La fatiga en el daño cerebral sobrevenido / Fatigue in patients with acquired brain damage

La fatiga es un síndrome multidimensional, complejo y frecuente en los pacientes con daño cerebral sobrevenido, influyendo negativamente en el proceso de neurorrehabilitación. Aparece desde etapas tempranas luego de la lesión y puede permanecer en el tiempo, recuperadas o no las secuelas del daño. La fatiga depende de circuitos neuronales superiores y se define como una percepción anómala de sobreesfuerzo. Tiene una prevalencia de 29% a 77% tras el ictus, 18% a 75% tras el traumatismo craneoencefálico (TCE) y 47% a 97% tras tumores cerebrales. La fatiga se asocia a factores como sexo femenino, edad avanzada, familia disfuncional, antecedentes patológicos específicos, estado funcional (p. ej. fatiga previa a la lesión), comorbilidades, estado anímico, discapacidad secundaria y uso de ciertos fármacos. Su estudio se realiza sobre todo a partir de escalas como la Escala de severidad de fatiga (Fatigue Severity Scale). Hoy en día existen avances en herramientas de imagen para su diagnóstico como la resonancia magnética funcional. En cuanto a su tratamiento, no existe aún terapia farmacológica definitiva, sin embargo, existen resultados positivos con terapias dentro de la neurorrehabilitación convencional, terapia lumínica y el uso del neurofeedback, estimulación eléctrica y magnética transcraneal. Esta revisión tiene como objetivo ayudar al profesional dedicado a la neurorrehabilitación a reconocer factores asociados modificables, así como terapias a su alcance para disminuir sus efectos nocivos en el paciente. (AU)

Fatigue is a complex, multidimensional syndrome that is prevalent in patients with acquired brain damage and has a negative impact on the neurorehabilitation process. It presents from early stages after the injury, and may persist over time, regardless of whether sequelae have resolved. Fatigue is conditioned by upper neuronal circuits, and is defined as an abnormal perception of overexertion. Its prevalence ranges from 29% to 77% after stroke, from 18% to 75% after traumatic brain injury, and from 47% to 97% after brain tumours. Fatigue is associated with factors including female sex, advanced age, dysfunctional families, history of specific health conditions, functional status (eg, fatigue prior to injury), comorbidities, mood, secondary disability, and the use of certain drugs. Assessment of fatigue is fundamentally based on such scales as the Fatigue Severity Scale (FSS). Advances have recently been made in imaging techniques for its diagnosis, such as in functional MRI. Regarding treatment, no specific pharmacological treatment currently exists; however, positive results have been reported for some conventional neurorehabilitation therapies, such as bright light therapy, neurofeedback, electrical stimulation, and transcranial magnetic stimulation. This review aims to assist neurorehabilitation professionals to recognise modifiable factors associated with fatigue and to describe the treatments available to reduce its negative effect on patients. (AU)

Fatigue in patients with acquired brain damage.

Fatigue is a complex, multidimensional syndrome that is prevalent in patients with acquired brain damage and has a negative impact on the neurorehabilitation process. It presents from early stages after the injury, and may persist over time, regardless of whether sequelae have resolved. Fatigue is conditioned by upper neuronal circuits, and is defined as an abnormal perception of overexertion. Its prevalence ranges from 29% to 77% after stroke, from 18% to 75% after traumatic brain injury, and from 47% to 97% after brain tumours. Fatigue is associated with factors including female sex, advanced age, dysfunctional families, history of specific health conditions, functional status (eg, fatigue prior to injury), comorbidities, mood, secondary disability, and the use of certain drugs. Assessment of fatigue is fundamentally based on such scales as the Fatigue Severity Scale (FSS). Advances have recently been made in imaging techniques for its diagnosis, such as in functional MRI. Regarding treatment, no specific pharmacological treatment currently exists; however, positive results have been reported for some conventional neurorehabilitation therapies, such as bright light therapy, neurofeedback, electrical stimulation, and transcranial magnetic stimulation. This review aims to assist neurorehabilitation professionals to recognise modifiable factors associated with fatigue and to describe the treatments available to reduce its negative effect on patients.

Forms of extramural research acquisition and product innovation: Data from econometric estimations.

This Data article provides a collection of Data and econometric estimates of the relationship between various forms of external research and Development (R&D) acquisition and product innovation. Specifically, the Data are elaborations on Eurostat (2015) and the EFIGE (2015) survey. Data relate to research acquired by external firms inside the group to which a company belongs, universities and research centres, and other companies. The Data presented here are additional information and analysis to the article of Carboni and Medda [1]. Data derive from econometric applications on the information contained in a survey of 13,621 European manufacturing firms. The econometric framework considers: (1) Potential non-linear effects of the age of firms on product innovation; (2) Geographical variation of innovative activity by the inclusion of 137 regional dummies (NUTS-2-level); (3) Intersectoral differences by the inclusion of 117 industrial dummies (3-digit NACE). We employ systems of equations regressions to take simultaneity end endogeneity into account. For this purpose, the model identification is accomplished through the use of a reduced form equation for R&D with two instrumental variables (IV) aimed at capturing regional technological environment. Specifically, we use an instrumental variable framework to compute the impact of external research on (1) the probability of implementing product innovations and (2) the market success of product innovations. The latter is measured by the share of total turnover of innovative products sales. Special focus is put on the potential role of the regional technological environment. For the computations we used the cmp command in STATA, which builds upon the maximum simulated likelihood analysis. The models are also estimated using the fractional response technique to check the 0-100% bounded nature of this variable. The Data presented here can be useful for companies to better design R&D strategies aimed at improving firms' organization, synergies, and growth. This may help strategic decision making, and a more efficient coordination of the complex process of production. Data are also useful for policy makers for designing public R&D schemes, both at the national and at the European level. Finally, the Data represent a useful starting point for future research concerning the proprietary structure of the firm and the workforce, innovation and R&D, internationalization, finance, and market.

Fatigue in patients with acquired brain damage. / La fatiga en el daño cerebral sobrevenido.

Fatigue is a complex, multidimensional syndrome that is prevalent in patients with acquired brain damage and has a negative impact on the neurorehabilitation process. It presents from early stages after the injury, and may persist over time, regardless of whether sequelae have resolved. Fatigue is conditioned by upper neuronal circuits, and is defined as an abnormal perception of overexertion. Its prevalence ranges from 29% to 77% after stroke, from 18% to 75% after traumatic brain injury, and from 47% to 97% after brain tumours. Fatigue is associated with factors including female sex, advanced age, dysfunctional families, history of specific health conditions, functional status (eg, fatigue prior to injury), comorbidities, mood, secondary disability, and the use of certain drugs. Assessment of fatigue is fundamentally based on such scales as the Fatigue Severity Scale (FSS). Advances have recently been made in imaging techniques for its diagnosis, such as in functional MRI. Regarding treatment, no specific pharmacological treatment currently exists; however, positive results have been reported for some conventional neurorehabilitation therapies, such as bright light therapy, neurofeedback, electrical stimulation, and transcranial magnetic stimulation. This review aims to assist neurorehabilitation professionals to recognise modifiable factors associated with fatigue and to describe the treatments available to reduce its negative effect on patients.

Cognitive performance of people with traumatic spinal cord injury: a cross-sectional study comparing people with subacute and chronic injuries.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To assess the impact of spinal cord injury (SCI) on cognitive function in individuals with subacute and chronic SCI. SETTING: National Hospital for SCI patients (Spain). METHODS: The present investigation was designed to determine the nature, pattern, and extent of cognitive deficits in a group of participants with subacute (n = 32) and chronic (n = 34) SCI, using a comprehensive battery of reliable and validated neuropsychological assessments to study a broad range of cognitive functions. Twenty-seven able-bodied subjects matched to the groups with SCI for age and educational level formed the control group. RESULTS: The neuropsychological assessment showed alterations in the domain of attention, processing speed, memory and learning, executive functions, and in recognition in participants with SCI. The prevalence of cognitive dysfunction in the chronic stage was also confirmed at the individual level. The comparison of the neuropsychological assessment between the groups with subacute and chronic SCI showed a worsening of cognitive functions in those with chronic SCI compared to the group with subacute SCI. CONCLUSIONS: In participants with SCI, cognitive dysfunctions are present in the subacute stage and worsen over time. From a clinical point of view, we confirmed the presence of cognitive dysfunction that may interfere with the first stage of rehabilitation which is the most intense and important. Moreover, cognitive dysfunction may be important beyond the end of the first stage of rehabilitation as it can affect an individual's quality of life and possible integration to society.

Dopamine-dependent changes of cortical excitability induced by transcranial static magnetic field stimulation in Parkinson's disease.

Transcranial static magnetic field stimulation (tSMS) is a recent low-cost non-invasive brain stimulation technique that decreases cortical excitability in healthy subjects. The objective of the present study was to test the ability of tSMS to modulate cortical excitability in patients with Parkinson's disease. We performed a randomized double-blind sham-controlled cross-over study to assess cortical excitability before and immediately after tSMS (or sham) applied for 10 min to the more affected motor cortex of patients with Parkinson's disease. Cortical excitability was quantified by the amplitude of motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation (TMS). tSMS significantly decreased MEP amplitudes in patients OFF medication (after overnight withdrawal of dopaminergic drugs), but not ON medication (after an acute dose of levodopa). The between-patients variability of tSMS-induced changes was significantly greater ON medication. The variability ON medication could be partly explained by disease progression, i.e. the more advanced the patient, the more likely it was to observe a switch from inhibitory tSMS plasticity OFF medication to paradoxical facilitatory plasticity ON medication. These results suggest that tSMS induces dopamine-dependent changes of cortical excitability in patients with Parkinson's disease.

Early spermatogenesis changes in traumatic complete spinal cord-injured adult patients.

STUDY DESIGN: Prospective longitudinal study. OBJECTIVES: To assess the impact of spinal cord injury (SCI) on the spermatogenesis of patients studied in the early subacute stage and ensuing months. SETTING: National hospital for SCI patients. METHODS: A prospective follow-up study was conducted on 28 male patients with complete SCI who were evaluated in the early subacute phase (~1 month), and 3 and 6 months after the injury. At each time point, fine needle aspiration biopsy samples were taken from the testes for cytological assessment, and serum levels of relevant hormones were measured. At the end of the study period, ejaculation was attempted for standard semen analyses. RESULTS: Cytological patterns indicative of defective spermatogenesis were found in 61%, 52% and 20% of the patients at 1, 3 and 6 months after SCI, respectively, suggesting an improvement over time. Serum hormone analyses showed a steady elevation of estradiol levels above the reference range, and increasing levels of testosterone, inhibin B and prolactin throughout the study period. Prolactin levels were above the reference range at all time points. Only 2 out of the 10 patients who were able to ejaculate at 6 months post injury showed normal sperm parameters. CONCLUSION: A majority of the patients showed impaired spermatogenesis soon after the injury, which in most cases recovered over time. That was accompanied by parallel increases in serum levels of inhibin B, testosterone and prolactin, possibly driving or reflecting the spermatogenesis recovery. Further studies are needed to elucidate the biological mechanisms underlying these changes.

Central fatigue induced by short-lasting finger tapping and isometric tasks: A study of silent periods evoked at spinal and supraspinal levels.

The neural substrates of fatigue induced by muscular activity have been addressed in depth in relation to isometric tasks. For these activities, when fatigue develops, it has been noted that the duration of the silent periods (SPs) increases in response to both transcranial magnetic stimulation (TMS) of primary motor cortex or electric cervicomedullary stimulation (CMS). However, fatigue is known to be task-dependent and the mechanisms giving rise to a decrease in motor performance during brief, fast repetitive tasks have been less studied. We hypothesized that fatigue induced by repetitive fast finger tapping may have physiological mechanisms different from those accounting for fatigue during an isometric contraction, even in cases of matched effort durations. In these tasks, we examined the contribution of spinal and supraspinal motor circuits to the production of fatigue. The tapping rate and maximal voluntary contractions (MVC), and TMS- and CMS-evoked SPs were obtained at the time of fatigue, and while subjects maintained maximal muscle activation after fast finger-tapping (or isometric activity) of different durations (10 or 30s). Results showed different mechanisms of fatigue triggered by isometric contraction and repetitive movements, even of short duration. Short-lasting repetitive movements induce fatigue within intracortical inhibitory circuits. They increased TMS-SPs, but not CMS-SPs. On the other hand, isometric contraction had a clear impact on spinal circuits. The consideration of these differences might help to optimize the study of fatigue in physiological conditions and neurological disorders.

Safety Study of Transcranial Static Magnetic Field Stimulation (tSMS) of the Human Cortex.

BACKGROUND: Transcranial static magnetic field stimulation (tSMS) in humans reduces cortical excitability. OBJECTIVE: The objective of this study was to determine if prolonged tSMS (2 h) could be delivered safely in humans. Safety limits for this technique have not been described. METHODS: tSMS was applied for 2 h with a cylindric magnet on the occiput of 17 healthy subjects. We assessed tSMS-related safety aspects at tissue level by measuring levels of neuron-specific enolase (NSE, a marker of neuronal damage) and S100 (a marker of glial reactivity and damage). We also included an evaluation of cognitive side effects by using a battery of visuomotor and cognitive tests. RESULTS: tSMS did not induce any significant increase in NSE or S100. No cognitive alteration was detected. CONCLUSIONS: Our data indicate that the application of tSMS is safe in healthy human subjects, at least within these parameters.

Cortical reorganization after spinal cord injury: always for good?

Plasticity constitutes the basis of behavioral changes as a result of experience. It refers to neural network shaping and re-shaping at the global level and to synaptic contacts remodeling at the local level, either during learning or memory encoding, or as a result of acute or chronic pathological conditions. 'Plastic' brain reorganization after central nervous system lesions has a pivotal role in the recovery and rehabilitation of sensory and motor dysfunction, but can also be "maladaptive". Moreover, it is clear that brain reorganization is not a "static" phenomenon but rather a very dynamic process. Spinal cord injury immediately initiates a change in brain state and starts cortical reorganization. In the long term, the impact of injury - with or without accompanying therapy - on the brain is a complex balance between supraspinal reorganization and spinal recovery. The degree of cortical reorganization after spinal cord injury is highly variable, and can range from no reorganization (i.e. "silencing") to massive cortical remapping. This variability critically depends on the species, the age of the animal when the injury occurs, the time after the injury has occurred, and the behavioral activity and possible therapy regimes after the injury. We will briefly discuss these dependencies, trying to highlight their translational value. Overall, it is not only necessary to better understand how the brain can reorganize after injury with or without therapy, it is also necessary to clarify when and why brain reorganization can be either "good" or "bad" in terms of its clinical consequences. This information is critical in order to develop and optimize cost-effective therapies to maximize functional recovery while minimizing maladaptive states after spinal cord injury.

A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee.

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS.

I-wave origin and modulation.

The human motor cortex can be activated by transcranial magnetic stimulation (TMS) evoking a high-frequency repetitive discharge of corticospinal neurones. The exact physiologic mechanisms producing the corticospinal activity still remain unclear because of the complexity of the interactions between the currents induced in the brain and the circuits of cerebral cortex, composed of multiple excitatory and inhibitory neurons and axons of different size, location, orientation and function. The aim of current paper is to evaluate whether the main characteristics of the activity evoked by single- and paired-pulse and repetitive TMS, can be accounted by the interaction of the induced currents in the brain with the key anatomic features of a simple cortical circuit composed of the superficial population of excitatory pyramidal neurons of layers II and III, the large pyramidal neurons in layer V, and the inhibitory GABA cells. This circuit represents the minimum architecture necessary for capturing the most essential cortical input-output operations of neocortex. The interaction between the induced currents in the brain and this simple model of cortical circuitry might explain the characteristics and nature of the repetitive discharge evoked by TMS, including its regular and rhythmic nature and its dose-dependency and pharmacologic modulation. The integrative properties of the circuit also provide a good framework for the interpretation of the changes in the cortical output produced by paired and repetitive TMS.

CB1 receptor antagonism/inverse agonism increases motor system excitability in humans.

CB1 receptor is highly expressed in cerebral structures related to motor control, such as motor cortex, basal ganglia and cerebellum. In the spinal cord, the expression of CB1 receptors has also been observed in ventral motor neurons, interneurons and primary afferents, i.e., in the cells that may be part of the circuits involved in motor control. It is known that the antagonist/inverse agonist of CB1 receptors Rimonabant penetrates the blood-brain barrier and produces a broad range of central psychoactive effects in humans. Based on the occurrence of central effects in humans treated with Rimonabant and on the location of CB1 receptors, we hypothesized that the application of Rimonabant can also affect the motor system. We tested the effects of a single dose of 20mg of Rimonabant on the excitability of motor cortex and of spinal motor neurons in order to detect a possible drug action on motor system at cortical and spinal levels. For this purpose we use classical protocols of transcranial magnetic and electrical stimulation (TMS and TES). Single and paired pulse TMS and TES were used to assess a number of parameters of cortical inhibition and cortical excitability as well as of the excitability of spinal motor neurons. We demonstrated that a single oral dose of 20mg of Rimonabant can increase motor system excitability at cortical and spinal levels. This opens new avenues to test the CB1R antagonists/inverse agonists for the treatment of a number of neurological dysfunctions in which can be useful to increase the excitability levels of motor system. Virtually all the disorders characterized by a reduced output of the motor cortex can be included in the list of the disorders that can be treated using CB1 antagonists/reverse agonists (e.g. stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, fatigue syndromes, parkinsonisms, etc.).

Spinal direct current stimulation modulates the activity of gracile nucleus and primary somatosensory cortex in anaesthetized rats.

Afferent somatosensory activity from the spinal cord has a profound impact on the activity of the brain. Here we investigated the effects of spinal stimulation using direct current, delivered at the thoracic level, on the spontaneous activity and on the somatosensory evoked potentials of the gracile nucleus, which is the main entry point for hindpaw somatosensory signals reaching the brain from the dorsal columns, and of the primary somatosensory cortex in anaesthetized rats. Anodal spinal direct current stimulation (sDCS) increased the spontaneous activity and decreased the amplitude of evoked responses in the gracile nucleus, whereas cathodal sDCS produced the opposite effects. At the level of the primary somatosensory cortex, the changes in spontaneous activity induced by sDCS were consistent with the effects observed in the gracile nucleus, but the changes in cortical evoked responses were more variable and state dependent. Therefore, sDCS can modulate in a polarity-specific manner the supraspinal activity of the somatosensory system, offering a versatile bottom-up neuromodulation technique that could potentially be useful in a number of clinical applications.

Spinal cord injury immediately decreases anesthetic requirements in rats.

STUDY DESIGN: Pharmacologically blocking the spinal cord produces sedative effects and reduces anesthesia requirements in patients and animals. Whether spinal cord injury also reduces anesthesia requirements remains unclear. METHODS: We retrospectively analyzed data from urethane-anesthetized rats (15) to assess anesthesia requirements immediately after complete thoracic transection of the spinal cord. The depth of anesthesia was monitored up to 12 h after spinal transection by the reflexes to noxious stimuli and by electrophysiological recordings from the infragranular layers of the primary somatosensory cortex. Whenever animals displayed electrophysiological and/or behavioral signs of activation, we delivered an additional dose of anesthesia. Anesthetic requirements in animals receiving spinal transection (n=11) were compared with control animals receiving 'sham' lesion (n=9). RESULTS: The cumulative dose necessary to maintain a stable level of anesthesia was significantly lower in transected animals compared with control animals. By about 7 h after spinal cord injury, on average the cumulative dose of urethane was only 1.13±0.14 of the original dose, compared with 1.64±0.19 of the original dose in control animals. CONCLUSIONS: Spinal transection immediately decreased anesthetic requirements in rats. To establish whether these results are relevant for patients with spinal cord injury will require further investigation.

Studying plasticity of sensory function: insight from pregnancy.

Plasticity of sensory function has become an object of study because of its proposed role in the recovery of function after central nervous system damage. Normal pregnancy may provide a useful in vivo model to study the effects of progressive reduction in the abdominal skin receptor density. As such changes are confined to abdominal skin, other parts of the body are only moderately affected by pregnancy and therefore can provide a control for other changes during pregnancy. The two-point discrimination test (TPDT) of the skin is a simple test of the sensory function. We conducted the TPDT in a pregnant population longitudinally studied at different pregnancy stages and in different skin regions. In this pregnant population, we found a reduction in sensory sensibility that was not skin region specific. In particular, the increase in abdominal circumference did not produce different effects of TPDT on the belly compared to the dorsum or the hand. This suggests that the sensory system is able to compensate for the reduction in peripheral information flow through central nervous system plasticity.

The effects of motor cortex rTMS on corticospinal descending activity.

Repetitive transcranial magnetic stimulation (rTMS) of the human motor cortex can produce long-lasting changes in the excitability of the motor cortex to single pulse transcranial magnetic stimulation (TMS). rTMS may increase or decrease motor cortical excitability depending critically on the characteristics of the stimulation protocol. However, it is still poorly defined which mechanisms and central motor circuits contribute to these rTMS induced long-lasting excitability changes. We have had the opportunity to perform a series of direct recordings of the corticospinal volley evoked by single pulse TMS from the epidural space of conscious patients with chronically implanted spinal electrodes before and after several protocols of rTMS that increase or decrease brain excitability. These recordings provided insight into the physiological basis of the effects of rTMS and the specific motor cortical circuits involved.