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Objective Hepatic encephalopathy (HE) is a potentially reversible brain dysfunction caused by liver failure. Altered synaptic plasticity is supposed to play a major role in the pathophysiology of HE. Here, we used paired associative stimulation with an inter-stimulus interval of 25 ms (PAS25), a transcranial magnetic stimulation (TMS) protocol, to test synaptic plasticity of the motor cortex in patients with manifest HE. Methods 23 HE-patients and 23 healthy controls were enrolled in the study. Motor evoked potential (MEP) amplitudes were assessed as measure for cortical excitability. Time courses of MEP amplitude changes after the PAS25 intervention were compared between both groups. Results MEP-amplitudes increased after PAS25 in the control group, indicating PAS25-induced synaptic plasticity in healthy controls, as expected. In contrast, MEP-amplitudes within the HE group did not change and were lower than in the control group, indicating no induction of plasticity. Conclusions Our study revealed reduced synaptic plasticity of the primary motor cortex in HE. Significance Reduced synaptic plasticity in HE provides a link between pathological changes on the molecular level and early clinical symptoms of the disease. This decrease may be caused by disturbances in the glutamatergic neurotransmission due to the known hyperammonemia in HE patients.

Conditioning transcranial magnetic stimulation (TMS) with subthreshold conditioning stimulus followed by supra-threshold test stimulus at inter-stimulus intervals (ISI) of 1–5 ms results in inhibition (SICI), while ISI at 10–15 ms results in facilitation (ICF). One concerning issue, applying ICF/SICI protocols on patients is the substantial protocol variability. Here, we hypothesized that increasing the number of CS could result in more robust ICF/SICI protocols. Twenty healthy subjects participated in the study. Motor-evoked potentials (MEP) were obtained from conditioning TMS with a varying number of conditioning stimuli in 3, 4, 10, and 15 ms ISI over the primary motor cortex. MEP amplitudes were then compared to examine excitability. TMS with 3, 5, and 7 conditioning stimuli but not with one conditioning stimulus induced ICF. Moreover, 10 ms ISI produced stronger ICF than 15 ms ISI. Significant SICI was only induced with one conditioning stimulus. Besides, 3 ms ISI resulted in stronger SICI than 4 ms ISI. Only a train of conditioning stimuli induced stable ICF and may be more advantageous than the classical paired pulse ICF paradigm. Supplementary Information The online version contains supplementary material available at 10.1007/s00221-020-06010-7.

Cortical facilitation assessed with triad conditioning transcranial magnetic stimulation has been termed triad-conditioned facilitation (TCF). TCF has been supposed to reflect increased intracortical facilitation (ICF) at short interstimulus intervals (ISI) around 10 ms and an intrinsic rhythm of the motor cortex at longer ISI around 25 ms. To gain further insight into the pathophysiological mechanism of TCF, we systematically studied the effect of suprathreshold conditioning stimulus (CS) and test stimulus (TS) intensity on TCF. Various CS intensities and TS intensities were used in a triad-conditioning paradigm that was applied to 11 healthy subjects. ISI between pulses were studied between 5 and 200 ms. TCF at 10 ms ISI enhanced with increasing CS intensity but decreased with increasing TS intensity. The duration of facilitation was longer with higher CS intensity. However, TCF at 25 ms ISI could not be elicited with none of the CS and TS intensities addressed here. Our results are consistent with the notion of TCF at short ISI reflecting ICF. The enhanced and prolonged facilitation with increase of CS without additional isolated facilitation at longer ISI suggest a prolongation of ICF. Electronic supplementary material The online version of this article (10.1007/s00221-020-05812-z) contains supplementary material, which is available to authorized users.

Lignocellulosic biorefining processes plant-derived biomass into a range of bio-based products. Currently, more than 40 lignocellulosic biorefineries are operating across Europe. Here, we address the challenges and future opportunities of this nascent industry by elucidating key elements of the biorefining sector, including feedstock sourcing, processing methods, and the bioproducts market.

The potential of microwave and ultrasound was evaluated for the pretreatment of brewer's spent grain (BSG). Under optimal conditions of microwave and ultrasound pretreatments, reducing sugar yields per 1 g of pretreated BSG were 64.4 ± 7 mg and 39.9 ± 6 mg, respectively. Subsequently, the pretreated BSG was evaluated as a substrate for production of Xylanopectinolytic enzymes using fungi isolated from spoiled fruits. Out of twenty-nine (29) isolates recovered, Mucor sp. (AB1) isolated from Bramley apple (Malus domestica) produced xylanopectinolytic enzymes with higher specific activity, and was selected for further studies. The highest enzyme activity (137 U/g, and 67 U/g BSG, for pectinase and xylanase, respectively) was achieved in a medium that contained 15 g of BSG, at pH 6, temperature of 30 °C, supplemented with 1% xylan or pectin for inducing the production of xylanase or pectinase, respectively. The partially purified xylanopectinolytic enzymes were optimally active at 60 °C and pH 5.

DYT-THAP1 dystonia is known to present a variety of clinical symptoms. To the best of our knowledge, this is the first case with DYT-THAP 1 dystonia and clinical signs of cerebellar involvement studied with transcranial magnetic stimulation in vivo. We report a case of a 51-year-old male DYT-THAP1 mutation carrier with dystonia, who additionally developed ataxia 1.5 years ago. To study cerebellar involvement in our patient, we used a TMS protocol called cerebellar inhibition (CBI). The lack of CBI in our patient strongly suggests cerebellar involvement. According to our findings, cerebellar syndrome may be part of the phenotypical spectrum of DYT-THAP1 mutations.

The EU aims to achieve a variety of ambitious climate change mitigation and sustainable development goals by 2030. To deliver on this aim, the European Commission (EC) launched the bioeconomy strategy in 2012. At the heart of this policy is the concept of the sustainable Biorefinery, which is based centrally on a cost-effective conversion of lignocellulosic biomass into bioenergy and bioproducts. The first generation of biorefineries was based on utilization of edible food crops, which raised a “food vs. fuel” debate and questionable sustainability issues. To overcome this, lignocellulosic feedstock options currently being pursued range from non-food crops to agroforestry residues and wastes. Notwithstanding this, advanced biorefining is still an emerging sector, with unanswered questions relating to the choice of feedstocks, cost-effective lignocellulosic pretreatment, and identification of viable end products that will lead to sustainable development of this industry. Therefore, this review aims to provide a critical update on the possible future directions of this sector, with an emphasis on its role in the future European bioeconomy, against a background of global developments.

Objective Previous animal work reported that hyperammonemia leads to opposing changes of GABAergic neurotransmission in terms of increase in the cerebellum and decrease in the cerebral cortex. In this study, we investigate GABAergic tone in the cerebellum in patients with hepatic encephalopathy (HE) at different stages of the disease and its relation to critical flicker frequency (CFF) and ataxia. Methods Cerebellar inhibition using transcranial magnetic stimulation was investigated in 15 patients with different stages of HE and 15 healthy controls. All patients were assessed using CFF and the score for assessment and rating of ataxia (SARA). Results Decreased cerebellar inhibition (CBI) was observed in manifest HE at interstimulus interval from 5 to 7 ms. However, the degree of CBI at 7 ms correlated significantly with disease severity measured with SARA and with CFF by trend. Conclusion Reduced CBI in HE patients indicates affection of the cerebellar efferent pathway. The disease severity dependent increase of CBI magnitude supports the notion of disease stage dependent increase of GABAergic neurotransmission in Purkinje cells. Significance The results support previous animal experiments showing increase of GABA-ergic neurotransmission in the cerebellum and decrease in the motor cortex in HE.

Niemann-Pick type C (NP-C) is a rare, neurodegenerative, lysosomal storage disease. Cortical excitability using different transcranial magnetic stimulation (TMS) protocols together with clinical and neuropsychological testing was longitudinally assessed in a patient with NP-C. Cerebellar inhibition, a measure for the integrity of the cerebello-thalamo-cortical network, was impaired. Short-latency afferent inhibition, a measure for cholinergic transmission, and cognitive functions were also impaired and improved under Miglustat treatment. Short interval intracortical facilitation, a marker for glutamatergic neurotransmission, was absent initially but increased after treatment with Miglustat. Our results provide new insights into pathophysiological mechanisms of NP-C and the response to Miglustat treatment.

Introduction Hepatic Encephalopathy (HE) is a frequent complication in patients suffering from liver cirrhosis. HE comprises a variety of neuropsychiatric and motor symptoms. Increased ammonia levels have been suggested as a key factor in the disease pathology. Using animal models, Cauli and colleagues reported that hyperammonemia may lead to brain area depending alteration of GABAergic neurotransmission with an increase of GABAeric tone in the cerebellum and a decrease in the cerebral cortex. Consistent with this data, recent work from our group revealed a reduced GABAergic tone in the motor cortex of patients with manifest HE using transcranial magnetic stimulation (TMS). The aim of this study is to probe how GABAergic cerebellar tone is altered in patients at different stages of HE and how this alteration is related to clinical parameters such as the critical flicker frequency and ataxia scoring. Methods 30 participants [15 patients with HE (5 minimal HE, 6 HE grade I, and 4 HE grade II) and 15 age matched healthy controls] were subjected to the following: 1- Critical flicker frequency (CFF) which is a sensitive and reliable parameter for quantification of low-grade HE in cirrhotic patients. 2- Cerebellar brain inhibition TMS paradigm (CBI): in this paradigm, a conditioning TMS pulse is applied over one hemisphere of the cerebellum followed by a test pulse over the contralateral motor cortex resulting in a motor evoked potential (MEP). In healthy subjects, the MEP is inhibited when the test stimulus is preceded by the conditioning stimulus at an interval between 5 and 7 ms through inhibition of the fascilitatory disynaptic dentato-thalamo-cortical pathway. 3- Score for assessment and rating of ataxia (SARA) to detect symptoms of cerebellar affection. Results Cerebellar inhibition at ISI 5–7 ms was significantly reduced in patients with HE compared to healthy controls. However, the magnitude of cerebellar inhibition at 7 ms increased with disease severity and correlated with SARA score and with CFF by trend. Conclusion Overall cerebellar inhibition is significantly reduced in patients with HE, suggesting affection of the dentato-thalamo-cortical pathway in this disease. However, the magnitude of cerebellar inhibition at 7 ms increases with disease severity and correlates with SARA score and with CFF by trend, supporting the hypothesis of disease stage dependent increase of GABAergic tone in the Purkinje cells. Our results are consistent with pervious animal in vitro data suggesting increased GABA-ergic tone in the cerebellum and decreased GABA-ergic tone in the motor cortex.