The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) of still unclear etiology. In recent years, the search for biomarkers facilitating its diagnosis, prognosis, therapy response, and other parameters has gained increasing attention. In this regard, in a previous meta-analysis comprising 22 studies, we found that MS is associated with higher nitrite/nitrate (NOx) levels in the cerebrospinal fluid (CSF) compared to patients with non-inflammatory other neurological diseases (NIOND). However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria varied. As a follow-up to our meta-analysis, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve MS patients compared to patients with somatic symptom disorder. To this end, we analyzed the serum and CSF levels of NOx in 117 patients (71 relapsing-remitting (RR) MS, 16 primary progressive (PP) MS, and 30 somatic symptom disorder). We found that RRMS and PPMS patients had higher serum NOx levels compared to somatic symptom disorder patients. This difference remained significant in the subgroup of MRZ-negative RRMS patients. In conclusion, the measurement of NOx in the serum might indeed be a valuable tool in supporting MS diagnosis.

Toward therapeutic electrophysiology: beta-band suppression as a biomarker in chronic local field potential recordings.

Adaptive deep brain stimulation (aDBS) is a promising concept for feedback-based neurostimulation, with the potential of clinical implementation with the sensing-enabled Percept neurostimulator. We aim to characterize chronic electrophysiological activity during stimulation and to validate beta-band activity as a biomarker for bradykinesia. Subthalamic activity was recorded during stepwise stimulation amplitude increase OFF medication in 10 Parkinson's patients during rest and finger tapping. Offline analysis of wavelet-transformed beta-band activity and assessment of inter-variable relationships in linear mixed effects models were implemented. There was a stepwise suppression of low-beta activity with increasing stimulation intensity (p = 0.002). Low-beta power was negatively correlated with movement speed and predictive for velocity improvements (p < 0.001), stimulation amplitude for beta suppression (p < 0.001). Here, we characterize beta-band modulation as a chronic biomarker for motor performance. Our investigations support the use of electrophysiology in therapy optimization, providing evidence for the use of biomarker analysis for clinical aDBS.

Motor Evoked Potentials Improve Targeting in Deep Brain Stimulation Surgery.

OBJECTIVES: One of the main challenges posed by the surgical deep brain stimulation (DBS) procedure is the successful targeting of the structures of interest and avoidance of side effects, especially in asleep surgery. Here, intraoperative motor evoked potentials (MEPs) might serve as tool to identify the pyramidal tract. We hypothesized that intraoperative MEPs are useful to define the distance to the pyramidal tract and reduce the occurrence of postoperative capsular side effects. MATERIALS AND METHODS: Motor potentials were evoked through both microelectrode and DBS-electrode stimulation during stereotactic DBS surgery on 25 subthalamic nuclei and 3 ventral intermediate thalamic nuclei. Internal capsule proximity was calculated for contacts on microelectrode trajectories, as well as for DBS-electrodes, and correlated with the corresponding MEP thresholds. Moreover, the predictivity of intraoperative MEP thresholds on the probability of postoperative capsular side effects was calculated. RESULTS: Intraoperative MEPs thresholds correlated significantly with internal capsule proximity, regardless of the stimulation source. Furthermore, MEPs thresholds were highly accurate to exclude the occurrence of postoperative capsular side effects. CONCLUSIONS: Intraoperative MEPs provide additional targeting guidance, especially in asleep DBS surgery, where clinical value of microelectrode recordings and test stimulation may be limited. As this technique can exclude future capsular side effects, it can directly be translated into clinical practice.

Altered motor cortical plasticity in patients with hepatic encephalopathy: A paired associative stimulation study.

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.

Influence of High Pass Filter Settings on Motor Evoked Potentials.

OBJECTIVE: Motor evoked potentials (MEP), obtained by transcranial magnetic stimulation (TMS) are a common tool in clinical research and diagnostic. Nevertheless, reports regarding the influence of filter settings on MEP are sparse. Here, we compared MEP amplitudes and signal to noise ratio (SNR) using multiple high pass filter (HPF) and notch filter settings. MATERIALS AND METHODS: Twenty healthy subjects were enrolled in the study. Recruitment curves were obtained with HPF settings varied at 10, 20, 50, and 100 Hz. The four HPF settings were tested both with and without 50 Hz active notch filter. Low pass filter was kept constant at 5 kHz. RESULTS: MEP amplitudes with HPF at 10 and 20 Hz were significantly higher than at 100 Hz, regardless of the notch filter. However, SNR did not differ among HPF settings. An active notch filter significantly improved SNR. CONCLUSION: The reduction in MEP amplitudes with HPF above 20 Hz may be due to noise reduction, since the different HPF conditions did not alter SNR. Thus, higher HPF above 50 Hz may be an option to reduce noise, the use of a notch filter may even improve SNR. SIGNIFICANCE: Our findings are relevant for the selection of filter settings and might be of importance to any researcher who utilizes TMS-MEP.

[Deep brain stimulation for Parkinson's disease]. / Tiefe Hirnstimulation bei Morbus Parkinson.

Deep brain stimulation is an established and evidence-based therapeutic option for the treatment of advanced Parkinson's disease. Main indication and inclusion criteria are the presence of idiopathic Parkinsonism with motor fluctuations and / or dyskinesias and / or with medication refractory tremor, a significant improvement of akinesia / rigidity in response to dopaminergic medication, the absence of relevant cognitive deficits and other significant comorbidities. DBS neurosurgery has a low risk of complications. The clinical programming should follow an established monopolar review algorithm. Regular follow-up visits are required for stimulation monitoring.

Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor Increases Therapeutic Window.

OBJECTIVES: Deep brain stimulation (DBS) of the posterior subthalamic area (PSA) and the ventral intermediate thalamic nucleus (VIM) is a well-established therapy for essential tremor (ET), but it is frequently associated with side effects like dysarthria or gait ataxia. Directional DBS (dDBS) may be a way to activate fiber tracts more selectively. Is dDBS for ET superior to omnidirectional DBS (oDBS) regarding therapeutic window and clinically as effective as oDBS? MATERIALS AND METHODS: Ten patients with ET treated with PSA/VIM-DBS were recruited. Therapeutic window served as primary outcome parameter; clinical efficacy, volume of neuronal activation, and total electrical energy delivered (TEED) served as secondary outcome parameters. Therapeutic window was calculated for all three dDBS directions and for oDBS by determining therapeutic thresholds and side effect thresholds. Clinical efficacy was assessed by comparing the effect of best dDBS and oDBS on tremor and ataxia rating scales, and accelerometry. Volume of neural activation and TEED were also calculated for both paradigms. RESULTS: For best dDBS, therapeutic window was wider and therapeutic threshold was lower compared to oDBS. While side effect threshold did not differ, volume of neural activation was larger for dDBS. In terms of clinical efficacy, dDBS was as effective as oDBS. CONCLUSIONS: dDBS for ET widens therapeutic window due to reduction of therapeutic threshold. Larger volume of neural activation for dDBS at side effect threshold supports the notion of persistent directionality even at higher intensities. dDBS may compensate for slightly misplaced leads and should be considered first line for PSA/VIM-DBS.

Impact of the number of conditioning pulses on motor cortex excitability: a transcranial magnetic stimulation study.

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.

Cerebellar Involvement in DYT-THAP1 Dystonia.

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.