programming parameters. This review highlights some of the rescue procedures that have been explored in suboptimal DBS cases for Parkinson’s disease, essential tremor, and dystonia. To date, the data is limited and difficult to generalize, but a large majority of published reports demonstrate positive results. The decision to proceed with such treatments should be made on a case by case basis. Larger studies are needed to clearly establish the benefit of rescue procedures and to establish for which patient populations they may be most appropriate. Full article

(This article belongs to the Special Issue Deep Brain Stimulation (DBS) Applications)

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Open AccessArticle

The Cluster Variation Method: A Primer for Neuroscientists

by Alianna J. Maren

Brain Sci. 2016, 6(4), 44; https://doi.org/10.3390/brainsci6040044 - 30 Sep 2016

Cited by 5 | Viewed by 6834

Abstract

Effective Brain–Computer Interfaces (BCIs) require that the time-varying activation patterns of 2-D neural ensembles be modelled. The cluster variation method (CVM) offers a means for the characterization of 2-D local pattern distributions. This paper provides neuroscientists and BCI researchers with a CVM tutorial [...] Read more.

Effective Brain–Computer Interfaces (BCIs) require that the time-varying activation patterns of 2-D neural ensembles be modelled. The cluster variation method (CVM) offers a means for the characterization of 2-D local pattern distributions. This paper provides neuroscientists and BCI researchers with a CVM tutorial that will help them to understand how the CVM statistical thermodynamics formulation can model 2-D pattern distributions expressing structural and functional dynamics in the brain. The premise is that local-in-time free energy minimization works alongside neural connectivity adaptation, supporting the development and stabilization of consistent stimulus-specific responsive activation patterns. The equilibrium distribution of local patterns, or configuration variables, is defined in terms of a single interaction enthalpy parameter (h) for the case of an equiprobable distribution of bistate (neural/neural ensemble) units. Thus, either one enthalpy parameter (or two, for the case of non-equiprobable distribution) yields equilibrium configuration variable values. Modeling 2-D neural activation distribution patterns with the representational layer of a computational engine, we can thus correlate variational free energy minimization with specific configuration variable distributions. The CVM triplet configuration variables also map well to the notion of a M = 3 functional motif. This paper addresses the special case of an equiprobable unit distribution, for which an analytic solution can be found. Full article

(This article belongs to the Special Issue Brain-Computer Interfaces: Current Trends and Novel Applications)

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Open AccessArticle

Effect of Experimental Cutaneous Hand Pain on Corticospinal Excitability and Short Afferent Inhibition

by Catherine Mercier, Martin Gagné, Karen T. Reilly and Laurent J. Bouyer

Brain Sci. 2016, 6(4), 45; https://doi.org/10.3390/brainsci6040045 - 29 Sep 2016

Cited by 15 | Viewed by 5436

Abstract

Sensorimotor integration is altered in people with chronic pain. While there is substantial evidence that pain interferes with neural activity in primary sensory and motor cortices, much less is known about its impact on integrative sensorimotor processes. Here, the short latency afferent inhibition [...] Read more.

Sensorimotor integration is altered in people with chronic pain. While there is substantial evidence that pain interferes with neural activity in primary sensory and motor cortices, much less is known about its impact on integrative sensorimotor processes. Here, the short latency afferent inhibition (SAI) paradigm was used to assess sensorimotor integration in the presence and absence of experimental cutaneous heat pain applied to the hand. Ulnar nerve stimulation was combined with transcranial magnetic stimulation to condition motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Four interstimulus intervals (ISI) were tested, based on the latency of the N20 component of the afferent sensory volley (N20−5 ms, N20+2 ms, N20+4 ms, N20+10 ms). In the PAIN condition, MEPs were smaller compared to the NEUTRAL condition (p = 0.005), and were modulated as a function of the ISI (p = 0.012). Post-hoc planned comparisons revealed that MEPs at N20+2 and N20+4 were inhibited compared to unconditioned MEPs. However, the level of inhibition (SAI) was similar in the PAIN and NEUTRAL conditions. This suggests that the interplay between pain and sensorimotor integration is not mediated through direct and rapid pathways as assessed by SAI, but rather might involve higher-order integrative areas. Full article

(This article belongs to the Special Issue Motor Control and Brain Plasticity)

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Open AccessArticle

Prenatal Ethanol Exposure and Whisker Clipping Disrupt Ultrasonic Vocalizations and Play Behavior in Adolescent Rats

by Jaylyn Waddell, Tianqi Yang, Eric Ho, Kristen A. Wellmann and Sandra M. Mooney

Brain Sci. 2016, 6(4), 43; https://doi.org/10.3390/brainsci6040043 - 28 Sep 2016

Cited by 10 | Viewed by 5157

Abstract

Prenatal ethanol exposure can result in social deficits in humans and animals, including altered social interaction and poor communication. Rats exposed to ethanol prenatally show reduced play fighting, and a combination of prenatal ethanol exposure and neonatal whisker clipping further reduces play fighting [...] Read more.

Prenatal ethanol exposure can result in social deficits in humans and animals, including altered social interaction and poor communication. Rats exposed to ethanol prenatally show reduced play fighting, and a combination of prenatal ethanol exposure and neonatal whisker clipping further reduces play fighting compared with ethanol exposure alone. In this study, we explored whether expression of hedonic ultrasonic vocalizations (USVs) correlated with the number of playful attacks by ethanol-exposed rats, rats subjected to postnatal sensory deprivation by whisker clipping or both compared to control animals. In normally developing rats, hedonic USVs precede such interactions and correlate with the number of play interactions exhibited in dyads. Pregnant Long-Evans rats were fed an ethanol-containing liquid diet or a control diet. After birth, male and female pups from each litter were randomly assigned to the whisker-clipped or non-whisker-clipped condition. Animals underwent a social interaction test with a normally developing play partner during early or late-adolescence. USVs were recorded during play. Prenatal ethanol exposure reduced both play and hedonic USVs in early adolescence compared to control rats and persistently reduced social play. Interestingly, ethanol exposure, whisker clipping and the combination abolished the significant correlation between hedonic USVs and social play detected in control rats in early adolescence. This relationship remained disrupted in late adolescence only in rats subjected to both prenatal ethanol and whisker clipping. Thus, both insults more persistently disrupted the relationship between social communication and social play. Full article

(This article belongs to the Special Issue Neurodegeneration in Developmental and Neoplastic Disorders of the Nervous System)

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Open AccessArticle

Morphology of Donor and Recipient Nerves Utilised in Nerve Transfers to Restore Upper Limb Function in Cervical Spinal Cord Injury

by Aurora Messina, Natasha Van Zyl, Michael Weymouth, Stephen Flood, Andrew Nunn, Catherine Cooper, Jodie Hahn and Mary P. Galea

Brain Sci. 2016, 6(4), 42; https://doi.org/10.3390/brainsci6040042 - 27 Sep 2016

Cited by 5 | Viewed by 6550

Abstract

Loss of hand function after cervical spinal cord injury (SCI) impacts heavily on independence. Multiple nerve transfer surgery has been applied successfully after cervical SCI to restore critical arm and hand functions, and the outcome depends on nerve integrity. Nerve integrity is assessed [...] Read more.

Loss of hand function after cervical spinal cord injury (SCI) impacts heavily on independence. Multiple nerve transfer surgery has been applied successfully after cervical SCI to restore critical arm and hand functions, and the outcome depends on nerve integrity. Nerve integrity is assessed indirectly using muscle strength testing and intramuscular electromyography, but these measures cannot show the manifestation that SCI has on the peripheral nerves. We directly assessed the morphology of nerves biopsied at the time of surgery, from three patients within 18 months post injury. Our objective was to document their morphologic features. Donor nerves included teres minor, posterior axillary, brachialis, extensor carpi radialis brevis and supinator. Recipient nerves included triceps, posterior interosseus (PIN) and anterior interosseus nerves (AIN). They were fixed in glutaraldehyde, processed and embedded in Araldite Epon for light microscopy. Eighty percent of nerves showed abnormalities. Most common were myelin thickening and folding, demyelination, inflammation and a reduction of large myelinated axon density. Others were a thickened perineurium, oedematous endoneurium and Renaut bodies. Significantly, very thinly myelinated axons and groups of unmyelinated axons were observed indicating regenerative efforts. Abnormalities exist in both donor and recipient nerves and they differ in appearance and aetiology. The abnormalities observed may be preventable or reversible. Full article

(This article belongs to the Special Issue Acute and Chronic Systemic Alterations Produced by Spinal Trauma)

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Open AccessReview

Immunomodulators as Therapeutic Agents in Mitigating the Progression of Parkinson’s Disease

by Bethany Grimmig, Josh Morganti, Kevin Nash and Paula C Bickford

Brain Sci. 2016, 6(4), 41; https://doi.org/10.3390/brainsci6040041 - 23 Sep 2016

Cited by 20 | Viewed by 6232

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder that primarily afflicts the elderly. It is characterized by motor dysfunction due to extensive neuron loss in the substantia nigra pars compacta. There are multiple biological processes that are negatively impacted during the pathogenesis of [...] Read more.

Parkinson’s disease (PD) is a common neurodegenerative disorder that primarily afflicts the elderly. It is characterized by motor dysfunction due to extensive neuron loss in the substantia nigra pars compacta. There are multiple biological processes that are negatively impacted during the pathogenesis of PD, and are implicated in the cell death in this region. Neuroinflammation is evidently involved in PD pathology and mitigating the inflammatory cascade has been a therapeutic strategy. Age is the number one risk factor for PD and thus needs to be considered in the context of disease pathology. Here, we discuss the role of neuroinflammation within the context of aging as it applies to the development of PD, and the potential for two representative compounds, fractalkine and astaxanthin, to attenuate the pathophysiology that modulates neurodegeneration that occurs in Parkinson’s disease. Full article

(This article belongs to the Special Issue Advances in Neuroimmunology)

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Brain Sci., Volume 6, Issue 4 (December 2016) – 25 articles

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