bluuebunny/crossref_metadata_2025 huggingface dataset:
Language improvements after TMS plus modified CILT: Pilot, open-protocol study with two, chronic nonfluent aphasia cases
Authors: Martin Paula I. , Treglia Ethan , Naeser Margaret A. , Ho Michael D. , Baker Errol H. , Martin Elizabeth G. , Bashir Shahid , Pascual-Leone Alvaro
Published: December 2019

Purpose: The purpose of this study was to investigate: 1) the feasibilty of administering a modified CILT (mCILT) treatment session immediately after TMS; and 2) if this combined therapy could improve naming and elicited propositional speech in chronic, nonfluent aphasia. Methods: Two chronic stroke patients with nonfluent aphasia (mild-moderate and severe) each received twenty minutes of rTMS to suppress the right pars triangularis, followed immediately by three hours of mCILT (5 days/week, 2 weeks). (Each patient had received TMS alone, 2–6 years prior.) Language evaluations were performed pre- TMS+mCILT, and post- at 1-2 months, and 6 or 16 months. Results: Both patients showed significant improvements in naming pictures, and elicited propositional speech at 1-2 months post- TMS+mCILT. The improved naming was still present at 6 months post- TMS+mCILT for P2; but not at 16 months post- TMS+mCILT for P1. Conclusions: It is feasible to administer mCILT for three hours immediately after a TMS session. It is unknown if the significant improvements in naming pictures, and elicited propositional speech were associated with the second series of TMS, or this first series of mCILT, or a combination of both. A larger, sham controlled clinical trial is warranted.
Motor recovery from constraint induced movement therapy is not constrained by extent of tissue damage following stroke
Authors: Gauthier Lynne V. , Mark Victor W. , Taub Edward , McCullars Adrianne , Barghi Ameen , Rickards Tyler , Hicks Jarrod , Uswatte Gitendra
Published: December 2019

Purpose: The purpose of this study was to delineate the relationship between several types of T1-weighted MRI pathology and motor rehabilitation potential following Constraint Induced Movement therapy (CI therapy) in chronic stroke. Methods: Stepwise regression was employed (n = 80) to identify predictors of motor recovery (prior to therapy) and of response to Constraint-Induced Movement therapy [measured via the Wolf Motor Function Test (WMFT) and Motor Activity Log (MAL)] from among the following: age, side of motor deficit, chronicity, gender, lesion volume, peri-infarct damage volume, white matter hypointensity volume, ventricular asymmetry, and lesion location. Results: Although extent of total stroke damage weakly correlated with poorer performance on the WMFT prior to therapy, this relationship was mediated by the location of the damage. No metric of tissue damage examined here was associated with real-world arm use at baseline (MAL at pre-treatment) or with CI therapy-induced improvement in either best motor performance upon request (WMFT) or spontaneous arm use for daily activities (MAL). Conclusions: In sum, the extent of brain tissue damage of any type examined here poorly predicted motor function and response to rehabilitation in chronic stroke.
Increasing human leg motor cortex excitability by transcranial high frequency random noise stimulation
Authors: Laczó Bence , Antal Andrea , Rothkegel Holger , Paulus Walter
Published: December 2019

Purpose: Transcranial random noise stimulation (tRNS) can increase the excitability of hand area of the primary motor cortex (M1). The aim of this study was to compare the efficacy of tRNS and transcranial direct current stimulation (tDCS) on the leg motor cortex. Method: Ten healthy subjects received anodal, cathodal tDCS, tRNS and sham stimulation for 10 min using 2 mA intensity during separate experimental sessions. Single pulse transcranial magnetic stimulation (TMS) induced motor evoked potential (MEP) measurements were used to assess motor cortical excitability changes after the stimulation. Results: Similar to the hand area, we found that both tRNS and anodal tDCS induced an increase of the amplitude of the MEPs. Anodal tDCS induced a constant gradual increase of corticospinal excitability until 60 min post-stimulation, whereas the effect of tRNS was immediate with a duration of 40 min following stimulation. The cathodal tDCS induced decrease in MEP amplitude did not reach statistical significance. Conclusion: Our results suggest that although the leg area has a deeper position in the cortex compared to the hand area, it can be reached by weak transcranial currents. Both anodal tDCS and tRNS had comparable effect on cortical excitability.
Increased tyrosine hydroxylase expression accompanied by glial changes within the non-lesioned hemisphere in the 6-hydroxydopamine model of Parkinson's disease
Authors: Schlachetzki Johannes C.M. , Marxreiter Franz , Regensburger Martin , Kulinich Anna , Winner Beate , Winkler Jürgen
Published: December 2019

Purpose: Parkinson's disease (PD) is characterized by striatal synaptic deafferentation followed by dopaminergic cell death in the substantia nigra pars compacta. Not only degenerative, but also regenerative, compensatory changes at distant sites of the primary lesion may occur in PD. The aim of the study was to analyze the temporal pattern of axonal and glial responses over a time course of six weeks post-lesioning. Methods: For this aim, 6-hydroxydopamine (6-OHDA) was injected unilaterally into the medial forebrain bundle and both lesioned and non-lesioned striata were analyzed. Results: We detected increased tyrosine hydroxylase (TH) immunoreactivity within the non-lesioned striatum six weeks after injection indicative either of increased TH expression or compensatory neuritic changes. An increased number of microglial cells was present in both lesioned and unlesioned striata. There was no obvious change in microglial phenotype or in pro-inflammatory cytokine gene expression within the striatum without any apparent switch into a pro-inflammatory phenotype. No changes were observed in the number of mature oligodendrocytes. Conclusions: This temporal pattern shows, that the non-lesioned striatum undergoes profound changes, involving increased TH expression accompanied by a glial response. A better understanding of this complex interplay of neuronal as well as glial components not only within the lesioned, but also non-lesioned striatum may help to restore local neural circuits in PD.
Impact of transcranial direct current stimulation on fatigue in multiple sclerosis
Authors: Saiote Catarina , Goldschmidt Thomas , Timäus Charles , Steenwijk Martijn D. , Opitz Alexander , Antal Andrea , Paulus Walter , Nitsche Michael A.
Published: December 2019

Purpose: Fatigue is a frequent and difficult to treat symptom affecting patients with multiple sclerosis (MS) with a profound negative impact on quality of life. Fatigue has been associated with functional and structural abnormalities of the frontal cortex, including frontal hypo-activation. The aim of this exploratory study was to assess whether fatigue symptoms can be reduced by excitability-enhancing anodal transcranial direct current stimulation (tDCS). Methods: In this sham-controlled, double-blind intervention study, tDCS was applied over the left prefrontal cortex of MS patients with fatigue for five consecutive days. Symptoms were tracked for 1 month via questionnaires. Lesion load at baseline was calculated for each patient and correlated with fatigue levels and responsiveness to stimulation. Results: In the whole group analysis the scores of the fatigue scales were not altered by tDCS. However, in an exploratory analysis we found a correlation between response to the stimulation regarding subjectively perceived fatigue and lesion load in the left frontal cortex: patients responding positively to anodal tDCS had higher lesion load, compared to non-responding patients. Conclusion: We conclude that in patient subgroups discernible by specific morphological alterations, tDCS may be a tool for MS fatigue management.
Usage of the middle finger shapes reorganization of the primary somatosensory cortex in patients with index finger amputation
Authors: Oelschläger M. , Pfannmöller J. , Langner I. , Lotze M.
Published: December 2019

Purpose: The primary somatosensory cortex (S1) is somatotopically reorganized after limb amputation. The duration of the amputation, the intensity of phantom limb pain but also a multifactoral model of altered cerebral input have been discussed to be associated with cortical changes. Patients with finger amputation rarely show phantom limb pain, the deafferented cortical area is small but other fingers might well overtake function. Method: We selected a group of index finger amputated patients and performed a high resolution (in plane: 1.5 mm2) S1-mapping during tactile stimulation of finger tips. Result: We found an interhemispheric imbalance of the distance between the thumb and middle finger only for the patient-group. When patients used their middle finger more they showed less interhemispheric imbalance, increased spatial tactile discrimination and increased fMRI-activation in response to stimulation. Phantom limb pain was not associated with somatotopic representation parameters in S1. Conclusions: Overall, our fMRI-data point to a usage dependent plasticity of Brodmann's area 3b in man.
Psychopathy: Developmental perspectives and their implications for treatment
Authors: Anderson Nathaniel E. , Kiehl Kent A.
Published: December 2019

Psychopathy is a mental disorder marked by deficient emotional responses, lack of empathy, and poor behavioral controls, commonly resulting in persistent antisocial deviance and criminal behavior. Accumulating research suggests that psychopathy follows a developmental trajectory with strong genetic influences, and which precipitates deleterious effects on widespread functional networks, particularly within paralimbic regions of the brain. While traditional therapeutic interventions commonly administered in prisons and forensic institutions have been notoriously ineffective at combating these outcomes, alternative strategies informed by an understanding of these specific neuropsychological obstacles to healthy development, and which target younger individuals with nascent symptoms of psychopathy are more promising. Here we review recent neurobehavioral and neuroimaging literature that informs our understanding of the brain systems compromised in psychopathy, and apply these data to a broader understanding of its developmental course, ultimately promoting more proactive intervention strategies profiting from adaptive neuroplasticity in youth.
Chronic pain: The role of learning and brain plasticity
Authors: Mansour A.R. , Farmer M.A. , Baliki M.N. , Apkarian A. Vania
Published: December 2019

Based on theoretical considerations and recent observations, we argue that continued suffering of chronic pain is critically dependent on the state of motivational and emotional mesolimbic-prefrontal circuitry of the brain. The plastic changes that occur within this circuitry in relation to nociceptive inputs dictate the transition to chronic pain, rendering the pain less somatic and more affective in nature. This theoretical construct is a strong departure from the traditional scientific view of pain, which has focused on encoding and representation of nociceptive signals. We argue that the definition of chronic pain can be recast, within the associative learning and valuation concept, as an inability to extinguish the associated memory trace, implying that supraspinal/cortical manipulations may be a more fruitful venue for adequately modulating suffering and related behavior for chronic pain. We briefly review the evidence generated to date for the proposed model and emphasize that the details of underlying mechanisms remain to be expounded.
Effects of psychotropic drugs on brain plasticity in humans
Authors: Paulzen Michael , Veselinovic Tanja , Gründer Gerhard
Published: December 2019

Although neurotransmitter-based hypotheses still prevail current thinking about the mechanism of action of psychotropic drugs, recent insight into the pathophysiology of psychiatric disorders has unveiled a range of new therapeutic actions of the drugs used to treat those disorders. Especially antidepressants seem to exert at least some of their effects via restoration of synaptic/neuronal plasticity. In addition, there is increasing evidence that several of the second-generation antipsychotics and some anticonvulsants affect neuronal survival/apoptosis as well as synaptic plasticity. Most of this evidence stems from work in animals. In this review, we will focus on the evidence for neuroplastic effects of psychotropic drugs in humans being aware of the fact that most of the data are derived from animals and that volumetric studies in humans can only indicate structural plasticity and not necessarily functional plasticity. However, as the data from human studies are rather poor and inconclusive, and sometimes even conflicting, it seems impossible to draw general conclusions. Until now studies on neuroplasticity in humans can only explain small pieces of the effects of psychotropic drugs on brain plasticity in humans. Nevertheless, future prospects for the development of new drugs targeting brain plasticity will be of importance and will complete this overview.
Neuroplasticity and memory formation in major depressive disorder: An imaging genetics perspective on serotonin and BDNF
Authors: Kuhn Manuel , Popovic Ana , Pezawas Lukas
Published: December 2019

A vast number of imaging studies have demonstrated the impact of serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) on emotion and memory-related networks in the context of Major Depressive Disorder (MDD). Underlying molecular mechanisms that affect the functionality of these networks have been examined in detail in animals and corroborate imaging findings. The crucial role of 5-HT and BDNF signaling in the context of MDD is reflected in the etiologic models of MDD such as the monoamine or neuroplasticity hypothesis as well as in pharmacological models of antidepressant response. While antidepressant drug treatment has been primarily linked to the modulation of emotion-related networks, cognitive behavioral therapy has been implicated in a top-down control of limbic structures. Initially, a simple lack of monoamines or BDNF has been proposed as causal factor of MDD etiology. However, recent findings suggest a much more complex neurobiology emphasizing epistatic and epigenetic mechanisms responsible for structural and functional changes observed in emotion and memory-related brain regions of healthy subjects and MDD patients. In this review, which focuses on neuroimaging studies in the context of MDD, the authors will provide a comprehensive overview of these networks as well as on the specific role of 5-HT and BDNF in their development and function.
Neurobiologically based interventions for autism spectrum disorders-rationale and new directions
Authors: Poustka Luise , Brandeis Daniel , Hohmann Sarah , Holtmann Martin , Bölte Sven , Banaschewski Tobias
Published: December 2019

Autism spectrum disorders (ASD) are heterogeneous, neurodevelopmental disorders with early onset, characterized by a triad of impairments in reciprocal interaction and communication as well as repetitive and restricted interests and activities. Though underlying causes still remain largely unknown, there is now evidence for abnormal growth trajectories in the early brain development in ASD during vulnerable periods and subsequent impairment of neuronal organization and differentiation of neuronal networks. A growing number of studies over the last 10 years support the efficacy of behaviorally based interventions in ASD for the improvement of social communication and behavioral functioning. In contrast, research on neurobiologically based therapies for ASD is still at its beginnings. In this article, we will provide a selective overview of novel interventions and trainings based on neurobiological principles. Directions and options for future research on treatment aiming at restoration of normal plasticity in disrupted brain circuits in ASD are discussed.
When the threat comes from inside the body: A neuroscience based learning perspective of the etiology of panic disorder
Authors: Hamm Alfons O. , Richter Jan , Pané-Farré Christiane A.
Published: December 2019

Unexpected, recurrent panic attacks and anxious apprehension are two distinct emotional phenomena that constitute the core symptoms for diagnosing panic disorder. Taking a neuroscience perspective the current review paper presents both epidemiological and experimental psychophysiological evidence suggesting that panic attacks can be conceptualized as an unconditioned circa defense response pattern to intense internal threat stimuli, characterized by strong autonomic surge and escape behavior and abnormal plastic changes of the brain. Anxious apprehension develops after the experience of such severe panic attacks as conditioned responses to mild body symptoms. Theoretically these conditioned fear responses can be considered as post-encounter defense characterized by increased selective attention, increased threat appraisal and defensive freezing and startle potentiation evidencing altered brain circuits evoked by mild body symptoms. Agoraphobic avoidance starts very early during the defensive cascade and can be conceived as motivated behavior driven by the incentive to be in a safe context that is under control of the individual.
Rethinking mental disorders: The role of learning and brain plasticity
Authors: Morris Sarah E. , Rumsey Judith M. , Cuthbert Bruce N.
Published: December 2019

Recent research in neurodevelopment, neuroplasticity and genetics is providing new insights into the etiogenesis of psychopathology, but progress in treatment development has been hampered by reliance on diagnostic categories that are characterized by heterogeneity and based primarily on phenomenology. The NIMH Research Domain Criteria (RDoC) initiative seeks to provide a neuroscience-based nosological framework for future research on psychopathology, categorizing individuals for research purposes using a dimensional approach that capitalizes on advances in modern neuroscience. These scientific advances and new approaches to classification can inform the development of novel, circuit-based interventions and the personalization of treatment. In this paper, we review key advances areas in clinical neuroscience, describe the RDoC project and highlight some emerging treatment approaches that are consistent with these developments.
Specificity and generalization of perceptual learning in low myopia
Authors: Casco Clara , Guzzon Daniela , Moise Monica , Vecchies Antonella , Testa Tiziano , Pavan Andrea
Published: December 2019

Purpose: In this study we investigated in observers with low myopia: (i) the pattern of lateral interactions between stimuli activating early cortical analyzers and its modulation by perceptual learning (PL), and (ii) whether PL transferred to untrained stimuli and tasks and whether it exhibits interocular transfer. Method: Participants (seven adults with low myopia) performed 12 training sessions. Participants were trained on a contrast detection task of a central Gabor target flanked by two co-oriented and co-aligned high contrast Gabor patches. Target-to-flankers separation along the vertical axis was varied from 2 wavelengths (λ) to 8λ. Results: The results showed that before PL facilitatory lateral interactions in the myopic eye were reduced in strength, but PL increased contrast sensitivity and improved facilitatory lateral interactions. However, PL did not transfer to different local/global orientations and lower spatial frequencies. On the other hand, PL resulted in an enhancement of the contrast sensitivity function (CSF) and of the uncorrected visual acuity (UCVA) both in the trained and untrained eye. Conclusions: Such improvements seem to be associated to a modulation of lateral interactions between target and flankers and it is likely to take place at a level in which the inputs from the two eyes converge.
Tongxinluo attenuates neuronal loss and enhances neurogenesis and angiogenesis in the ipsilateral thalamus and improves neurological outcome after focal cortical infarction in hypertensive rats
Authors: Chen Li , Wang Xiaoting , Chen Xinran , Xing Shihui , Zhang Jian , Li Jingjing , Dang Chao , Liu Gang , Dang Ge , Zeng Jinsheng
Published: December 2019

Purpose: Tongxinluo, a well-known traditional Chinese medicine complex, has been widely used for the treatment of cerebrovascular diseases in China. The present study was to explore whether treatment with tongxinluo could improve neurological function and alleviate secondary damage in the ipsilateral thalamus after focal cortical infarction in hypertensive rats. Methods: Tongxinluo was given through oral gavage starting 24 h after distal middle cerebral artery occlusion (MCAO). Neurological function was assessed and then rats were sacrificed 7 and 14 days after MCAO. Brains were harvested for examining infarction volume, Nissl staining and immunofluorescence analysis. Results: Compared with vehicle treatment, tongxinluo remarkably improved neurological function without reducing infarction volume, attenuated neuronal loss and astrocyte activation in the ipsilateral thalamus 7 and 14 days after MCAO (all p < 0.05). Also, tongxinluo markedly increased the number of BrdU+/nestin+ and BrdU+/NeuN+ cells 14 days after MCAO. Moreover, vascular density, the number of BrdU+ vascular endothelial cells, and vascular perimeter in the ipsilateral thalamus were markedly increased in the tongxinluo group relative to that of the vehicle group (all p < 0.05). Conclusion: Administration of tongxinluo 24 h after cortical infarction may promote neurogenesis and angiogenesis in the ipsilateral thalamus and improves neurological function after cortical infarction in rats.
Changes in the gray matter volume during compensation after vestibular neuritis: A longitudinal VBM study
Authors: Hong Sung-Kwang , Kim Ja Hee , Kim Hyung-Jong , Lee Hyo-Jeong
Published: December 2019

Purpose: Peripheral vestibular dysfunction following vestibular neuritis (VN) often persists but functional recovery of balance can be variable. The authors compared structural changes in the brain before and after post-VN compensation and related it to the functional recovery. Methods: Nine patients diagnosed with unilateral VN were included. Brain MRI and clinical observation were performed within 2 days of acute VN diagnosis and were repeated 3 months after the first exam. Voxel-based morphometry (VBM) analysis for longitudinal data was performed using VBM8 toolbox running within SPM8. Changes in local grey matter volume (GMV) were examined using a paired t-test and clinical relevance was tested using correlation analyses with functional improvement. Results: Significant increases in GMV were observed in the vestibular cortex, bilateral hippocampus, visual cortices and the cerebellum. GMV decreased in cerebellar regions, including the vermis, and in the prefrontal cortex. Increases in GMV in visual cortices and cerebellum were associated with the poorest recovery of balance, which might be explained by functional substitution. Conclusions: The structural layout of vestibular compensation suggests that memory and motor planning are closely related to this process. Vision seems to be a major source of functional substitution, as has been previously demonstrated. This study, however, is the first longitudinal analysis of brain structural changes associated with recovery of balance following unilateral VN.
Altered expression of myelin-associated inhibitors and their receptors after traumatic brain injury in the mouse
Authors: Israelsson Charlotte , Flygt Johanna , Åstrand Elaine , Kiwanuka Olivia , Bengtsson Henrik , Marklund Niklas
Published: December 2019

Purpose: When central nervous system axons are injured, regeneration is partly inhibited by myelin-associated inhibitors (MAIs). Following traumatic brain injury (TBI) in the rat, pharmacological neutralisation of the MAIs Nogo-A and myelin-associated glycoprotein (MAG) resulted in improved functional outcome. In contrast, genetic or pharmacological neutralization of the MAI receptors Nogo-66 receptor 1 (NgR1) or paired-immunoglobulin like receptor-B (PirB) showed an unaltered or impaired outcome following TBI in mice. The aim of the present study was thus to evaluate the MAI expression levels following TBI in mice. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure total RNA isolated from brains of young adult male C57BL/6 mice at one, three or seven days following controlled cortical impact TBI or sham injury. Hippocampal and neocortical tissue ipsi- and contralateral to the injury was analyzed for Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), MAG, and the MAI receptors PirB and NgR1, including its co-receptor Lingo1. Results: Compared to sham-injured controls, PirB neocortical expression was significantly upregulated at one day and NgR1 expression downregulated at seven days post-TBI. In the hippocampus, transcriptional upregulation was observed in Nogo-A (one day post-injury), MAG and PirB at seven days post-injury. In contrast, the hippocampal transcripts of NgR1 and Lingo1 were decreased at seven days post-injury. The expression of OMgp was unaltered at all time points post-injury. Conclusion: These results suggest that early dynamic changes in MAI gene expression occur following TBI in the mouse, particularly in the hippocampus, which may play an inhibitory role for post-injury regeneration and plasticity.
Altered top-down cognitive control and auditory processing in tinnitus: evidences from auditory and visual spatial stroop
Authors: Araneda Rodrigo , De Volder Anne G. , Deggouj Naïma , Philippot Pierre , Heeren Alexandre , Lacroix Emilie , Decat Monique , Rombaux Philippe , Renier Laurent
Published: December 2019

Purpose: Tinnitus is the perception of a sound in the absence of external stimulus. Currently, the pathophysiology of tinnitus is not fully understood, but recent studies indicate that alterations in the brain involve non-auditory areas, including the prefrontal cortex. Here, we hypothesize that these brain alterations affect top-down cognitive control mechanisms that play a role in the regulation of sensations, emotions and attention resources. Methods: The efficiency of the executive control as well as simple reaction speed and processing speed were evaluated in tinnitus participants (TP) and matched control subjects (CS) in both the auditory and the visual modalities using a spatial Stroop paradigm. Results: TP were slower and less accurate than CS during both the auditory and the visual spatial Stroop tasks, while simple reaction speed and stimulus processing speed were affected in TP in the auditory modality only. Conclusions: Tinnitus is associated both with modality-specific deficits along the auditory processing system and an impairment of cognitive control mechanisms that are involved both in vision and audition (i.e. that are supra-modal). We postulate that this deficit in the top-down cognitive control is a key-factor in the development and maintenance of tinnitus and may also explain some of the cognitive difficulties reported by tinnitus sufferers.
The effects of 4-aminopyridine on focal nerve conduction block
Authors: Hsueh I.-H. , Toyoshima E. , Mayer R.F.
Published: December 2019

In order to test whether 4-aminopyridine (4-AP), a potassium channel blocker, may be of therapeutic value in demyelinating neuropathies, a focal tibial nerve conduction block with demyelination was produced in adult rats by an intraneural microinjection of potassium tellurite. Onset and recovery of the lesion were monitored by evoked compound muscle action potentials (CMAP) activated from the proximal and distal nerve one day before and 1, 4, 7, 14, 21 and 28 days after the injection. Intraperitoneal 4-AP (2 mg/kg) or buffered saline were injected prior to the potassium tellurite and 6 days per week for 28 days. The data show that 4-AP is tolerated, it does not prevent conduction block, and only has a modest effect on increasing its recovery from day 4 to 7 (91 % increase in CMAP ratio compared with control of 35%). Recovery is similar by day 28 in 4-AP treated or untreated animals. These results suggest that 4-AP will have limited use in the therapy of subacute demyelinating neuropathies.
Factors affecting septal graft amelioration of differential reinforcement of low rates (DRL) and activity deficits after fimbria-fornix lesions
Authors: Dunnett S.B. , Martel F.L. , Rogers D.C. , Finger S.
Published: December 2019

Wound-derived trophic factors released by the injured brain are thought to reach a peak 1–2 weeks after injury. It has been proposed that such factors can promote the survival, growth and functional capacity of embryonic tissue grafts. To test the generality of this hypothesis, control rats and rats with aspirative fimbria-fornix lesions were compared with 5 groups of rats with lesions and septal grafts implanted either in the same session as the lesion or after delays from 10 days to 9 months. Animals were assessed 3 months post-transplantation on an operant differential reinforcement of low rates (DRL) task and on a test of spontaneous locomotor activity. Lesions produced impairments on all measures of DRL performance. Two graft groups showed amelioration of the DRL deficits, one graft group was unchanged, and the deficits were exacerbated in two others. There was no clear relationship between lesion–graft interval and recovery. An inverse relationship was seen, however, between recovery and the developmental age of the donor tissue. In contrast, significant recovery from lesion-induced hyperactivity was observed in the two graft groups with tissue derived from the oldest embryos. There were no clear relationships between recovery on either test, lesion–graft interval, and AChE-positive reinnervation of the host brain. The results provide further evidence that septal grafts can reverse behavioural deficits induced by fimbria-fornix lesions under some conditions, but suggest that the timing of graft surgery may not be as important a factor as donor age in this model system.
Some hypotheses concerning axon regeneration
Authors: Wilson David L. , Perry G.W.
Published: December 2019

We review evidence related to several hypotheses concerning the mechanism of axon regeneration and present new data addressing one hypothesis. That one hypothesis concerns the signal that initiates changes in the cell bodies of neurons after axon damage. We identify a molecule that has a number of the properties expected of such a signal. We also review the hypothesis that induction of some genes is tightly correlated with nerve regeneration, and conclude that such a correlation is not so ‘tight’. Nevertheless, proteins whose rate of synthesis or transport is increased in some systems are good candidates for playing important roles in regrowth. A third hypothesis, that mammalian CNS neurons fail to regenerate because of a failure to induce growth-associated proteins, is probably not true. Growth-associated proteins appear to be induced, at least transiently, in some cases where regeneration is abortive. The state of the neuron undoubtedly is important in regeneration, but many neurons, even in the CNS, appear to be able to support axon regrowth given the proper environment. Thus, support seems stronger for the view that the environment at the site of damage (including surfaces and growth factors) determines whether significant regrowth occurs in most cases.
Insulin-like growth factor II gene expression: relationship to the development and regeneration of neuromuscular synapses
Authors: Ishii Douglas N.
Published: December 2019

The mechanisms responsible for the formation, loss, and regeneration of vertebrate synapses are still shrouded in mystery. Recent data suggesting that insulin-like growth factor II (IGF-II) may play a special role in the nervous system are reviewed. In particular, studies now show that the IGF-II gene is selectively expressed in a manner consistent with its involvement in the formation of the neural circuitry. The prenatal up-regulation and postnatal down-regulation of IGF-II transcripts in muscle are closely correlated with the prenatal accumulation and postnatal elimination, respectively, of polyneuronal innervation at the neuromuscular junction. Use and disuse of nerve and muscle can profoundly alter the developmental rate at which superfluous synapses are eliminated. Such alteration may result through modification of the rate at which postnatal down-regulation of IGF-II mRNA content occurs. Moreover, IGF-II mRNA content is correlated with the capacity of muscle to regenerate synapses. The IGF-II gene may be the first example of a gene which can regulate the development and turnover of vertebrate synapses.
Regeneration of the rat sciatic nerve in the silicone chamber model
Authors: Danielsen Nils
Published: December 2019

The silicone nerve regeneration chamber is a useful model to investigate the cellular and molecular events underlying successful regeneration in the peripheral nervous system. In this model a transected rat sciatic nerve with a 10-mm interstump gap, is repaired with a silicone chamber. The spatial-temporal sequence of regeneration in the silicone chamber has been examined in detail. The chamber rapidly becomes filled with fluid which contains neurotrophic activity for neurons in vitro. The second event to occur is the formation of a fibrin matrix connecting the two nerve stumps. This matrix is then invaded by cellular elements in the following order: perineurial-like cells, vasculature, Schwann cells, and axons. The silicone chamber model also allows manipulation of the regeneration process. Prefilling the chamber at the time of implantation with phosphate-buffered saline or dialyzed plasma stimulates nerve regeneration. Multiple injections into the chamber of a mixture containing laminin, testosterone, and ganglioside GM1 increase the size and the vascularization of the regenerate. Specially designed chambers divided into two compartments by a longitudinally inserted nitrocellulose strip have been used to examine the effects of substrate-bound trophic factors on nerve regeneration. Fibroblast growth factor containing chambers have an improved regeneration and vascularization as compared to controls.
Regeneration in vitro of axolotl peripheral and central axons
Authors: Tonge D. A. , Clarke J. D. W. , Hunter K. , Golding J.
Published: December 2019

Peripheral nerves and spinal cords of axolotls were maintained in organ culture for periods of up to 2 weeks. Sensory axons in peripheral nerves and the dorsal funiculus of the spinal cord showed regeneration through the crush site within about 2 days. Axonal regeneration also occurred in peripheral nerves after cutting but was dependent on close contact between proximal and distal stumps of nerve. When cells in the distal stump of nerve were killed by freezing, axonal regeneration was inhibited.
Nerve regeneration problems in a clinical perspective
Authors: Lundborg Göran
Published: December 2019

Injuries to peripheral nerves represent a challenging clinical problem. In spite of the use of microsurgical techniques, repair of severed nerves seldom results in complete recovery of motor and sensory functions. Misdirection of axons at the suture line as well as a slow axonal outgrowth contribute to the bad results. Recent experimental data indicate that growth factors, synthesized by the damaged nerve tissue as well as protein-associated neurite-promoting factors in the local micro-environment play an important role for the regulation of axonal growth and directionality. Future studies should aim at an application of this knowledge to the clinical treatment of nerve injuries.
Pulsed electromagnetic fields stimulate nerve regeneration in vitro and in vivo
Authors: Sisken Betty F. , Kanje Martin , Lundborg Göran , Kurtz Warren
Published: December 2019

The influence of non-invasive, low level, pulsed electromagnetic fields (PEMF) on regeneration was tested on in vitro and in vivo models. Cultures of dorsal root ganglia were exposed to 2 Hz PEMF, amplitude of 0.05 mTesla while rats after a ‘crush’ lesion of sciatic nerves were exposed to 2 Hz PEMF, amplitude of 0.3 mTesla. In in vitro experiments, relative to controls, cultures treated with PEMF exhibited a significant increase in neurite outgrowth with dense labeling of neurons and neurites on autoradiographs after incorporation of [3H]proline into new proteins. In vivo exposure of rats to PEMF for 3, 4 or 6 days after lesioning produced a 22% increase in the regeneration rate relative to controls with no effect on the initial delay period. When rats were exposed to PEMF before lesioning without further treatment, the same degree of stimulation of axonal sprouting was obtained. Reduction of the amplitude from 0.3 mTesla to 0.06 mTesla eliminated this pre-exposure response. Alterations in the distribution of new proteins synthesized 2 weeks after PEMF treatment provide additional evidence for its influence at the whole body and cellular levels.
Fetal tectal transplants in the cortex of adult rats become innervated both by retinal ganglion cell axons regenerating through peripheral nerve grafts and by cortical neurons
Authors: Thanos Solon , Vanselow Jens
Published: December 2019

The present work elucidates the connectivity of adult retinal ganglion cell axons regenerating through grafted peripheral nerve segments with co-grafted immature brain target cells. The optic nerve of rats was transected intraorbitally and its segment distal to the transection was replaced by a 3 cm length of peroneus communis graft, that is known to permit regeneration of a certain proportion of the severed axonal population. Five weeks after optic nerve transection and peripheral nerve transplantation the regenerating optic tract axons were guided into rat fetal mesencephalic co-grafts (E14–16) placed in superficial cavities prepared in the occipital cortex. The rationale of the experimental setup was based on the fact that regrowth of retinal axons started at the 6th day after transection, whereas the fastest-growing axons reached the distal end of the transplanted peripheral nerve 4 weeks later growing with a velocity of about 1.33 mm/day. Therefore, grafting the fetal superior colliculus at the time axons arrive distally resulted in ingrowth of several hundreds of retinal axons into this immature, retinoreceptive brain tissue. Retinal axons which penetrated the fetal grafts contacted tectal neurons and GFAP-immunoreactive glia and formed typical retinocollicular axonal arbors as detected by anterograde labeling with RITC from the retina. In addition, sprouting fibers from the adjacent adult cortical neurons penetrated frequently the fetal transplants. By ‘bridging’ lesions with peripheral nerve pieces and providing immature neurons as targets for growing neurites, this transplantation model is suitable for investigations on whether regenerating adult neurites are capable of reforming connections. The co-transplantation technique may serve as a tool for understanding whether interrupted circuitries in the central nervous system can be functionally restored over long distances by the use of peripheral nerve grafts and immature nervous system tissue.
Influence of needle lumen size on viability of injected dispersed and clumped foetal brain cells
Authors: Detta Allah , Hitchcock Edward
Published: December 2019

Foetal tissue from cortex, striatum, cerebellum and mesencephalon of human foetuses of gestational age 18 weeks have been examined for cell viability pre- and postpassage through needles of varying dimensions. Fully dispersed cells have less viability than cell clumps, but needle lumenar sizes employed in this study do not appear to have any significant influence on viability as measured by the vital staining method. There is a tendency of narrower needles to adversely affect viability of both dispersed and clumped cells; the vulnerability of component cells, i.e. neurones or glia has not been determined.
Modifications in the cytoskeleton transported by slow component A during axonal regeneration
Authors: Filliatreau Ghislaine , Hässig Raymonde , Di Giamberardino Luigi
Published: December 2019

We studied the modifications occurring in the parent cytoskeleton carried by SCa (the slower of the two slow axonal transport subcomponents) after peripheral nerve crush. The proteins transported in rat sciatic motor axons were radiolabelled by injecting [35S]methionine into the ventral horn of the spinal cord, and the nerve was crushed so as to entrap only the proteins transported by SCa along the parent axon. Two weeks after the crush, the regenerating nerve was removed and the distributions of the polymerized and unpolymerized radiolabelled cytoskeletal proteins were compared with those in normal, non-regenerating nerves. We found that in the parent axons, most of the radioactive neurofilaments were arrested by the crush, but microtubules, soluble tubulin, insoluble and soluble actin were normally transported. Thus, when the resulting cytoskeleton transported by SCa entered the daughter axon, it was enriched in microtubules and actin, and partially depleted of neurofilaments. This cytoskeleton contained larger proportions of soluble tubulin and insoluble actin than the parent cytoskeleton, but retained its coordinated progression and transport velocity, suggesting that after axotomy, the main destiny of the parent cytoskeleton carried by SCa is to become the equivalent cytoskeleton in the daughter axons.
Preliminary experiments in nerve regeneration through laser-drilled holes in silicon chips
Authors: Rosen Joseph M. , Grosser Morton , Hentz Vincent R.
Published: December 2019

Many of the present limitations of peripheral nerve repair might be overcome by performing nerve repairs at the axon level. One approach to nerve repair at this level would be to implant a neuroprosthesis in the form of a microelectronic switchboard which could route the connections of regenerated axons to their correct destinations. This requires a merger of microsurgery and microelectronics. Three steps are needed to achieve this goal. (1) The achievement of in vivo compatibility and electrical contact between axons and a material compatible with microelectronics. (2) The fabrication of a microelectronic neuroprosthesis with electrodes to establish communication with the axon. (3) The development of signal processing hardware and software to control the mapping of the regenerated axons. This report describes preliminary experiments in regenerating peripheral nerve axons through an electronic-grade silicon chip with laser-drilled holes small enough to capture either one or a few axons per hole. We have observed the viability of such nerves in 4 rats for 6 months to 1 year, and in two primates for more than 3 months. As our experiments show, this technique is not yet as effective as suture repair, but the development of a neuroprosthesis that communicates with peripheral nerve axons could have applications including nerve repair, neuroma, and nerve grafts, as well as interfacing the peripheral nervous system to prostheses of other kinds.
Effect of MPTP on primate chromaffin cells in vitro: relevance for adrenal medullary cell transplantation
Authors: Notter Mary F.D. , Kaniuki Marcello , Felten Suzanne Y. , Hansen John T. , Gash Don M.
Published: December 2019

Primate adrenal medullary cells were exposed to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in vitro to examine the effect of this neurotoxic agent on chromaffin cells. Chromaffin cells from monkey and humans were cultured in the presence of 100 ng/ml nerve growth factor for 1 week and then exposed to 150 μM MPTP or its active metabolite methylpyridinium ion (MPP+) for an additional week. Cells which had extended neurites in the presence of NGF showed no morphological effect in response to MPTP or MPP+ at the light microscopic level. However, there was a significant loss in catecholamines as seen by histofluorescence and high performance liquid chromotography (HPLC). Electron microscopy revealed a depletion in dense-core vesicles in chromaffin cells after chronic exposure to MPTP while the mitochondria appeared similar to those observed in control cells. Replacement of MPTP medium with standard medium stimulated restoration of catecholamine histofluorescence after 7 days. An acute 15 min pretreatment of chromaffin cells with MPTP or MPP+ induced secretion of catecholamines over a 1 h pulse, with MPP+ producing the maximum and more rapid secretion as determined by HPLC. These data indicate that MPTP induces a dramatic loss in catecholamines in primate chromaffin cells in vitro after both acute and chronic exposures; however, removal of the toxic agent permits restoration of catecholamines without permanent effect on the integrity of these cells.
Adverse effects of catecholaminergic drugs following unilateral cerebellar ablations
Authors: Boyeson Michael G. , Feeney Dennis M.
Published: December 2019

The following experiment was designed to examine the effects of unilateral cerebellar cortex lesions and pharmacological postinjury treatments with catecholamine drugs on recovery of beam walking ability in rats. Rats trained on a beam walking task were initially given either amphetamine, haloperidol, or a combination of the drugs at 24 h after injury, and tested at various intervals after drug administration. Six total doses were given to animals at 5d intervals during recovery. All drugs retarded recovery of function on the beam walking task compared to saline controls. Animals with cortical lesions that involved the deep cerebellar nuclei showed no recovery on the beam, regardless of group assignment. Phenoxybenzamine and propranalol were both ineffective in reinstating the beam walking deficit in those animals that demonstrated recovery on the beam walking task. The results indicate that the cerebellum plays a particularly important role in recovery of beam walking ability, and may contribute to beam walking recovery commonly observed after sensorimotor cortex ablations.