Follow-up after 5.5 years of treatment with methylphenidate for mental fatigue and cognitive function after a mild traumatic brain injury.

Objective: Prolonged mental fatigue and cognitive impairments are common after a mild traumatic brain injury (TBI). This sets limits for rehabilitation and for regaining the capacity for work and participation in social life.Method: This follow-up study, over a period of approximately 5.5 years was designed to evaluate the effect and safety of methylphenidate treatment for mental fatigue after a mild TBI. A comparison was made between those who had continued, and those who had discontinued the treatment. The effect was also evaluated after a four-week treatment break.Results: Significant improvement in mental fatigue, depression, and anxiety for the group treated with methylphenidate (p < .001) was found, while no significant change was found for the group without methylphenidate. The methylphenidate treatment group also improved their processing speed (p = .008). Withdrawal produced a pronounced and significant deterioration in mental fatigue, depression, and anxiety and a slower processing speed. This indicates that the methylphenidate effect is reversible if discontinued and that continued methylphenidate treatment can be a prerequisite for long-term improvement. The effect was found to be stable and safe over the years.Conclusion: We suggest methylphenidate to be a possible treatment option for patients with post-TBI symptoms including mental fatigue and cognitive symptoms.

Effect of the monoaminergic stabiliser (-)-OSU6162 on mental fatigue following stroke or traumatic brain injury.

OBJECTIVE: The purpose of the present study was to evaluate the efficacy and safety of (-)-OSU6162 in doses up to 30 mg b.i.d. in patients suffering from mental fatigue following stroke or traumatic brain injury (TBI). METHODS: This 4 + 4 weeks double-blind randomised cross-over study included 30 patients afflicted with mental fatigue following a stroke or head trauma occurring at least 12 months earlier. Efficacy was assessed using the Mental Fatigue Scale (MFS), the Self-rating Scale for Affective Syndromes [Comprehensive Psychopathological Rating Scale (CPRS)], the Frenchay Activity Index (FAI), and a battery of neuropsychological tests. Safety was evaluated by recording spontaneously reported adverse events (AEs). RESULTS: There were significant differences on the patients' total FAI scores (p = 0.0097), the subscale FAI outdoor scores (p = 0.0243), and on the trail making test (TMT-B) (p = 0.0325) in favour of (-)-OSU6162 treatment. Principal component analysis showed a clear overall positive treatment effect in 10 of 28 patients; those who responded best to treatment had their greatest improvements on the MFS. Reported AEs were mild or moderate in severity and did not differ between the (-)-OSU6162 and the placebo period. CONCLUSION: The most obvious beneficial effects of (-)-OSU6162 were on the patients' activity level, illustrated by the improvement on the FAI scale. Moreover, a subgroup of patients showed substantial improvements on the MFS. Based on these observed therapeutic effects, in conjunction with the good tolerability of (-)-OSU6162, this compound may offer promise for treating at least part of the symptomatology in patients suffering from stroke- or TBI-induced mental fatigue.

Anti-inflammatory effects induced by pharmaceutical substances on inflammatory active brain astrocytes-promising treatment of neuroinflammation.

BACKGROUND: Pharmaceutical treatment with probable anti-inflammatory substances that attack cells in various ways including receptors, ion channels, or transporter systems may slow down the progression of inflammatory conditions. Astrocytes and microglia are the most prominent target cells for inflammation in the central nervous system. Their responses upon inflammatory stimuli work through the NO/cyclic GMP/protein kinase G systems that can downregulate the ATP-induced Ca2+ signaling, as well as G protein activities which alter Na+ transporters including Na+/K+-ATPase pump activity, Toll-like receptor 4 (TLR4), glutamate-induced Ca2+ signaling, and release of pro-inflammatory cytokines. The rationale for this project was to investigate a combination of pharmaceutical substances influencing the NO and the Gi/Gs activations of inflammatory reactive cells in order to make the cells return into a more physiological state. The ATP-evoked Ca2+ signaling is important maybe due to increased ATP release and subsequent activation of purinergic receptors. A balance between intercellular Ca2+ signaling through gap junctions and extracellular signaling mediated by extracellular ATP may be important for physiological function. METHODS: Astrocytes in primary cultures were incubated with lipopolysaccharide in a physiological glucose concentration for 24 h to induce inflammatory reactivity. The probable anti-inflammatory substances sildenafil and 1α,25-Dihydroxyvitamin D3 together with endomorphin-1, naloxone, and levetiracetam, were used in the presence of high glucose concentration in the medium to restore the cells. Glutamate-, 5-HT-, and ATP-evoked intracellular Ca2+ release, Na+/K+-ATPase expression, expression of inflammatory receptors, and release of tumor necrosis factor alpha were measured. RESULTS: Sildenafil in ultralow concentration together with 1α,25-Dihydroxyvitamin D3 showed most prominent effects on the ATP-evoked intracellular Ca2+ release. The µ-opioid agonist endomorphin-1, the µ-opioid antagonist naloxone in ultralow concentration, and the antiepileptic agent levetiracetam downregulated the glutamate-evoked intracellular Ca2+ release and TLR4. The combination of the pharmaceutical substances in high glucose concentration downregulated the glutamate- and ATP-evoked Ca2+ signaling and the TLR4 expression and upregulated the Na+/K+-ATPase pump. CONCLUSION: Pharmaceutical treatment with the combination of substances that have potential anti-inflammatory effects, which attack different biochemical mechanisms in the cells may exert decisive effects to downregulate neuroinflammation in the nervous system.

Assessment and treatment of mental fatigue after a traumatic brain injury.

Mental fatigue is a frequently occurring symptom after mild, moderate or severe traumatic brain injury (TBI). Such mental fatigue may become a long-lasting problem, irrespective of severity and even after recovery from other neurological or psychiatric symptoms. Two characteristics of this mental fatigue are that patients easily become exhausted and there is generally a long recovery time. There is a need to increase knowledge and awareness of mental fatigue as it interferes considerably with work, studies, and social activities. Assessment is difficult and few treatment studies have been carried out. For the purposes of assessment, the development of the Mental Fatigue Scale is described here, and we also summarise the few treatment studies found for fatigue after TBI. Symptom alleviation is reported through Mindfulness-Based Stress Reduction (MBSR), light therapy and for the psychostimulant methylphenidate and the dopamine stabiliser (-)-OSU6162. However, more knowledge of the origin of mental fatigue and its underlying mechanisms is needed for development of more efficient therapeutic methods. Prospective randomised trials focusing on long-term outcomes are warranted and should include both pharmacological and non-pharmacological treatments.

Microglial self-defence mediated through GLT-1 and glutathione.

Glutamate is stored in synaptic vesicles in presynaptic neurons. It is released into the synaptic cleft to provide signalling to postsynaptic neurons. Normally, the astroglial glutamate transporters GLT-1 and GLAST take up glutamate to mediate a high signal-to-noise ratio in the synaptic signalling, and also to prevent excitotoxic effects by glutamate. In astrocytes, glutamate is transformed into glutamine, which is safely transported back to neurons. However, in pathological conditions, such as an ischemia or virus infection, astroglial transporters are down-regulated which could lead to excitotoxicity. Lately, it was shown that even microglia can express glutamate transporters during pathological events. Microglia have two systems for glutamate transport: GLT-1 for transport into the cells and the x (c) (-) system for transport out of the cells. We here review results from our work and others, which demonstrate that microglia in culture express GLT-1, but not GLAST, and transport glutamate from the extracellular space. We also show that TNF-α can induce increased microglial GLT-1 expression, possibly associating the expression with inflammatory systems. Furthermore, glutamate taken up through GLT-1 may be used for direct incorporation into glutathione and to fuel the intracellular glutamate pool to allow cystine uptake through the x (c) (-) system. This can lead to a defence against oxidative stress and have an antiviral function.

[Mental fatigue - possible explanations, diagnostic methods and possible treatments]. / Hjärntrötthet ­ ett osynligt gissel.

Mental fatigue or brain fatigue is a pathological and disabling symptom with diminished mental energy. It can be a long-lasting consequence after trauma or disease affecting the brain. The person can do most things in the moment and can be perceived as completely healthy, but the mental energy is insufficient over time and affects the ability to work and participate in social activities. After a conversation, for example, the person can be completely drained of energy and the recovery time is disproportionally long. Here we describe the phenomenon of mental fatigue, provide an explanatory model for how the condition can arise, point out diagnostic methods and possible treatments, which are currently in the research stage but may be implemented in healthcare within the foreseeable future.

Long-Lasting Pathological Mental Fatigue After Brain Injury-A Dysfunction in Glutamate Neurotransmission?

Long-lasting mental or cognitive fatigue may be a disabling symptom after physically recovered skull trauma, stroke, infection, or inflammation in the central nervous system (CNS). It is difficult to go back to work and participate in familiar social activities, as typically the person is only able to remain mentally active for short periods, and if mentally exhausted, the recovery time will be disproportionally long. Mental fatigue after traumatic brain injury correlates with brain information processing speed. Information processing is energy consuming and requires widespread and specific neural signaling. Glutamate signaling is essential for information processing, including learning and memory. Low levels and the fine-tuning of extracellular glutamate are necessary to maintain a high precision in information processing. The astroglial cells are responsible for the fine-tuning of the glutamate transmission, but this capacity is attenuated by substances or conditions associated with neuro-inflammation in brain pathology. In this paper, we extend our previously presented hypothesis on the cellular mechanisms underlying mental fatigue suggesting a dysfunction in the astroglial support of the glutamate transmission. Changes in other neurotransmitters such as dopamine, serotonin, norepinephrine, GABA, and acetylcholine after brain injury are also taken into consideration.

Primary cultures from cerebral cortex and hippocampus enriched in glutamatergic and GABAergic neurons.

The aim was to define a primary culture system enriched in neurons using a defined culture medium, and characterize the model system as to cellular morphology and neuronal phenotypes. We found that these primary neuron enriched cultures from either newborn rat cerebral cortex or hippocampus contain small GABAergic and large glutamatergic neurons as well as astrocytes and microglia. Astrocytes in these cultures are morphologically differentiated with long, slender processes and interact with soluble factors responsible for induction and expression of the glutamate transporter GLT-1. The cultures achieve the highest expression of the vesicular glutamate transporter 1 (VGLUT1) and GLT-1 after 20 days in vitro. Conditioned media from these neuron enriched cultures also induced GLT-1 expression in primary astrocytic cultures, which were free from neurons. The amount of glutamatergic neurons guides the morphological maturation of astrocytes and GLT-1 expression both in the neuron enriched cultures and in the conditioned media supplemented astrocytic cultures. Interestingly, these cultures were not influenced or activated by the inflammatory stimulus lipopolysaccharide. This suggests that soluble factors from neurons protect microglia and astrocytes to become inflammatory reactive. In conclusion we have developed a well characterized culture model system enriched in neurons, taken from newborn rats and cultured in defined media. The neurons express different neuronal phenotypes. Such a model system is valuable when studying interactions between neurons and glial cells.

A self-assessment questionnaire for mental fatigue and related symptoms after neurological disorders and injuries.

PRIMARY OBJECTIVE: The purpose was to evaluate a new self-reporting scale for assessment of mental fatigue and its usefulness in describing mental fatigue after neurological diseases and injuries. Mental fatigue is suggested to comprise a spectrum of items including sensory, emotional and cognitive symptoms. METHODS AND PROCEDURES: Mental fatigue and related symptoms were measured with a self-assessment scale on different diagnostic groups with neurological injuries and diseases as well as healthy controls. The scale covers sleep, sensory, emotional and cognitive domains, mental recovery and 24-hour variation. RESULTS: There were significant correlations between all the questions in the self-assessing scale and also a high internal consistency among items (Cronbach's alpha of 0.944). Despite the different aetiologies of mental fatigue and related symptoms, the individuals rated the questions in a similar way. The total sum of scores, as well as the separate questions showed significantly lower values for healthy controls compared to mental fatigue groups. CONCLUSION: In spite of the different aetiology of mental fatigue, the items included in the scale were significant for different diseases with co-occurring mental fatigue. The self-reported scale is suggested to be a valuable tool for assessment of mental fatigue in different diagnoses.

Evidence of Construct Validity for the Modified Mental Fatigue Scale When Used in Persons with Cerebral Palsy.

Introduction: Fatigue impacts negatively on everyday activities in individuals with cerebral palsy (CP). More knowledge is needed about how mental fatigue is manifested in this target group. The purpose of this study was to gather evidence about the validity of the modified Mental Fatigue Scale (m-MFS) in adults with CP.Methods: Mixed sequential exploratory design. The respondents were ten persons aged 22-56 with CP (MACS I-II).Results: The respondents perceived the m-MFS as easy to read and understand. Its structure was characterised as straightforward and the text of the rating options was deemed to assist identification with life situations. Very good agreement was seen between the respondents' and the instrument designers' intended meaning for the items in the m-MFS; the weighted kappa was 0.92.Conclusion: This study showed evidence of construct validity, based on response processes and content, for use of the modified MFS in adults with CP.

The complement-derived anaphylatoxin C5a increases microglial GLT-1 expression and glutamate uptake in a TNF-alpha-independent manner.

Microglia can express Na+-dependent high-affinity glutamate transporters during pathological conditions in the CNS. The transporter expression seems to be activation dependent, and we therefore sought to identify factors that could induce it, in addition to the well-known effect of lipopolysaccharide (LPS) that is mediated by tumour necrosis factor-alpha (TNF-alpha). The complement-derived anaphylatoxins C3a and C5a are of potential interest as the complement system is activated in nearly all insults to the nervous system, and both C3a and C5a have been shown to protect against excitotoxicity. We have found that C5a, but not C3a, increased the expression of the microglial glutamate transporter GLT-1 in a dose-dependent manner without eliciting or modulating the release of TNF-alpha. However, the increase was not as prominent as the one induced by LPS, indicating that the microglia are in different activity states. The increase in microglial GLT-1 expression led to an increased functional uptake of glutamate without affecting the release. This suggests that C5a-stimulated microglia can be self- and neuroprotective by removing extracellular glutamate.

Mental fatigue and impaired information processing after mild and moderate traumatic brain injury.

PRIMARY OBJECTIVE: Mental fatigue is a common symptom after brain injury. Its mechanisms are not fully understood and it has been difficult to find an objective way of measuring it. The aim was to compare cognitive tests with a new self-assessment questionnaire about mental fatigue. METHODS AND PROCEDURES: Individuals reporting mental fatigue for 6 months or more after mild traumatic brain injury (MTBI) or traumatic brain injury (TBI) and controls were assessed for subjective fatigue, information processing speed, working memory and attention. Depression and anxiety were also assessed in the individuals with brain injury. RESULTS: Individuals with MTBI or TBI reported significantly more problems with mental fatigue and related symptoms than controls. A significantly decreased information processing speed (digit symbol-coding, reading speed, trail making test) was found in those on sick leave due to MTBI or TBI, compared to controls. Divided attention was affected to a lesser extent and no effect was detected on working memory. CONCLUSION: Mental fatigue after MTBI can last for several years. It can be profoundly disabling and affect working capacity as well as social activities. Subjective mental fatigue following brain injury is suggested to mainly correlate with objectively measured information processing speed.

Long-term mental fatigue after traumatic brain injury and impact on employment status.

OBJECTIVE: Long-term mental fatigue following traumatic brain injury is endorsed as one of the most distressing symptoms, interfering considerably with return to work and social life. The objective of this cross-sectional study was to estimate the prevalence of long-term mental fatigue after traumatic brain injury and to evaluate its association with employment status. METHODS: All patients (age range 19-65 years) diagnosed with traumatic brain injury irrespective of severity at Kungälv Hospital, Kungälv, Sweden, over a period of 5 years (n = 613) were invited by post to respond to questions about their injury, employment status and complete a questionnaire about mental fatigue, the Mental Fatigue Scale (MFS). RESULTS: A response rate of 38% was achieved. Among respondents, 39% scored above the MFS cut-off of 10.5. Higher MFS scores were associated with decreased employment status (p < 0.001). Rating on the MFS was higher for women, for those with a longer initial duration of acute post-traumatic brain injury symptoms, and for those who had previously experienced a traumatic brain injury. No association was found between mental fatigue and age, severity of injury, or time since injury. CONCLUSION: Long-term mental fatigue was frequent among people who had experienced a traumatic brain injury, and a higher rating on the MFS was associated with decreased employment status.

Exposure of cultured astroglial and microglial brain cells to 900 MHz microwave radiation.

The rapid rise in the use of mobile communications has raised concerns about health issues related to low-level microwave radiation. The head and brain are usually the most exposed targets in mobile phone users. In the brain, two types of glial cells, the astroglial and the microglial cells, are interesting in the context of biological effects from microwave exposure. These cells are widely distributed in the brain and are directly involved in the response to brain damage as well as in the development of brain cancer. The aim of the present study was to investigate whether 900 MHz radiation could affect these two different glial cell types in culture by studying markers for damage-related processes in the cells. Primary cultures enriched in astroglial cells were exposed to 900 MHz microwave radiation in a temperature-controlled exposure system at specific absorption rates (SARs) of 3 W/kg GSM modulated wave (mw) for 4, 8 and 24 h or 27 W/kg continuous wave (cw) for 24 h, and the release into the extracellular medium of the two pro-inflammatory cytokines interleukin 6 (Il6) and tumor necrosis factor-alpha (Tnfa) was analyzed. In addition, levels of the astroglial cell-specific reactive marker glial fibrillary acidic protein (Gfap), whose expression dynamics is different from that of cytokines, were measured in astroglial cultures and in astroglial cell-conditioned cell culture medium at SARs of 27 and 54 W/kg (cw) for 4 or 24 h. No significant differences could be detected for any of the parameters studied at any time and for any of the radiation characteristics. Total protein levels remained constant during the experiments. Microglial cell cultures were exposed to 900 MHz radiation at an SAR of 3 W/kg (mw) for 8 h, and I16, Tnfa, total protein and the microglial reactivity marker ED-1 (a macrophage activation antigen) were measured. No significant differences were found. The morphology of the cultured astroglial cells and microglia was studied and appeared to be unaffected by microwave irradiation. Thus this study does not provide evidence for any effect of the microwave radiation used on damage-related factors in glial cells in culture.

Glial neuronal signaling in the central nervous system.

Glial cells are known to interact extensively with neuronal elements in the brain, influencing their activity. Astrocytes associated with synapses integrate neuronal inputs and release transmitters that modulate synaptic sensitivity. Glial cells participate in formation and rebuilding of synapses and play a prominent role in protection and repair of nervous tissue after damage. For glial cells to take an active part in plastic alterations under physiological conditions and pathological disturbances, extensive specific signaling, both within single cells and between cells, is required. In recent years, intensive research has led to our first insight into this signaling. We know there are active connections between astrocytes in the form of networks promoting Ca2+ and ATP signaling; we also know there is intense signaling between astrocytes, microglia, oligodendrocytes, and neurons, with an array of molecules acting as signaling substances. The cells must be functionally integrated to facilitate the enormous dynamics of and capacity for reconstruction within the nervous system. In this paper, we summarize some basic data on glial neuronal signaling to provide insight into synaptic modulation and reconstruction in physiology and protection and repair after damage.

Novel computer tests for identification of mental fatigue after traumatic brain injury.

BACKGROUND: Mental fatigue is one of the most significant post-traumatic brain injury symptoms. It is currently not possible to objectively identify. OBJECTIVE: This study investigated whether a complex computer cognitive test with load on endurance, processing speed and attention were more demanding for participants suffering from mental fatigue after brain injury compared with a control group. METHOD: Seventy-six subjects of mild traumatic brain injury (mTBI) and 45 healthy controls were included in the study. All subjects with mTBI had been suffering from mental fatigue for six months or more. Mental fatigue was screened using the Mental Fatigue Scale (MFS). Cognitive function was measured for information processing speed and working memory, and with a novel computer test. RESULTS: The mTBI group rated MFS significantly higher than the control group. The results revealed a significantly slower information processing speed for the mTBI subjects and a poorer performance on the working memory test. The computer test revealed a less efficient performance over time for the TBI subjects compared to the control group. CONCLUSIONS: The results indicate a less efficient performance over time in complex and demanding cognitive tasks for individuals experiencing from mental fatigue after brain injury.

On the potential role of glutamate transport in mental fatigue.

Mental fatigue, with decreased concentration capacity, is common in neuroinflammatory and neurodegenerative diseases, often appearing prior to other major mental or physical neurological symptoms. Mental fatigue also makes rehabilitation more difficult after a stroke, brain trauma, meningitis or encephalitis. As increased levels of proinflammatory cytokines are reported in these disorders, we wanted to explore whether or not proinflammatory cytokines could induce mental fatigue, and if so, by what mechanisms.It is well known that proinflammatory cytokines are increased in major depression, "sickness behavior" and sleep deprivation, which are all disorders associated with mental fatigue. Furthermore, an influence by specific proinflammatory cytokines, such as interleukin (IL)-1, on learning and memory capacities has been observed in several experimental systems. As glutamate signaling is crucial for information intake and processing within the brain, and due to the pivotal role for glutamate in brain metabolism, dynamic alterations in glutamate transmission could be of pathophysiological importance in mental fatigue. Based on this literature and observations from our own laboratory and others on the role of astroglial cells in the fine-tuning of glutamate neurotransmission we present the hypothesis that the proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta and IL-6 could be involved in the pathophysiology of mental fatigue through their ability to attenuate the astroglial clearance of extracellular glutamate, their disintegration of the blood brain barrier, and effects on astroglial metabolism and metabolic supply for the neurons, thereby attenuating glutamate transmission. To test whether our hypothesis is valid or not, brain imaging techniques should be applied with the ability to register, over time and with increasing cognitive loading, the extracellular concentrations of glutamate and potassium (K+) in humans suffering from mental fatigue. At present, this is not possible for technical reasons. Therefore, more knowledge of neuronal-glial signaling in in vitro systems and animal experiments is important.In summary, we provide a hypothetic explanation for a general neurobiological mechanism, at the cellular level, behind one of our most common symptoms during neuroinflammation and other long-term disorders of brain function. Understanding pathophysiological mechanisms of mental fatigue could result in better treatment.

Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons.

The effect of the novel antiepileptic drug levetiracetam on caffeine (10 mM)-induced intracellular calcium ([Ca2+]i) response was investigated in rat hippocampal neurons in culture, with the aim of exploring the cellular mechanisms of this new drug. Levetiracetam significantly reduced caffeine-induced [Ca2+]i) response, with maximum inhibition at 32 microM. The R-enantiomer of levetiracetam, ucb L060, which is devoid of anticonvulsant activity, at 32 microM had no effect on caffeine-induced [Ca2+]i) response. Caffeine 10 mM also induced epileptiform field potentials in rat hippocampal slices : single stimuli evoked repetitive population spikes and spontaneous field bursts regularly occurred. Levetiracetam (32 microM) significantly inhibited the amplitudes and the number of caffeine-induced repeated population spikes and delayed the appearance of spontaneous bursts, while ucb L060 (32 microM) completely lacked anti-caffeine activity. These results suggest that the inhibition of caffeine-induced Ca release from intra-neuronal stores might be an excitability-reducing effect of levetiracetam, contributing to its antiepileptic activity.