bluuebunny/crossref_metadata_2025 huggingface dataset:
Upper extremity improvements in chronic stroke: Coupled bilateral	load training
Authors: Cauraugh James H. , Coombes Stephen A. , Lodha Neha , Naik Sagar K. , Summers Jeffery J.
Published: December 2019

Background: The current treatment intervention study determined the effect of coupled bilateral training (i.e., bilateral movements and EMG-triggered neuromuscular stimulation) and resistive load (mass) on upper extremity motor recovery in chronic stroke.

Methods: Thirty chronic stroke subjects were randomly assigned to one of three behavioral treatment groups and completed 6 hours of rehabilitation in 4 days: (1) coupled bilateral training with a load on the unimpaired hand, (2) coupled bilateral training with no load on the unimpaired hand, and (3) control (no stimulation assistance or load).

Results: Separate mixed design ANOVAs revealed improved motor capabilities by the coupled bilateral groups. From the pretest to the posttest, both the coupled bilateral no load and load groups moved a higher number of blocks and demonstrated more regularity in the sustained contraction task. Faster motor reaction times across test sessions for the coupled bilateral load group provided additional evidence for improved motor capabilities.

Conclusions: Together these behavioral findings lend support to the contribution of coupled bilateral training with a load on the unimpaired arm to improved motor capabilities on the impaired arm. This evidence supports a neural explanation in that simultaneously moving both limbs during stroke rehabilitation training appears to activate balanced interhemispheric interactions while an extra load on the unimpaired limb provides stability to the system.
Different postischemic protein expression of the	GABA$_{A}$ receptor α2 subunit and	the plasticity-associated protein MAP1B after treatment with BDNF versus G-CSF	in the rat brain
Authors: Müller Harald D. , Neder Angelika , Sommer Clemens , Schäbitz Wolf-Rüdiger
Published: December 2019

Purpose: Recent data indicate that both brain-derived neurotrophic factor (BDNF) and granulocyte-colony stimulating factor (G-CSF) exert substantial neuroregenerative effects and improve functional outcome after ischemic stroke. In the present study, we checked for potential differences in the postischemic modulation of various excitatory and inhibitory neurotransmitter receptors as well as various marker molecules for structural plasticity by BDNF versus G-CSF.

Methods: Adult male Wistar rats were subjected to photothrombotic ischemia and subsequently treated with NaCl, BDNF or G-CSF, respectively. After 6 weeks, postischemic protein expression of the NR1, GluR1 and α2 subunit of the NMDA, AMPA and GABA $_{A}$ receptor, respectively, was semiquantitatively determined ipsi- and contralateral to the ischemic lesion. Structural plasticity was further analyzed immunohistochemically using antibodies against MAP1B, MAP2 and synaptophysin.

Results: Only BNDF caused a significantly reduced postischemic protein expression of the GABA $_{A}$ receptor α2 subunit and the NR1 subunit of the NMDA receptor in the hippocampus. Furthermore, BDNF compared to G-CSF increased MAP1B protein expression in the periischemic regenerative region.

Conclusions: Although both BDNF and G-CSF have been shown to improve postischemic functional outcome to a similar extent, exogenous administration results in different underlying structural reorganization processes suggesting specific modulations of plasticity-associated events by these trophic factors.
Lasting effects of repeated rTMS application in focal hand	dystonia
Authors: Borich Michael , Arora Sanjeev , Kimberley Teresa Jacobson
Published: December 2019

Purpose: Focal hand dystonia (FHD) is a rare but potentially devastating disorder involving involuntary muscle spasms and abnormal posturing that impairs functional hand use. Increased cortical excitability and lack of inhibitory mechanisms have been associated with these symptoms. This study investigated the short- and long-term effects of repeated administrations of repetitive-transcranial magnetic stimulation (rTMS) on cortical excitability and handwriting performance.

Methods: Six subjects with FHD and nine healthy controls were studied. All subjects with FHD received rTMS (1Hz) to the premotor cortex (PMC) for five consecutive days; of those, three subjects received five days of sham rTMS completed ten days prior to real treatment. Healthy subjects received one real rTMS session. Cortical silent period (CSP) and measures of handwriting performance were compared before and after treatment and at ten-day post-treatment follow-up.

Results: At baseline, significant differences in CSP and pen pressure were observed between subjects with FHD and healthy controls. Differences in CSP and pen velocity between subjects in real and sham rTMS groups were observed across treatment sessions and maintained at follow-up.

Conclusions: After five days of rTMS to PMC, reduced cortical excitability and improved handwriting performance were observed and maintained at least ten days following treatment in subjects with FHD. These preliminary results support further investigation of the therapeutic potential of rTMS in FHD.
Chondroitinase ABC and acute electrical stimulation are beneficial	for muscle reinnervation after sciatic nerve transection in rats
Authors: Beaumont Eric , Cloutier Frédéric-Charles , Atlan Michael , Rouleau Dominique M. , Beaumont Pierre H.
Published: December 2019

Purpose: nerve regeneration and functional recovery are often incomplete after peripheral nerve damage. The aim of this study was to determine if chondroitinase ABC injection at the lesion site, 1 hour of electrical stimulation and the combination of these treatments at the time of repair could be effective in promoting muscle reinnervation.

Methods: the right sciatic nerve was completely sectioned in 32 female Sprague-Dawley rats. End-to-end microsuture repair was undertaken and fibrin glue was added. Five groups were studied: 1) suture (S) + fibrin glue (F) only; 2) S + F + chondroitinase ABC; 3) S + F + electrical stimulation; 4) S + F + chondroitinase ABC + electrical stimulation; 5) uninjured nerve.

Results: post recovery kinematics showed larger excursion of the hip-ankle-toe angle during walking in groups 2, 3 and 4 than in group 1 (p< 0.05). In vivo electromyographic activity and maximal muscle force were similar between groups 2, 3, 4 and 5, with higher values in all of them compared to group 1 (p< 0.05). Also, the distal stump of the sciatic nerve was excised, and cross-sectioning revealed that the number of axons were similar in all groups.

Conclusions: 150 days after nerve transection, recovery was incomplete with S and F only. Chondroitinase ABC injection at the lesion site and/or 1 hour of electrical stimulation of the proximal nerve stump were beneficial in promoting nerve regeneration and functional muscle reinnervation.
Multipotent mesenchymal stromal cells attenuate chronic	inflammation and injury-induced sensitivity to mechanical stimuli in	experimental spinal cord injury
Authors: Abrams M. Birdsall , Dominguez Cecilia , Pernold Karin , Reger Roxanne , Wiesenfeld-Hallin Zsuzsanna , Olson Lars , Prockop Darwin
Published: December 2019

Purpose: Previous reports established that after a contusion injury to the rat spinal cord, locomotor function was enhanced by the transplantation of cells from bone marrow referred to as either mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). It has also been established that neural stem cells (NSCs) enhance locomotor function after transplantation into the injured rat spinal cord. However, the beneficial effects of NSCs are limited by graft-induced allodynia-like responses. Little is known about the effects of MSCs on sensory function in spinal cord injury. Therefore, the objective of this research was to determine whether transplantation of MSCs into the injured rat spinal cord induces allodynia-like responses.

Methods: Contusion injuries of two different severities were induced in rats to examine the effects of transplantation with MSCs on sensorimotor deficits. The effects of MSCs on chronic inflammation were investigated, since inflammation is reported to have a role in the sensorimotor deficits associated with spinal cord injury. In addition, observations in other models suggest that MSCs possess immunosuppressive effects.

Results: We found that in contrast to previous observations with the transplantation of neural stem cells, transplantation of MSCs did not induce allodynia. MSCs attenuated injury-induced sensitivity to mechanical stimuli but had no effect on injury-induced sensitivity to cold stimuli. MSCs also significantly attenuated the chronic inflammatory response as assayed by GFAP immunoreactivity for reactive astrocytes and ED1 immunoreactivity for activated macrophages/microglia. In addition, transplantation of MSCs increased white matter volumes and decreased cyst size in sections of the cord containing the lesion.

Conclusion: The results suggest that the sensorimotor enhancements produced by MSCs can at least in part be explained by anti-inflammatory/immunosuppressive effects of the cells, similar to such effects of these cells observed in other experimental models.
Grafted neural progenitors migrate and form neurons after	experimental traumatic brain injury
Authors: Wallenquist U. , Brännvall K. , Clausen F. , Lewén A. , Hillered L. , Forsberg-Nilsson K.
Published: December 2019

Purpose: Neural stem and progenitor cells (NSPC) generate neurons and glia, a feature that makes them attractive for cell replacement therapies. However, efforts to transplant neural progenitors in animal models of brain injury typically result in high cell mortality and poor neuronal differentiation.

Methods: In an attempt to improve the outcome for grafted NSPC after controlled cortical impact we transplanted Enhanced Green Fluorescent Protein (EGFP)-positive NSPC into the contra lateral ventricle of mice one week after injury.

Results: Grafted EGFP-NSPC readily migrated to the injured hemisphere where we analyzed the proportion of progenitors and differentiated progeny at different time points. Transplantation directly into the injured parenchyma, resulted in few brains with detectable EGFP-NSPC. On the contrary, in more than 90% of the mice that received a transplant into the lateral ventricle detectable EGFP-positive cells were found. The cells were integrated into the lateral ventricle wall of the un-injured hemisphere, throughout the corpus callosum, and in the cortical perilesional area. At one-week post transplantation, grafted cells that had migrated to the perilesion area mainly expressed markers of neural progenitors and neurons, while in the corpus callosum and the ventricular lining, grafted cells with a glial fate were more abundant. After 3 months, grafted cells in the perilesion area were less abundant whereas cells that had migrated to the walls of the third- and lateral- ventricle of the injured hemisphere were still detectable, suggesting that the injury site remained a hostile environment.

Conclusion: Transplantation to the lateral ventricle, presumably for being a neurogenic region, provides a favorable environment improving the outcome for grafted NSPC both in term of their appearance at the cortical site of injury, and their acquisition of neural markers.
Neuroplasticity and cognitive aging: The scaffolding theory of	aging and cognition
Authors: Goh Joshua O. , Park Denise C.
Published: December 2019

A recent proposal called the Scaffolding Theory of Cognitive Aging (STAC) postulates that functional changes with aging are part of a lifespan process of compensatory cognitive scaffolding that is an attempt to alleviate the cognitive declines associated with aging. Indeed, behavioral studies have shown that aging is associated with both decline as well as preservation of selective cognitive abilities. Similarly, neuroimaging studies have revealed selective changes in the aging brain that reflect neural decline as well as compensatory neural recruitment. While aging is associated with reductions in cortical thickness, white-matter integrity, dopaminergic activity, and functional engagement in posterior brain regions such as the hippocampus and occipital areas, there are compensatory increases in frontal functional engagement that correlate with better behavioral performance in older adults. In this review, we discuss these age-related behavioral and brain findings that support the STAC model of cognitive scaffolding and additionally integrate the findings on neuroplasticity as a compensatory response in the aging brain. As such, we also examine the impact of external experiences in facilitating neuroplasticity in older adults. Finally, having laid the foundation for STAC, we briefly describe a proposed intervention trial (The Synapse Program) designed to evaluate the behavioral and neural impact of engagement in lifestyle activities that facilitates successful cognitive scaffolding using a controlled experiment where older adult participants are randomly assigned to different conditions of engagement.
Mesulam's frontal lobe mystery re-examined
Authors: Burgess Paul W. , Alderman Nick , Volle Emmanuelle , Benoit Roland G. , Gilbert Sam J.
Published: December 2019

Purpose: Mesulam's (1986) mystery is that some patients with frontal lobe damage may show no cognitive impairment according to traditional office-based assessment procedures, yet nevertheless show marked cognitive handicap in everyday life. Mesulam suggested that "the office setting may introduce sufficient external structure to suppress some of these behavioral tendencies" (p. 322). We ask if it is indeed the office setting that is the problem, or whether it is that traditional assessments do not measure the full range of cognitive functions supported by prefrontal cortex.

Method: Neuropsychological case series study and review.

Results: Traditional methods for assessing cognitive deficits following frontal lobe damage typically do not measure the full range of deficits that can occur. In particular, rostral prefrontal cortex supports functions which are not routinely assessed yet are crucial to competent everyday life performance. These include meta-memory functions (e.g. context and source memory), complex behavioural co-ordination (e.g. prospective memory and multitasking), and mentalizing.

Conclusions: New clinical assessment procedures are required urgently. These could be based, in principle, both on recent experimental findings from cognitive neuroscience, and observation of behaviour outside office settings. These procedures could then be administered in an office setting.
Cognition and equilibrium regulation in development and aging
Authors: Labouvie-Vief Gisela
Published: December 2019

Purpose: Changes in emotion-cognition relationships in later life comprise a pattern of both vulnerabilities and strengths. To integrate this pattern of diversity, I propose a neo-Piagetian extension of the concepts of equilibrium and disequilibrium processes to the relationship beyond cognition to encompass emotional activation and arousal, and beyond youth to the full life span.

Content: Beginning with a simple, Cannon-type equilibrium based on the response to increasing deviation from ideal end states of correcting through tension reduction, a more complex model is outlined that additionally uses tension amplification aimed at enlargement of the range over which stability is maintained, i.e., permits processes of developmental progression. Parallel to cognitive development, emotional development is described as the emergence of more complex cognitive-affective structures out of original automatic, biologically based ones. In that process, tension thresholds are raised, and the functional range over which equilibrium can be maintained is widened, as higher-order representations become part of the regulatory network. These progressive movements provide well automated emotion regulation whose effectiveness increases well into middle and late life.

Conclusions: In contrast to development, aging is ultimately characterized by a lowering of tension thresholds similar to developmental regression. However, as in the purely intellectual realm, that process is offset by the previous automatization and crystallization of cognitive-affective schemas becomes evident only as a result of increasing constraints on fluid capacities, as in advancing age and/or high load of cognitive effort and/or emotional activation.
Measuring compensation and its plasticity across the	lifespan
Authors: Zöllig Jacqueline , Eschen Anne
Published: December 2019

Purpose. The present paper integrates two important aspects when studying compensation: (1) the knowledge about specific compensational mechanisms and (2) the consideration of lifelong changes in these mechanisms (i.e., plasticity of compensation). Hence, the paper addresses the questions (a) which neural networks are supporting successful cognitive performance across development, (b) what are the associated compensational mechanisms and (c) are these compensational mechanisms plastic across the lifespan. Methods. To answer these questions, we suggest to integrate behavioural and neuroimaging methods and present specific methods and their advantages and disadvantages. Results. We will illustrate the relevance of this integration by presenting data using ERPs and (s)LORETA to study compensational processes across the lifespan in a higher order cognitive function, i.e., delayed intentional behaviour. A higher activation in old adults or adolescents in successful trials compared to young adults is considered compensatory as specialized cortical regions are selectively recruited in response to task demands. Conclusions. Findings show that whereas the performance outcome might be the same across age groups, underlying processes and activations might be fundamentally different. We conclude with a discussion about specific implications of this integrative approach when studying the adaptive potentials and limits of human cognition.
Postural compensation for vestibular loss and implications for	rehabilitation
Authors: Horak Fay B.
Published: December 2019

Purpose: This chapter summarizes the role of the vestibular system in postural control so that specific and effective rehabilitation can be designed that facilitates compensation for loss of vestibular function.

Methods: Patients with bilateral or unilateral loss of peripheral vestibular function are exposed to surface perturbations to quantify automatic postural responses. Studies also evaluated the effects of audio- and vibrotactile-biofeedback to improve stability in stance and gait.

Results: The most important role of vestibular information for postural control is to control orientation of the head and trunk in space with respect to gravitoinertial forces, particularly when balancing on unstable surfaces. Vestibular sensory references are particularly important for postural control at high frequencies and velocities of self-motion, to reduce trunk drift and variability, to provide an external reference frame for the trunk and head in space; and to uncouple coordination of the trunk from the legs and the head-in-space from the body CoM.

Conclusions: The goal of balance rehabilitation for patients with vestibular loss is to help patients 1) use remaining vestibular function, 2) depend upon surface somatosensory information as their primary postural sensory system, 3) learn to use stable visual references, and 4) identify efficient and effective postural movement strategies.
Saccade and vestibular ocular motor adaptation
Authors: Schubert Michael C. , Zee David S.
Published: December 2019

Purpose: This paper focuses on motor learning within the saccadic and vestibulo-ocular reflex (VOR) oculomotor systems, vital for our understanding how the brain keeps these subsystems calibrated in the presence of disease, trauma, and the changes that invariably accompany normal development and aging. We will concentrate on new information related to multiple time scales of saccade motor learning, adaptation of the VOR during high-velocity impulses, and the role of saccades in VOR adaptation. The role of the cerebellum in both systems is considered.

Methods: Review of data involving saccade and VOR motor learning.

Results: Data supports learning within the saccadic and VOR oculomotor systems is influenced by 1). Multiple time scales, with different rates of both learning and forgetting (seconds, minutes, hours, days, and months). In the case of forgetting, relearning on a similar task may be faster. 2). Pattern of training, learning and forgetting are not similarly achieved. Different contexts require different motor behaviors and rest periods between training sessions can be important for memory consolidation.

Conclusions: The central nervous system has the difficult task of determining where blame resides when motor performance is impaired (the credit assignment problem). Saccade and VOR motor learning takes place at multiple levels within the nervous system, from alterations in ion channel and membrane properties on single neurons, to more complex changes in neural circuit behavior and higher-level cognitive processes including prediction.
Glial cell line-derived neurotrophic factor (GDNF) gene delivery	protects cortical neurons from dying following a traumatic brain injury
Authors: Minnich Jennie E. , Mann Sarah L. , Stock Megan , Stolzenbach Kathryn A. , Mortell Bridget M. , Soderstrom Katherine E. , Bohn Martha C. , Kozlowski Dorothy A.
Published: December 2019

Purpose: The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) gene delivery was examined in a rodent model of traumatic brain injury (TBI), the controlled cortical impact (CCI).

Methods: An adenoviral vector harboring human GDNF (AdGDNF) or green fluorescent protein (AdGFP) was injected unilaterally into the forelimb sensorimotor cortex (FL-SMC) of the rat one week prior to a unilateral CCI. Tests of forelimb function and asymmetry were administered for 2 weeks post-injury. At 2 weeks post-injury, animals were sacrificed and contusion size, neuronal survival, neurodegeneration, and virally-mediated GDNF and GFP protein expression were measured.

Results: Rats injected with AdGDNF had significantly smaller contusions, more surviving neurons, and less neurodegeneration than AdGFP injected and uninjected injured animals. GDNF gene delivery also resulted in significantly faster recovery of forelimb coordination and a smaller initial preference for the uninjured forelimb during exploration of the walls of a platform. However, overall recovery of symmetrical forelimb use was not achieved.

Conclusions: The discrepancy between neural protection and behavioral recovery suggests that while GDNF gene delivery provided a high degree of protection of damaged cortical neurons in this model of TBI, it may not have fully protected their terminals and synaptic functioning, resulting in only mild protection against behavioral deficits.
Vimentin and GFAP responses in astrocytes after contusion trauma	to the murine brain
Authors: Ekmark-Lewén Sara , Lewén Anders , Israelsson Charlotte , Li Gui Lin , Farooque Mohammad , Olsson Yngve , Ebendal Ted , Hillered Lars
Published: December 2019

Purpose: Astroglial responses after traumatic brain injury are difficult to detect with routine morphological methods. The aims for this study were to compare the temporal and spatial expression pattern of vimentin- and glial fibrillary acidic protein (GFAP) in a weight drop model of mild cerebral contusion injury in the rat. We also wanted to study the vimentin response with immunohistochemistry and vimentin mRNA RT-PCR analysis in severe cortical contusion injury produced by the controlled cortical impact in the mouse.

Methods: Vimentin and GFAP immunohistochemistry (1day, 3 days and 7 days) combined with vimentin mRNA RT-PCR analysis (1 h, 4 h, 22 h, 3 days and 7 days) were used after experimental traumatic brain injury in the rat and mouse.

Results: Increases in post-traumatic vimentin mRNA levels in the cortex and in the hippocampus appeared together with vimentin immunoreactivity in astrocytes in the perimeter of the cortical lesion, in the subcortical white matter and in the hippocampus starting at one day after severe trauma. GFAP immunostaining revealed hypertrophic astrocytes peaking at day 3 in the perifocal cortical region. There was no significant increase in GFAP immunoreactivity in the white matter in the rat. However, in the mouse there was a slight increase in the number of GFAP positive cells in this region, 3 days after trauma. Overall the pattern of vimentin immunoreactivity was very similar in the rat and mouse.

Conclusions: Vimentin immunoreactivity was more sensitive than the GFAP staining method to demonstrate the distribution and time course of astrocyte reactions after a contusion injury, especially in the white matter distant from the cortical lesion.
Management of the patient with chronic dizziness
Authors: Bronstein A.M. , Lempert Th
Published: December 2019

In this review we present a pragmatic approach to the patient with chronic vestibular symptoms. Even in the chronic patient a retrospective diagnosis should be attempted, in order to establish how the patient reached the current situation. Simple questions are likely to establish if the chronic dizzy symptoms started as benign paroxysmal positional vertigo (BPPV), vestibular neuritis, vestibular migraine, Meniere's disease or as a brainstem stroke. Then it is important to establish if the original symptoms are still present, in which case they need to be treated (e.g. repositioning maenouvres for BPPV, migraine prophylaxis) or if you are only dealing with chronic dizzy symptoms. In addition the doctor or physiotherapist needs to establish if the process of central vestibular compensation has been impeded due to additional clinical problems, e.g. visual problems (squints, cataract operation), proprioceptive deficit (neuropathy due to diabetes or alcohol), additional neurological or orthopaedic problems, lack of mobility or confidence, such as fear of falling or psychological disorders. A general neurological examination should also be conducted, amongst other reasons to make sure your patient's `chronic dizziness' is not due to a neurological gait disorder. Treatment of the syndrome of chronic dizziness is multidisciplinary but rehabilitation and simple counselling should be available to all patients. In contrast, vestibular suppressants or tranquilisers should be reduced or, if possible, stopped.
Integrated center for research and treatment of vertigo, balance	and ocular motor disorders
Authors: Brandt Thomas , Zwergal Andreas , Jahn Klaus , Strupp Michael
Published: December 2019

The German BMBF (German Ministry of Education and Research) has decided to establish an Integrated Center for Research and Treatment (IFB $^{LMU}$ ) of Vertigo, Balance and Ocular Motor Disorders in Munich in 2010. With funding of \psfig{figure=eur.eps,width=1.8mm}50 million over a ten-year period, the long-term continuation of the IFB $^{LMU}$ is envisioned.
Vestibular function after acute vestibular neuritis
Authors: Halmagyi G.M. , Weber K.P. , Curthoys I.S.
Published: December 2019

Purpose: To review the extent and mechanism of the recovery of vestibular function after sudden, isolated, spontaneous, unilateral loss of most or all peripheral vestibular function – usually called acute vestibular neuritis.

Methods: Critical review of published literature and personal experience.

Results: The symptoms and signs of acute vestibular neuritis are vertigo, vomiting, nystagmus with ipsiversive slow-phases, ipsiversive lateropulsion and ocular tilt reaction (the static symptoms) and impairment of vestibulo-ocular reflexes from the ipsilesional semicircular canals on impulsive testing (the dynamic symptoms). Peripheral vestibular function might not improve and while static symptoms invariably resolve, albeit often not totally, dynamic symptoms only improve slightly if at all.

Conclusions: The persistent loss of balance that some patients experience after acute vestibular neuritis can be due to inadequate central compensation or to incomplete peripheral recovery and vestibular rehabilitation has a role in the treatment of both.
The multimodal prospects for neuroprotection and disease	modification in epilepsy: Relationship to its challenging neurobiology
Authors: Hamed Sherifa A.
Published: December 2019

Cumulative evidences from experimental and clinical studies indicate that in some patients, not only prolonged but also repetitive brief seizures, may trigger series of damage promoting mechanisms which evolve over a period of time (up to years). They result in progressive degeneration and loss of function of several neuronal cell populations, thus rending the brain abnormal and resistant to antiepileptic medications (AEDs). This probably explains that in some patients, a) there is a delay from the onset of brain insult to the seizure onset, and b) suppression of seizures by AEDs is alone insufficient without clear prediction of disease progression. In this review, the analysis of information follows the assumption that epilepsy is a slowly progressive and a neurobiologically pleotropic disorder. Interaction between genes, neurotransmitters, ion channels, acid-base balance, mitochondria, calcium, glutamate and oxidative/antioxidants mechanisms, will determine the fate of the epilepsy process. The concept of neuroprotection aims not only to suppress seizures (anticonvulsant effect), but also to strengthen the auto-protective and repair mechanisms (antiepileptogenic and disease-modification effects) which prevent the development of spontaneous seizures, cognitive and behavioral problems later in life. This review is focusing on molecular evaluation of several models of epilepsy for the potential to follow disease modification and neuroprotection. Although AEDs of today possess multiple mechanisms of action, but mostly they are treating one part of the disease which is the seizures and do not offer high prospects of modification of the disease. This review is also discussing the prospects of novel drugs, molecular manipulations and cell therapy which address disease modification as approachs that will dominate the field of drug development and research on epilepsy in the future.
Cerebral restorative plasticity from normal ageing to brain	diseases: A "never ending story"
Authors: Landi Doriana , Rossini Paolo Maria
Published: December 2019

Brain plasticity can be considered the main result of brain communication with the 'external' and 'internal' environment. Learning new skills as well as endogenous brain function recovery following a lesion are based on neural plasticity, a dynamic phenomenon occurring in response to modification of conscious and pre- or sub-conscious experiences as they progressively stabilize at the synaptic and neural networks level. In spite of previously accepted theory, brain plasticity occurs throughout lifespan being an inner property of the system. Different models of brain plasticity are examined in relation with different modifications of the CNS: healthy brain ageing, neurodegenerative disorders, ischemic stroke and multiple sclerosis. A clarification of advantageous as well as of aberrant brain plasticity mechanisms in pathological conditions may help to improve the development of rehabilitation methods to better address and facilitate such processes.
rTMS effects on levodopa induced dyskinesias in Parkinson's	disease patients: Searching for effective cortical targets
Authors: Koch Giacomo
Published: December 2019

Long-term therapy with levodopa and dopamine agonists in Parkinson's disease (PD) patients is complicated by the development of fluctuations in motor response, such as levo-dopa induced dyskinesia (LID). Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently put forward as a possible therapeutic tool able to LID in PD. Trains of 1 Hz rTMS applied either over the supplementary motor area (SMA) or the primary motor cortex (M1) were able to induce a transient reduction in the severity of LID, confirming that an over-activity of these areas plays a crucial role in the pathophysiology of LID. However, repeated sessions of rTMS were not effective in inducing persistent beneficial clinical effects. Functional or metabolic changes have been reported in the cerebellum in studies in PD patients treated with procedures known to alleviate LID, such as deep brain stimulation. Therefore, the effects of rTMS applied over the lateral cerebellum has been recently tested in patients with LID. A two-week course of bilateral cerebellar rTMS induced persistent clinical beneficial effects, reducing peak-dose LID for up to four weeks after the end of the daily stimulation period. These findings demonstrate that rTMS is a potential tool in individuating the best cortical targets and the optimal parameters of stimulation able to improve LID in dyskinetic PD patients.
Influence of repetitive transcranial magnetic stimulation on	special symptoms in depressed patients
Authors: Höppner Jacqueline , Berger Christoph , Walter Uwe , Padberg Frank , Buchmann Johannes , Herwig Uwe , Domes Gregor
Published: December 2019

Since various studies, including multi-centre studies, investigating the effect of repetitive transcranial magnetic stimulation (rTMS) in depression have shown different results, it is now important to research, which symptoms of depression are most responsive to this kind of non-invasive brain stimulation. Furthermore, an increasing interest of rTMS as a potential tool for treatment of neurological and psychiatric disorders should be recorded. Therefore, it is critical to investigate dopaminergic functional interactions in the prefrontal cortex, and in particular, the effect of dorsolateral prefrontal cortex stimulation on clinical symptoms depending on dopaminergic concentrations in various brain regions. This short review summarizes important preliminary data, which focus on the symptom-oriented effects of rTMS in depression.
Quadripulse stimulation – A new patterned rTMS
Authors: Hamada Masashi , Ugawa Yoshikazu
Published: December 2019

A new patterned repetitive transcranial magnetic stimulation (rTMS) protocol, quadripulse stimulation (QPS), can produce a broad range of motor cortical plasticity ranging from MEP suppression to MEP facilitation depending on the interval of the pulses within a burst. In addition to inducing lasting cortical plastic changes, QPS can also be used to evaluate priming effects: when used as a priming stimulation, which does not induce an LTP- or LTD-like phenomena itself, it can nevertheless change the threshold for LTP- or LTD-like plasticity caused by a consecutive stimulation. This enables us to examine metaplasticity theory in more details in humans. Another application of QPS might be to induce symptomatic relief in patients with neurological or psychiatric disorders, such as Parkinson's disease, depression, or intractable pain.
The response to repetitive stimulation of human motor cortex is	influenced by the history of synaptic activity
Authors: Todd G. , Ridding M.C.
Published: December 2019

Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), can modify cortical excitability in a lasting fashion. The modification can be bi-directional in nature and holds considerable therapeutic promise for a number of neurological conditions. However, the effectiveness of these techniques is currently limited by large intra- and inter-subject variability in the response. A number of factors that contribute to response variability have now been identified, with one of the most important being the history of synaptic activity within the cortical region being targeted by stimulation. In this review we discuss what is currently known about the influence of behaviourally, or experimentally, induced changes in synaptic activity in the cortical (or interconnected) region being targeted by stimulation on the response to rTMS techniques. Understanding such influences is a critical step in the development of effective therapeutic paradigms employing such techniques.
Brain stimulation and brain repair – rTMS: from animal experiment	to clinical trials – what do we know?
Authors: Platz Thomas , Rothwell John C.
Published: December 2019

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of stimulating the brain that changes excitability at the site of stimulation as well as at distant anatomically connected sites. Since the effects can outlast the period of stimulation for minutes or hours and are thought to be depend, at least in part, on changes in the efficiency of synaptic connections in the cortex, the method has generated much interest as a potential therapeutic intervention in a wide range of neurological and psychiatric conditions. A symposium on brain stimulation and brain recovery was held in Greifswald (Germany) in 2010 to exchange of state-of-the-art knowledge about rTMS effects from animal experiments to clinical trials in conditions such as stroke, Parkinson disease, and depression. There was enormous interest in the effects of rTMS and signs of therapeutic success in mainly small clinical trials. However, it was also clear that some of our models of the effects of rTMS, such as upregulation or downregulation of specific brain areas may need further development if they are to account for all the observations that have been made so far. The results of the symposium are made available by lab reviews of members of the symposium's faculty. This editorial provides an overview.
Restoration of cognitive deficits after statin feeding in TBI
Authors: Chauhan Neelima B. , Gatto Rodolfo
Published: December 2019

Purpose: Traumatic brain injury (TBI) is a global health concern and growing socio-economic burden with limited treatment options. Behavioral assessment in experimental TBI with candidate therapeutic interventions is critical in order to expedite clinical translation. Statins constitute one of the potential treatment options based on their proven beneficial effects in various models of neurotrauma. We compared functional outcome after dietary intervention with representative hydrophilic Pravastatin or lipophilic Simvastatin and Lovastatin to test if different statins will differentially affect cognitive outcomes after injury in a controlled cortical impact injury (CCI) mouse model of TBI.

Methods: Mice were subjected to TBI with a controlled cortical impact produced on the left somatosensory-parietal cortex between bregma −1.82 and −2.06, fed with Simvastatin/Lovastatin/Pravastatin (2 mg/kg) for 8 weeks, evaluated for learning, memory and spontaneous exploration behavior followed by immunocytochemistry of an axonal marker.

Results: Results indicate that feeding of TBI mice with Simvastatin and Lovastatin significantly improved spatial learning and memory, restored spontaneous exploration and restored axonal integrity (Simvastatin > Lovastatin). On the other hand, Pravastatin failed to improve spatial learning or memory or exploration or axonal damage.

Conclusions: Current findings confirm maximum benefits rendered by Simvastatin and reinforce Simvastatin as the candidate therapy for treating TBI.
Delayed rehabilitation with task-specific therapies improves forelimb function after a cervical spinal cord injury
Authors: Dai Haining , MacArthur Linda , McAtee Marietta , Hockenbury Nicole , Das Paramita , Bregman Barbara S.
Published: December 2019

Purpose: The effect of activity based therapies on restoring forelimb function in rats was evaluated when initiated one month after a cervical spinal cord injury. Methods: Adult rats received a unilateral over-hemisection of the spinal cord at C4/5, which interrupts the right side of the spinal cord and the dorsal columns bilaterally, resulting in severe impairments in forelimb function with greater impairment on the right side. One month after injury rats were housed in enriched housing and received daily training in reaching, gridwalk, and CatWalk. A subset of rats received rolipram for 10 days to promote axonal plasticity. Rats were tested weekly for six weeks for reaching, elevated gridwalk, CatWalk, and forelimb use during vertical exploration. Results: Rats exposed to enriched housing and daily training significantly increased the number of left reaches and pellets grasped and eaten, reduced the number of right forelimb errors on the gridwalk, increased right forelimb use during vertical exploration, recovered more normal step cycles, and reduced their hindlimb base of support on the CatWalk compared to rats in standard cages without daily training. Conclusions: Delayed rehabilitation with enriched housing and daily forelimb training significantly improved skilled, sensorimotor, and automatic forelimb function together after cervical spinal cord injury.
Long-term morphometric stabilization of regenerating retinal ganglion cells in the adult rat
Authors: Chiwitt Carolin , Prokosch Verena , Seeger Johannes , Thanos Solon
Published: December 2019

Purpose: Adult retinal ganglion cells (RGCs) can regenerate their cut axons within peripheral nerve grafts used to replace the distal optic nerve stump. We examined the long-term stabilization of RGCs by guiding their regenerating axons into different termination areas. Methods: The optic nerve (ON) of adult rats was completely cut intraorbitally and its ocular stump was connected with different visual target areas (cortex, midbrain) or with non-visual areas (e.g. muscle). Control groups consisted of blind ending graft and ON cut without graft. The function of the retina was regularly examined by electroretinography. At one, six and nine months postsurgery RGCs were retrogradely labelled with 4-(4-(didecylamino)styryl)-N-methylpyridinium iodide and examined morphometrically. Regenerating RGCs were categorized into three major classes representing the morphological types I, II and III. Results: Our data show that regenerating RGCs remain stable up to nine months after grafting at the ON, although the numbers of axons are low, that is less than 1%, and this number is not significantly effected by reconnection with targets. However, there are significant quantitatively and morphometrically assessable differences between the experimental groups depending on the tissue the RGCs are connected with visual targets. Regenerating RGCs show the highest stability in morphology if reconnected with visual target tissue. Conclusions: Adult RGCs of the rat can be reconnected with visual centers using a peripheral nerve graft. This reconnection stabilizes the cells at morphological and the retina at functional levels for a long period of time, although it does not significantly increase cell survival.
Roles of exogenous and endogenous FGF-2 in animal models of depression
Authors: Jarosik J. , Legutko B. , Werner S. , Unsicker K. , von Bohlen und Halbach O.
Published: December 2019

Purpose: Several members of the fibroblast growth factor (FGF) family have been shown to be dysregulated in individuals with major depression, and treatment with antidepressants has been reported to increase FGF-2 mRNA levels in the forebrain. Methods: We have used the tail suspension test (TST), and olfactory bulbectomy (OBX), and FGF-2 deficient mice to investigate putative roles of FGF-2 as an antidepressant and mediator of antidepressive drug actions. Results: FGF-2 applied intraventricularly generated antidepressant-like effects in the TST. FGF-2, similar to the antidepressant amitriptyline, attenuated neuron demise in the piriform cortex and posterolateral cortical nucleus of the amygdala following OBX. Moreover, OBX induced reduction in hippocampal neurogenesis could be ameliorated by subsequent treatment with either amitriptyline or FGF-2. Furthermore, FGF-2 was effective in reversing depressive-like behavior induced by OBX, monitored in the locomotor activity and the passive avoidance test. In bulbectomized FGF-2 deficient mice, treatment with amitriptyline protected neurons, but failed to reverse behavioral alterations. Conclusions: Together, these results suggest that FGF-2 constitutes both a potential target for antidepressive treatments and an important growth factor in the cytokine network underlying the actions of antidepressive drugs. The results further suggest a requirement of endogenous FGF-2 for mediating behavioral, but not neuroprotective actions of amitriptyline.
Hemispatial neglect reflected on visual memory
Authors: Luukkainen-Markkula R. , Tarkka I.M. , Pitkänen K. , Sivenius J. , Hämäläinen H.
Published: December 2019

Purpose: Recent studies of hemispatial neglect have revealed both lateralized and nonlateralized attention mechanisms contributing to the syndrome. In addition, neglect patients show impaired spatial working memory and diminished working memory capacity. The aim of this study was to investigate, how neglect would be reflected in their performances in commonly used clinical visual memory tests. Methods: Twelve patients with right hemisphere lesions and left neglect and twelve matched controls were assessed with the Behavioural Inattention Test, the visual reproduction of the WMS-R, the object memory test, the Rey figure test and the list learning test. Visuo-spatial span was explored with the Corsi block test. Results: The severity of neglect was significantly associated with the naming of objects from the left side, with the copying of the Rey figure and with the immediate visual reproduction of the WMS-R. In comparison to the matched controls, the patients named and copied fewer items from both sides and showed impaired immediate and delayed recall of visual material, more so from the left side. After recovery, patients were still impaired in their visual search, whereas their immediate reproduction of visual material was no longer significantly different from the control subjects. The deficit in delayed recall of visual material persisted and was lateralized to the left side of the recollected memories. The role of hemianopia was analyzed. Conclusions: Patients with neglect exhibited spatial working memory bias and diminished nonlateralized attention capacity in encoding and immediate recall. The deficit in delayed recall was lateralized to the left side of memorized material.
Brain stimulation procedures for treatment of contralesional spatial neglect
Authors: Oliveri Massimiliano
Published: December 2019

The application of brain stimulation techniques for modulation of cortical excitability changes underlying spatial neglect following right-brain-damage has been the first application of brain stimulation in the rehabilitation setting. Several factors concur in making neglect a prototype of cognitive disorders that can be modulated by brain stimulation: 1) neglect is highly lateralized deficit, 2) neglect is a network disorder in which lesion of a network node impacts affects excitability of intrahemispehric and interhemispheric connections, and 3) lesions of the right hemisphere, the most frequent cause of neglect, are associated with a transcallosally mediated increase of facilitation of the left hemisphere more frequently than are lesions of the left hemisphere associated with right hemisphere facilitation. We review the main applications of TMS for modulation of neglect disorder and we discuss the different potentialities of inhibition of the unaffected and facilitation of the affected hemisphere. Moreover, we suggest potential interactions of TMS with other behavioral techniques in the rehabilitation setting.