Publications by authors named "Marcus L F Janssen"

41 Publications

Multicenter Validation of Individual Preoperative Motor Outcome Prediction for Deep Brain Stimulation in Parkinson's Disease.

Stereotact Funct Neurosurg 2021 Nov 25:1-9. Epub 2021 Nov 25.

Department of Neurology and Clinical Neurophysiology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for Parkinson's disease (PD) patients suffering from motor response fluctuations despite optimal medical treatment, or severe dopaminergic side effects. Despite careful clinical selection and surgical procedures, some patients do not benefit from STN DBS. Preoperative prediction models are suggested to better predict individual motor response after STN DBS. We validate a preregistered model, DBS-PREDICT, in an external multicenter validation cohort.

Methods: DBS-PREDICT considered eleven, solely preoperative, clinical characteristics and applied a logistic regression to differentiate between weak and strong motor responders. Weak motor response was defined as no clinically relevant improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) II, III, or IV, 1 year after surgery, defined as, respectively, 3, 5, and 3 points or more. Lower UPDRS III and IV scores and higher age at disease onset contributed most to weak response predictions. Individual predictions were compared with actual clinical outcomes.

Results: 322 PD patients treated with STN DBS from 6 different centers were included. DBS-PREDICT differentiated between weak and strong motor responders with an area under the receiver operator curve of 0.76 and an accuracy up to 77%.

Conclusion: Proving generalizability and feasibility of preoperative STN DBS outcome prediction in an external multicenter cohort is an important step in creating clinical impact in DBS with data-driven tools. Future prospective studies are required to overcome several inherent practical and statistical limitations of including clinical decision support systems in DBS care.
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http://dx.doi.org/10.1159/000519960DOI Listing
November 2021

Predicting mortality of individual patients with COVID-19: a multicentre Dutch cohort.

BMJ Open 2021 07 19;11(7):e047347. Epub 2021 Jul 19.

Department of Internal Medicine, Flevoziekenhuis, Almere, Flevoland, The Netherlands.

Objective: Develop and validate models that predict mortality of patients diagnosed with COVID-19 admitted to the hospital.

Design: Retrospective cohort study.

Setting: A multicentre cohort across 10 Dutch hospitals including patients from 27 February to 8 June 2020.

Participants: SARS-CoV-2 positive patients (age ≥18) admitted to the hospital.

Main Outcome Measures: 21-day all-cause mortality evaluated by the area under the receiver operator curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value. The predictive value of age was explored by comparison with age-based rules used in practice and by excluding age from the analysis.

Results: 2273 patients were included, of whom 516 had died or discharged to palliative care within 21 days after admission. Five feature sets, including premorbid, clinical presentation and laboratory and radiology values, were derived from 80 features. Additionally, an Analysis of Variance (ANOVA)-based data-driven feature selection selected the 10 features with the highest F values: age, number of home medications, urea nitrogen, lactate dehydrogenase, albumin, oxygen saturation (%), oxygen saturation is measured on room air, oxygen saturation is measured on oxygen therapy, blood gas pH and history of chronic cardiac disease. A linear logistic regression and non-linear tree-based gradient boosting algorithm fitted the data with an AUC of 0.81 (95% CI 0.77 to 0.85) and 0.82 (0.79 to 0.85), respectively, using the 10 selected features. Both models outperformed age-based decision rules used in practice (AUC of 0.69, 0.65 to 0.74 for age >70). Furthermore, performance remained stable when excluding age as predictor (AUC of 0.78, 0.75 to 0.81).

Conclusion: Both models showed good performance and had better test characteristics than age-based decision rules, using 10 admission features readily available in Dutch hospitals. The models hold promise to aid decision-making during a hospital bed shortage.
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http://dx.doi.org/10.1136/bmjopen-2020-047347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290951PMC
July 2021

Auditory thalamus dysfunction and pathophysiology in tinnitus: a predictive network hypothesis.

Brain Struct Funct 2021 Jul 2;226(6):1659-1676. Epub 2021 May 2.

Department of Neuropsychology and Psychopharmacology, University of Maastricht, Universiteitssingel 40, 6229, Maastricht, The Netherlands.

Tinnitus is the perception of a 'ringing' sound without an acoustic source. It is generally accepted that tinnitus develops after peripheral hearing loss and is associated with altered auditory processing. The thalamus is a crucial relay in the underlying pathways that actively shapes processing of auditory signals before the respective information reaches the cerebral cortex. Here, we review animal and human evidence to define thalamic function in tinnitus. Overall increased spontaneous firing patterns and altered coherence between the thalamic medial geniculate body (MGB) and auditory cortices is observed in animal models of tinnitus. It is likely that the functional connectivity between the MGB and primary and secondary auditory cortices is reduced in humans. Conversely, there are indications for increased connectivity between the MGB and several areas in the cingulate cortex and posterior cerebellar regions, as well as variability in connectivity between the MGB and frontal areas regarding laterality and orientation in the inferior, medial and superior frontal gyrus. We suggest that these changes affect adaptive sensory gating of temporal and spectral sound features along the auditory pathway, reflecting dysfunction in an extensive thalamo-cortical network implicated in predictive temporal adaptation to the auditory environment. Modulation of temporal characteristics of input signals might hence factor into a thalamo-cortical dysrhythmia profile of tinnitus, but could ultimately also establish new directions for treatment options for persons with tinnitus.
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http://dx.doi.org/10.1007/s00429-021-02284-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203542PMC
July 2021

Impact of Procedural Sedation on the Clinical Outcome of Microelectrode Recording Guided Deep Brain Stimulation in Patients with Parkinson's Disease.

J Clin Med 2021 Apr 7;10(8). Epub 2021 Apr 7.

Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.

Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) has become a routine treatment of advanced Parkinson's disease (PD). DBS surgery is commonly performed under local anesthesia (LA) to obtain reliable microelectrode recordings. However, procedural sedation and/or analgesia (PSA) is often desirable to improve patient comfort. The impact of PSA in addition to LA on outcome is largely unknown. Therefore, we performed an observational study to assess the effect of PSA compared to LA alone during STN DBS surgery on outcome in PD patients.

Methods: Seventy PD patients (22 under LA, 48 under LA + PSA) scheduled for STN DBS implantation were included. Dexmedetomidine, clonidine or remifentanil were used for PSA. The primary outcome was the change in Movement Disorders Society Unified Parkinson's Disease Rating Score III (MDS-UPDRS III) and levodopa equivalent daily dosage (LEDD) between baseline, one month before surgery, and twelve months postoperatively. Secondary outcome measures were motor function during activities of daily living (MDS-UPDRS II), cognitive alterations and surgical adverse events. Postoperative assessment was conducted in "on" stimulation and "on" medication conditions.

Results: At twelve months follow-up, UPDRS III and UPDRS II scores in "on" medication conditions were similar between the LA and PSA groups. The two groups showed a similar LEDD reduction and an equivalent decline in executive function measured by the Stroop Color-Word Test, Trail Making Test-B, and verbal fluency. The incidence of perioperative and postoperative adverse events was similar between groups.

Conclusion: This study demonstrates that PSA during STN DBS implantation surgery in PD patients was not associated with differences in motor and non-motor outcome after twelve months compared with LA only.
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http://dx.doi.org/10.3390/jcm10081557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068017PMC
April 2021

[Clinical course of COVID-19 in the Netherlands: an overview of 2607 patients in hospital during the first wave].

Ned Tijdschr Geneeskd 2021 01 11;165. Epub 2021 Jan 11.

Maastricht UMC.

Objective: To systematically collect clinical data from patients with a proven COVID-19 infection in the Netherlands.

Design: Data from 2579 patients with COVID-19 admitted to 10 Dutch centers in the period February to July 2020 are described. The clinical data are based on the WHO COVID case record form (CRF) and supplemented with patient characteristics of which recently an association disease severity has been reported.

Methods: Survival analyses were performed as primary statistical analysis. These Kaplan-Meier curves for time to (early) death (3 weeks) have been determined for pre-morbid patient characteristics and clinical, radiological and laboratory data at hospital admission.

Results: Total in-hospital mortality after 3 weeks was 22.2% (95% CI: 20.7% - 23.9%), hospital mortality within 21 days was significantly higher for elderly patients (> 70 years; 35, 0% (95% CI: 32.4% - 37.8%) and patients who died during the 21 days and were admitted to the intensive care (36.5% (95% CI: 32.1% - 41.3%)). Apart from that, in this Dutch population we also see a risk of early death in patients with co-morbidities (such as chronic neurological, nephrological and cardiac disorders and hypertension), and in patients with more home medication and / or with increased urea and creatinine levels.

Conclusion: Early death due to a COVID-19 infection in the Netherlands appears to be associated with demographic variables (e.g. age), comorbidity (e.g. cardiovascular disease) but also disease char-acteristics at admission.
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January 2021

Special Issue: Trends in Clinical Deep Brain Stimulation.

J Clin Med 2021 Jan 6;10(2). Epub 2021 Jan 6.

School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.

Deep brain stimulation (DBS) has been successfully applied in several neurological and psychiatric disorders [...].
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http://dx.doi.org/10.3390/jcm10020178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825417PMC
January 2021

Noise-induced neurophysiological alterations in the rat medial geniculate body and thalamocortical desynchronization by deep brain stimulation.

J Neurophysiol 2021 02 6;125(2):661-671. Epub 2021 Jan 6.

School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

The thalamic medial geniculate body (MGB) is uniquely positioned within the neural tinnitus networks. Deep brain stimulation (DBS) of the MGB has been proposed as a possible novel treatment for tinnitus, yet mechanisms remain elusive. The aim of this study was to characterize neurophysiologic hallmarks in the MGB after noise exposure and to assess the neurophysiological effects of electrical stimulation of the MGB. Fourteen male Sprague-Dawley rats were included. Nine subjects were unilaterally exposed to a 16-kHz octave-band noise at 115 dB for 90 min, five received sham exposure. Single units were recorded from the contralateral MGB where spontaneous firing, coefficient of variation, response type, rate-level functions, and thresholds were determined. Local field potentials and electroencephalographical (EEG) recordings were performed before and after high-frequency DBS of the MGB. Thalamocortical synchronization and power were analyzed. In total, 214 single units were identified ( = 145 in noise-exposed group, = 69 in control group). After noise exposure, fast-responding neurons become less responsive or nonresponsive without change to their spontaneous rate, whereas sustained- and suppressed-type neurons exhibit enhanced spontaneous activity without change to their stimulus-driven activity. MGB DBS suppressed thalamocortical synchronization in the β and γ bands, supporting suppression of thalamocortical synchronization as an underlying mechanism of tinnitus suppression by high frequency DBS. These findings contribute to our understanding of the neurophysiologic consequences of noise exposure and the mechanism of potential DBS therapy for tinnitus. Separate functional classes of MGB neurons might have distinct roles in tinnitus pathophysiology. After noise exposure, fast-responding neurons become less responsive or nonresponsive without change to their spontaneous firing, whereas sustained and suppressed neurons exhibit enhanced spontaneous activity without change to their stimulus-driven activity. Furthermore, results suggest desynchronization of thalamocortical β and γ oscillations as a mechanism of tinnitus suppression by MGB DBS.
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http://dx.doi.org/10.1152/jn.00752.2019DOI Listing
February 2021

Machine learning prediction of motor response after deep brain stimulation in Parkinson's disease-proof of principle in a retrospective cohort.

PeerJ 2020 18;8:e10317. Epub 2020 Nov 18.

Department of Neurosurgery, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.

Introduction: Despite careful patient selection for subthalamic nucleus deep brain stimulation (STN DBS), some Parkinson's disease patients show limited improvement of motor disability. Innovative predictive analysing methods hold potential to develop a tool for clinicians that reliably predicts individual postoperative motor response, by only regarding clinical preoperative variables. The main aim of preoperative prediction would be to improve preoperative patient counselling, expectation management, and postoperative patient satisfaction.

Methods: We developed a machine learning logistic regression prediction model which generates probabilities for experiencing weak motor response one year after surgery. The model analyses preoperative variables and is trained on 89 patients using a five-fold cross-validation. Imaging and neurophysiology data are left out intentionally to ensure usability in the preoperative clinical practice. Weak responders ( = 30) were defined as patients who fail to show clinically relevant improvement on Unified Parkinson Disease Rating Scale II, III or IV.

Results: The model predicts weak responders with an average area under the curve of the receiver operating characteristic of 0.79 (standard deviation: 0.08), a true positive rate of 0.80 and a false positive rate of 0.24, and a diagnostic accuracy of 78%. The reported influences of individual preoperative variables are useful for clinical interpretation of the model, but cannot been interpreted separately regardless of the other variables in the model.

Conclusion: The model's diagnostic accuracy confirms the utility of machine learning based motor response prediction based on clinical preoperative variables. After reproduction and validation in a larger and prospective cohort, this prediction model holds potential to support clinicians during preoperative patient counseling.
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http://dx.doi.org/10.7717/peerj.10317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680051PMC
November 2020

The association between surgical characteristics and cognitive decline following deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Clin Neurol Neurosurg 2021 01 3;200:106341. Epub 2020 Nov 3.

Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, the Netherlands. Electronic address:

Objective: Despite optimal improvement in motor functioning, both short- and long-term studies have reported small but consistent changes in cognitive functioning following STN-DBS in Parkinson's disease (PD). The aim of the present study was to explore whether surgical characteristics were associated with cognitive decline one year following STN-DBS.

Methods: We retrospectively analyzed 49 PD patients who underwent bilateral STN-DBS. Cognitive change scores were related to the number of microelectrode recording (MER) trajectories, the STN length as measured by MER, and cortical entry points. Regression analyses were corrected for age at surgery, disease duration, education and preoperative levodopa responsiveness. Patients were then divided into a cognitive and non-cognitive decline group for each neuropsychological test and compared regarding demographic and surgical characteristics.

Results: One year postoperatively, significant declines were found in verbal fluency, Stroop Color-Word test and Trail Making Test B (TMT-B). Only changes in TMT-B were associated with the coronal entry point in the right hemisphere. The number of MER trajectories and STN length were not associated with cognitive change scores. When comparing the cognitive decline and non-cognitive decline groups, no significant differences were found in surgical characteristics.

Conclusions: The electrode passage through the right prefrontal lobe may contribute to subtle changes in executive function. However, only few patients showed clinically relevant cognitive decline. The use of multiple MER trajectories and a longer STN length were not associated with cognitive decline one year following surgery. From a cognitive point of view, DBS may be considered a relatively safe procedure.
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http://dx.doi.org/10.1016/j.clineuro.2020.106341DOI Listing
January 2021

Serial measurements in COVID-19-induced acute respiratory disease to unravel heterogeneity of the disease course: design of the Maastricht Intensive Care COVID cohort (MaastrICCht).

BMJ Open 2020 09 29;10(9):e040175. Epub 2020 Sep 29.

Department of Intensive Care, Maastricht University Medical Center+, Maastricht, The Netherlands.

Introduction: The course of the disease in SARS-CoV-2 infection in mechanically ventilated patients is unknown. To unravel the clinical heterogeneity of the SARS-CoV-2 infection in these patients, we designed the prospective observational Maastricht Intensive Care COVID cohort (MaastrICCht). We incorporated serial measurements that harbour aetiological, diagnostic and predictive information. The study aims to investigate the heterogeneity of the natural course of critically ill patients with a SARS-CoV-2 infection.

Methods And Analysis: Mechanically ventilated patients admitted to the intensive care with a SARS-CoV-2 infection will be included. We will collect clinical variables, vital parameters, laboratory variables, mechanical ventilator settings, chest electrical impedance tomography, ECGs, echocardiography as well as other imaging modalities to assess heterogeneity of the course of a SARS-CoV-2 infection in critically ill patients. The MaastrICCht is also designed to foster various other studies and registries and intends to create an open-source database for investigators. Therefore, a major part of the data collection is aligned with an existing national intensive care data registry and two international COVID-19 data collection initiatives. Additionally, we create a flexible design, so that additional measures can be added during the ongoing study based on new knowledge obtained from the rapidly growing body of evidence. The spread of the COVID-19 pandemic requires the swift implementation of observational research to unravel heterogeneity of the natural course of the disease of SARS-CoV-2 infection in mechanically ventilated patients. Our study design is expected to enhance aetiological, diagnostic and prognostic understanding of the disease. This paper describes the design of the MaastrICCht.

Ethics And Dissemination: Ethical approval has been obtained from the medical ethics committee (Medisch Ethische Toetsingscommissie 2020-1565/3 00 523) of the Maastricht University Medical Centre+ (Maastricht UMC+), which will be performed based on the Declaration of Helsinki. During the pandemic, the board of directors of Maastricht UMC+ adopted a policy to inform patients and ask their consent to use the collected data and to store serum samples for COVID-19 research purposes. All study documentation will be stored securely for fifteen years after recruitment of the last patient. The results will be published in peer-reviewed academic journals, with a preference for open access journals, while particularly considering deposition of the manuscripts on a preprint server early.

Trial Registration Number: The Netherlands Trial Register (NL8613).
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http://dx.doi.org/10.1136/bmjopen-2020-040175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526030PMC
September 2020

Influence of Anesthesia and Clinical Variables on the Firing Rate, Coefficient of Variation and Multi-Unit Activity of the Subthalamic Nucleus in Patients with Parkinson's Disease.

J Clin Med 2020 Apr 24;9(4). Epub 2020 Apr 24.

School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands.

Background: Microelectrode recordings (MER) are used to optimize lead placement during subthalamic nucleus deep brain stimulation (STN-DBS). To obtain reliable MER, surgery is usually performed while patients are awake. Procedural sedation and analgesia (PSA) is often desirable to improve patient comfort, anxiolysis and pain relief. The effect of these agents on MER are largely unknown. The objective of this study was to determine the effects of commonly used PSA agents, dexmedetomidine, clonidine and remifentanil and patient characteristics on MER during DBS surgery.

Methods: Data from 78 patients with Parkinson's disease (PD) who underwent STN-DBS surgery were retrospectively reviewed. The procedures were performed under local anesthesia or under PSA with dexmedetomidine, clonidine or remifentanil. In total, 4082 sites with multi-unit activity (MUA) and 588 with single units were acquired. Single unit firing rates and coefficient of variation (CV), and MUA total power were compared between patient groups.

Results: We observed a significant reduction in MUA, an increase of the CV and a trend for reduced firing rate by dexmedetomidine. The effect of dexmedetomidine was dose-dependent for all measures. Remifentanil had no effect on the firing rate but was associated with a significant increase in CV and a decrease in MUA. Clonidine showed no significant effect on firing rate, CV or MUA. In addition to anesthetic effects, MUA and CV were also influenced by patient-dependent variables.

Conclusion: Our results showed that PSA influenced neuronal properties in the STN and the dexmedetomidine (DEX) effect was dose-dependent. In addition, patient-dependent characteristics also influenced MER.
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http://dx.doi.org/10.3390/jcm9041229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230272PMC
April 2020

Effect of Anesthesia on Microelectrode Recordings During Deep Brain Stimulation Surgery: A Narrative Review.

J Neurosurg Anesthesiol 2021 Oct;33(4):300-307

Neurology.

Deep brain stimulation (DBS) is an effective surgical treatment for patients with various neurological and psychiatric disorders. Clinical improvements rely on careful patient selection and accurate electrode placement. A common method for target localization is intraoperative microelectrode recording (MER). To facilitate MER, DBS surgery is traditionally performed under local or regional anesthesia. However, sedation or general anesthesia is sometimes needed for patients who are unable to tolerate the procedure fully awake because of severe motor symptoms, psychological distress, pain, or other forms of discomfort. The effect of anesthetic drugs on MER is controversial but likely depends on the type and dose of a particular anesthetic agent, underlying disease, and surgical target. In this narrative review, we provide an overview of the current literature on the anesthetic drugs most often used for sedation and anesthesia during DBS surgery, with a focus on their effects on MERs.
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http://dx.doi.org/10.1097/ANA.0000000000000673DOI Listing
October 2021

Effect of Anesthesia on Microelectrode Recordings during Deep Brain Stimulation Surgery in Tourette Syndrome Patients.

Stereotact Funct Neurosurg 2019 8;97(4):225-231. Epub 2019 Nov 8.

School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.

Background: Deep brain stimulation (DBS) is an accepted treatment for patients with medication-resistant Tourette syndrome (TS). Sedation is commonly required during electrode implantation to attenuate anxiety, pain, and severe tics. Anesthetic agents potentially impair the quality of microelectrode recordings (MER). Little is known about the effect of these anesthetics on MER in patients with TS. We describe our experience with different sedative regimens on MER and tic severity in patients with TS.

Methods: The clinical records of all TS patients who underwent DBS surgery between 2010 and 2018 were reviewed. Demographic data, stimulation targets, anesthetic agents, perioperative complications, and MER from each hemisphere were collected and analyzed. Single-unit activity was identified by filtering spiking activity from broadband MER data and principal component analysis with K-means clustering. Vocal and motor tics which caused artifacts in the MER data were manually selected using visual and auditory inspection.

Results: Six patients underwent bilateral DBS electrode implantation. In all patients, the target was the anterior internal globus pallidus. Patient comfort and hemodynamic and respiratory stability were maintained with conscious sedation with one or more of the following anesthetic drugs: propofol, midazolam, remifentanil, clonidine, and dexmedetomidine. Good quality MER and clinical testing were obtained in 9 hemispheres of 6 patients. In 3 patients, MER quality was poor on one side.

Conclusion: Cautiously applied sedative drugs can provide patient comfort, hemodynamic and respiratory stability, and suppress severe tics, with minimal interference with MER.
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http://dx.doi.org/10.1159/000503691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979431PMC
March 2020

Alleviation of Tinnitus With High-Frequency Stimulation of the Dorsal Cochlear Nucleus: A Rodent Study.

Trends Hear 2019 Jan-Dec;23:2331216519835080

1 Department of Ear Nose and Throat/Head and Neck Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.

Deep brain stimulation of the central auditory pathway is emerging as a promising treatment modality for tinnitus. Within this pathway, the dorsal cochlear nucleus (DCN) plays a key role in the pathophysiology of tinnitus and is believed to be a tinnitus generator. We hypothesized that high-frequency stimulation (HFS) of the DCN would influence tinnitus-related abnormal neuronal activity within the auditory pathway and hereby suppress tinnitus. To this end, we assessed the effect of HFS of the DCN in a noise-induced rat model of tinnitus. The presence of tinnitus was verified using the gap prepulse inhibition of the acoustic startle response paradigm. Hearing thresholds were determined before and after noise trauma by measuring the auditory brainstem responses. In addition, changes in neuronal activity induced by noise trauma and HFS were assessed using c-Fos immunohistochemistry in related structures. Results showed tinnitus development after noise trauma and hearing loss ipsilateral to the side exposed to noise trauma. During HFS of the DCN, tinnitus was suppressed. There was no change in c-Fos expression within the central auditory pathway after HFS. These findings suggest that DCN-HFS changes patterns of activity and results in information lesioning within the network and hereby blocking the relay of abnormal tinnitus-related neuronal activity.
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http://dx.doi.org/10.1177/2331216519835080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419256PMC
November 2019

An update on adaptive deep brain stimulation in Parkinson's disease.

Mov Disord 2018 12 24;33(12):1834-1843. Epub 2018 Oct 24.

Departments of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands.

Advancing conventional open-loop DBS as a therapy for PD is crucial for overcoming important issues such as the delicate balance between beneficial and adverse effects and limited battery longevity that are currently associated with treatment. Closed-loop or adaptive DBS aims to overcome these limitations by real-time adjustment of stimulation parameters based on continuous feedback input signals that are representative of the patient's clinical state. The focus of this update is to discuss the most recent developments regarding potential input signals and possible stimulation parameter modulation for adaptive DBS in PD. Potential input signals for adaptive DBS include basal ganglia local field potentials, cortical recordings (electrocorticography), wearable sensors, and eHealth and mHealth devices. Furthermore, adaptive DBS can be applied with different approaches of stimulation parameter modulation, the feasibility of which can be adapted depending on specific PD phenotypes. Implementation of technological developments like machine learning show potential in the design of such approaches; however, energy consumption deserves further attention. Furthermore, we discuss future considerations regarding the clinical implementation of adaptive DBS in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587997PMC
December 2018

Inhibition of Experimental Tinnitus With High Frequency Stimulation of the Rat Medial Geniculate Body.

Neuromodulation 2019 Jun 13;22(4):416-424. Epub 2018 Aug 13.

Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.

Background: Neuromodulation is a promising treatment modality for tinnitus, especially in chronic and severe cases. The auditory thalamus plays a key role in the pathophysiology of tinnitus, as it integrates and processes auditory and limbic information.

Objective: The effect of high frequency stimulation and low frequency stimulation of the medial geniculate bodies on tinnitus in a noise-induced tinnitus rat model is assessed.

Materials And Methods: Presence of tinnitus was verified using the gap-induced prepulse inhibition of the acoustic startle response paradigm. Hearing thresholds were determined before and after noise trauma with auditory brainstem responses. Anxiety-related side-effects were evaluated in the elevated zero maze and open field.

Results: Results show tinnitus development after noise exposure and preserved hearing thresholds of the ear that was protected from noise trauma. We found that high frequency stimulation of the medial geniculate bodies suppressed tinnitus. This effect maintained directly after stimulation when the stimulator was turned off. Low frequency stimulation did not have any effects on the gap:no-gap ratio of the acoustic startle response.

Conclusion: High frequency stimulation of the MGB has a direct and residual suppressing effect on tinnitus in this animal model. Low frequency stimulation of the MGB did not inhibit tinnitus.
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http://dx.doi.org/10.1111/ner.12795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618158PMC
June 2019

Single-Cell Recordings to Target the Anterior Nucleus of the Thalamus in Deep Brain Stimulation for Patients with Refractory Epilepsy.

Int J Neural Syst 2019 May 2;29(4):1850012. Epub 2018 Apr 2.

* Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising treatment for patients with refractory epilepsy. However, therapy response varies and precise positioning of the DBS lead is potentially essential for maximizing therapeutic efficacy. We investigate if single-cell recordings acquired by microelectrode recordings can aid targeting of the ANT during surgery and hypothesize that the neuronal firing properties of the target region relate to clinical outcome. We prospectively included 10 refractory epilepsy patients and performed microelectrode recordings under general anesthesia to identify the change in neuronal signals when approaching and transecting the ANT. The neuronal firing properties of the target region, anatomical locations of microelectrode recordings and active contact positions of the DBS lead along the recorded trajectory were compared between responders and nonresponders to DBS. We obtained 19 sets of recordings from 10 patients (five responders and five nonresponders). Amongst the 403 neurons detected, 365 (90.6%) were classified as bursty. Entry into the ANT was characterized by an increase in firing rate while exit of the ANT was characterized by a decrease in firing rate. Comparing the trajectories of responders to nonresponders, we found differences neither in the neuronal firing properties themselves nor in their locations relative to the position of the active contact. Single-cell firing rate acquired by microelectrode recordings under general anesthesia can thus aid targeting of the ANT during surgery, but is not related to clinical outcome in DBS for patients with refractory epilepsy.
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http://dx.doi.org/10.1142/S0129065718500120DOI Listing
May 2019

Serotonergic neurons mediate the anxiolytic effect of l-DOPA: Neuronal correlates in the amygdala.

Neurobiol Dis 2018 02 3;110:20-28. Epub 2017 Nov 3.

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33076 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33076 Bordeaux, France. Electronic address:

Anxiety in Parkinson's disease is a comorbid non-motor symptom that alters the quality of life of patients. Its neuronal substrates and those of l-Dopa treatment are still poorly known. Using different combinations of monoaminergic system lesions in the rat, we addressed the contribution of these systems in the efficacy of l-DOPA on anxiety and on the neuronal activity of basolateral amygdala (BLA), a brain structure involved in anxiety. Anxiety, locomotor activity and motor performance were assessed using the elevated plus maze, the open field and the skinner box, respectively. The neuronal activity of BLA was electrophysiologically recorded and the loss of dopamine, noradrenaline and serotonin neurons was quantified by immunohistochemistry and stereology. Selective bilateral lesion of dopamine neurons, with or without the additional lesions of noradrenaline and/or serotonin neurons, induced anxiety disorder. l-Dopa significantly decreased anxiety in animals with bilateral lesion of dopamine neurons alone or combined with that of noradrenaline neurons. In these two groups, l-DOPA enhanced the firing rate of BLA neurons. However, in animals with combined lesions of dopamine and serotonin neurons or in animals with lesions of the three monoaminergic systems, l-Dopa was no longer able to decrease anxiety behavior or to change the electrophysiological parameters of BLA neurons. Our data provide the first evidence of the key and positive role of the serotonergic system in the combined efficacy of l-Dopa on anxiety and the paralleled BLA neuronal activity, suggesting that the enhancement of the activity of serotonin neurons may boost the anxiolytic action of l-DOPA.
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http://dx.doi.org/10.1016/j.nbd.2017.11.001DOI Listing
February 2018

Hearing assessment during deep brain stimulation of the central nucleus of the inferior colliculus and dentate cerebellar nucleus in rat.

PeerJ 2017 6;5:e3892. Epub 2017 Oct 6.

Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Recently it has been shown in animal studies that deep brain stimulation (DBS) of auditory structures was able to reduce tinnitus-like behavior. However, the question arises whether hearing might be impaired when interfering in auditory-related network loops with DBS.

Methods: The auditory brainstem response (ABR) was measured in rats during high frequency stimulation (HFS) and low frequency stimulation (LFS) in the central nucleus of the inferior colliculus (CIC,  = 5) or dentate cerebellar nucleus (DCBN,  = 5). Besides hearing thresholds using ABR, relative measures of latency and amplitude can be extracted from the ABR. In this study ABR thresholds, interpeak latencies (I-III, III-V, I-V) and V/I amplitude ratio were measured during off-stimulation state and during LFS and HFS.

Results: In both the CIC and the CNBN groups, no significant differences were observed for all outcome measures.

Discussion: DBS in both the CIC and the CNBN did not have adverse effects on hearing measurements. These findings suggest that DBS does not hamper physiological processing in the auditory circuitry.
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http://dx.doi.org/10.7717/peerj.3892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633028PMC
October 2017

Tonic and phasic changes in anteromedial globus pallidus activity in Tourette syndrome.

Mov Disord 2017 Jul 29;32(7):1091-1096. Epub 2017 May 29.

The Leslie & Susan Goldschmied (Gonda) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.

Background: Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics.

Objective: Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome.

Methods: Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries.

Results: The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed.

Conclusions: The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27043DOI Listing
July 2017

Cortico-subthalamic inputs from the motor, limbic, and associative areas in normal and dopamine-depleted rats are not fully segregated.

Brain Struct Funct 2017 Aug 24;222(6):2473-2485. Epub 2016 Dec 24.

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 146, Rue Léo-Saignat, 33000, Bordeaux Cedex, France.

The subthalamic nucleus (STN) receives monosynaptic glutamatergic afferents from different areas of the cortex, known as the "hyperdirect" pathway. The STN has been divided into three distinct subdivisions, motor, limbic, and associative parts in line with the concept of parallel information processing. The extent to which the parallel information processing coming from distinct cortical areas overlaps in the different territories of the STN is still a matter of debate and the proposed role of dopaminergic neurons in maintaining the coherence of responses to cortical inputs in each territory is not documented. Using extracellular electrophysiological approaches, we investigated to what degree the motor and non-motor regions in the STN are segregated in control and dopamine (DA) depleted rats. We performed electrical stimulation of different cortical areas and recorded STN neuronal responses. We showed that motor and non-motor cortico-subthalamic pathways are not fully segregated, but partially integrated in the rat. This integration was mostly present through the indirect pathway. The spatial distribution and response latencies were the same in sham and 6-hydroxydopamine lesioned animals. The inhibitory phase was, however, less apparent in the lesioned animals. In conclusion, this study provides the first evidence that motor and non-motor cortico-subthalamic pathways in the rat are not fully segregated, but partially integrated. This integration was mostly present through the indirect pathway. We also show that the inhibitory phase induced by GABAergic inputs from the external segment of the globus pallidus is reduced in the DA-depleted animals.
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http://dx.doi.org/10.1007/s00429-016-1351-5DOI Listing
August 2017

The impact of deep brain stimulation on tinnitus.

Surg Neurol Int 2016 14;7(Suppl 35):S848-S854. Epub 2016 Nov 14.

Department of Ear Nose and Throat/Head and Neck Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Tinnitus is a disorder of the nervous system that cannot be adequately treated with current therapies. The effect of neuromodulation induced by deep brain stimulation (DBS) on tinnitus has not been studied well. This study investigated the effect of DBS on tinnitus by use of a multicenter questionnaire study.

Methods: Tinnitus was retrospectively assessed prior to DBS and at the current situation (with DBS). From the 685 questionnaires, 443 were returned. A control group was one-to-one matched to DBS patients who had tinnitus before DBS ( = 61). Tinnitus was assessed by the tinnitus handicap inventory (THI) and visual analog scales (VAS) of loudness and burden.

Results: The THI decreased significantly during DBS compared to the situation prior to surgery (from 18.9 to 15.1, < .001), which was only significant for DBS in the subthalamic nucleus (STN). The THI in the control group (36.9 to 35.5, = 0.50) and other DBS targets did not change. The VAS loudness increased in the control group (5.4 to 6.0 < .01).

Conclusion: DBS might have a modulatory effect on tinnitus. Our study suggests that DBS of the STN may have a beneficial effect on tinnitus, but most likely other nuclei linked to the tinnitus circuitry might be even more effective.
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http://dx.doi.org/10.4103/2152-7806.194156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134112PMC
November 2016

Spatial Localization of Sources in the Rat Subthalamic Motor Region Using an Inverse Current Source Density Method.

Front Neural Circuits 2016 3;10:87. Epub 2016 Nov 3.

Biomedical Signals and Systems Group, MIRA institute for Biomedical Engineering and Technical Medicine, University of Twente Enschede, Netherlands.

In this study we introduce the use of the current source density (CSD) method as a way to visualize the spatial organization of evoked responses in the rat subthalamic nucleus (STN) at fixed time stamps resulting from motor cortex stimulation. This method offers opportunities to visualize neuronal input and study the relation between the synaptic input and the neural output of neural populations. Motor cortex evoked local field potentials and unit activity were measured in the subthalamic region, with a 3D measurement grid consisting of 320 measurement points and high spatial resolution. This allowed us to visualize the evoked synaptic input by estimating the current source density (CSD) from the measured local field potentials, using the inverse CSD method. At the same time, the neuronal output of the cells within the grid is assessed by calculating post stimulus time histograms. The CSD method resulted in clear and distinguishable sources and sinks of the neuronal input activity in the STN after motor cortex stimulation. We showed that the center of the synaptic input of the STN from the motor cortex is located dorsal to the input from globus pallidus. For the first time we have performed CSD analysis on motor cortex stimulation evoked LFP responses in the rat STN as a proof of principle. Our results suggest that the CSD method can be used to gain new insights into the spatial extent of synaptic pathways in brain structures.
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http://dx.doi.org/10.3389/fncir.2016.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093117PMC
October 2017

Deep brain stimulation of the inferior colliculus in the rodent suppresses tinnitus.

Brain Res 2016 11 31;1650:118-124. Epub 2016 Aug 31.

Department of Ear Nose and Throat/Head and Neck Surgery, Maastricht University Medical Center, Maastricht, The Netherlands; Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

In animal models of tinnitus pathological neuronal activity has been demonstrated. Deep brain stimulation disrupts pathological neuronal activity and might therefore be a potential treatment for patients who suffer severely from tinnitus. In this study, the effect of DBS in the inferior colliculi is investigated in an animal model of tinnitus. The external cortex of the inferior colliculus was targeted because of the key position of the inferior colliculus within the auditory network and the relation of the external cortex with the limbic system. In this study we show the effect of DBS in the inferior colliculus on tinnitus using a within-subject experimental design. After noise trauma, rats showed a significant increase in gap:no gap ratio of the gap-induced prepulse inhibition at 16 and 20kHz (p<0.05), indicating the presence of tinnitus in these frequency bands. During DBS the gap:no gap ratio returned back to baseline (p<0.05). Hearing thresholds before and during DBS did not differ, indicating that hearing function is probably not impaired by electrical stimulation. In summary, this study shows that DBS of the inferior colliculi is effective in reducing behavioral signs of tinnitus in an animal model. Impaired hearing function could not be objectified as a side effect of stimulation.
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http://dx.doi.org/10.1016/j.brainres.2016.08.046DOI Listing
November 2016

The antidepressant effects of ventromedial prefrontal cortex stimulation is associated with neural activation in the medial part of the subthalamic nucleus.

Behav Brain Res 2015 Feb 13;279:17-21. Epub 2014 Nov 13.

Department of Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands; Department of Neurosurgery, Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address:

The nucleus accumbens (NAc), ventromedial prefrontal cortex (vmPFC), and cingulate gyrus (Cg) are key regions in the control of mood-related behaviors. Electrical stimulation of these areas induces antidepressant-like effects in both patients and animal models. Another structure whose limbic connections are receiving more interest in the context of mood-related behaviors is the medial part of the subthalamic nucleus (STN). Here, we tested the hypothesis that the mood-related effects of NAc, vmPFC, and Cg are accompanied by changes in the neural activity of the STN. We performed high-frequency stimulation (HFS) of the NAc, vmPFC, and Cg. Animals were behaviorally tested for hedonia and forced swim immobility; and the cellular activities in the different parts of the STN were assessed by means of c-Fos immunoreactivity (c-Fos-ir). Our results showed that HFS of the NAc and vmPFC, but not Cg reduced anhedonic-like and forced swim immobility behaviors. Interestingly, there was a significant increase of c-Fos-ir in the medial STN with HFS of the vmPFC, but not the NAc and Cg as compared to the sham. Correlation analysis showed that the medial STN is associated with the antidepressant-like behaviors in vmPFC HFS animals. No behavioral correlation was found with respect to behavioral outcome and activity in the lateral STN. In conclusion, HFS of the vmPFC induced profound antidepressant-like effects with enhanced neural activity in the medial part of the STN.
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http://dx.doi.org/10.1016/j.bbr.2014.11.008DOI Listing
February 2015

Subthalamic nucleus high-frequency stimulation for advanced Parkinson's disease: motor and neuropsychological outcome after 10 years.

Stereotact Funct Neurosurg 2014 29;92(6):381-7. Epub 2014 Oct 29.

Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Since the introduction of subthalamic nucleus deep brain stimulation (STN DBS), many clinical studies have shown that this therapy is safe and effective in the short and medium term. Only little is known about long-term results.

Objectives: To provide an analysis of motor and cognitive outcome 10 years after STN DBS.

Methods: In this observational cohort study, we report on the motor and cognitive outcome in a cohort of 26 Parkinson's disease patients who were prospectively followed up for 10 years after STN DBS surgery.

Results: In the early post-operative phase, improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) III (10.6, p < 0.01) and IV (2.5, p < 0.01) was seen as well as a 32% reduction in levodopa equivalent dose (p < 0.01). After 5 years, a worsening of the motor performance was observed. The worsening of motor performance was mainly due to a deterioration in bradykinesia (12.4 ± 4.6, p < 0.05) and axial symptoms (6.9 ± 2.8, p < 0.01). Memory function seemed to improve in the short term, but there was a significant decline between 1 and 5 years after surgery (p < 0.01). Mood remained relatively stable during follow-up, and one third of the patients showed impulsive behaviour after surgery.

Conclusions: The motor performance of patients showed deterioration over time, due to an increase in bradykinesia and axial symptoms.
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http://dx.doi.org/10.1159/000366066DOI Listing
October 2015

An experimental model for Huntington's chorea?

Behav Brain Res 2014 Apr 8;262:31-4. Epub 2014 Jan 8.

Department of Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands; Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands; European Graduate School of Neuroscience (EURON) , The Netherlands. Electronic address:

Clinically, Huntington's disease (HD) is well known for the predominant motor symptom chorea, which is a hyperkinetic motor disorder. The only experimental model currently described in the literature, as far as we are aware of, exhibiting hyperkinetic movements is the transgenic rat model of HD. We assessed and characterized these hyperkinetic movements in detail and investigated the effect of tetrabenazine (TBZ) treatment. TBZ is an effective drug in the treatment of chorea in HD patients. Our results showed that the hyperkinetic movements fulfilled the clinical-behavioral criteria of a choreiform movement. Administration of TBZ reduced the number of these hyperkinetic movements substantially. These findings suggest that the hyperkinetic movements observed in this animal model can be considered as a choreiform movement disorder. This makes these animals unique and provides opportunities for chorea-research.
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http://dx.doi.org/10.1016/j.bbr.2013.12.036DOI Listing
April 2014

Electrical stimulation of the motor cortex enhances progenitor cell migration in the adult rat brain.

Exp Brain Res 2013 Nov 4;231(2):165-77. Epub 2013 Sep 4.

Departments of Neuroscience and Neurosurgery, Maastricht University Medical Center (MUMC), PO Box 5800, 6202 AZ, Maastricht, The Netherlands,

Clinical and preclinical investigations suggest that epidural stimulation of the motor cortex (MC) can improve stroke-induced neurological deficits. The mechanisms involved in stimulation-induced recovery are not well understood and might involve neurogenesis-related processes. Here, we addressed the question whether MC stimulation influences processes of migration and differentiation of neuronal progenitor cells in vivo. Epidural stimulation electrodes were implanted at the level of the MC in rats, and electrical current was applied for a period of 1 month. Increased cell proliferation was observed in the subventricular zone (SVZ). We also found evidences for enhanced cell migration toward the source of current, a process known as electrotaxis. Some of these cells expressed the neuronal marker, NeuN. In addition, our results indicate that MC stimulation enhances neuronal activity of the dorsal raphe nucleus, leading to an increase in the expression of 5-hydroxytryptamine in the SVZ. It is known that such an increase can promote formation of new cells in the SVZ. Our findings suggest that epidural MC stimulation influences neurogenesis-related processes in animal models.
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http://dx.doi.org/10.1007/s00221-013-3680-4DOI Listing
November 2013

Cortically evoked potentials in the human subthalamic nucleus.

Neurosci Lett 2013 Feb 4;539:27-31. Epub 2013 Feb 4.

MIRA institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems group, University of Twente, Enschede, The Netherlands.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms in Parkinson's disease (PD) patients. However, in a substantial number of patients the beneficial effects of STN DBS are overshadowed by psychiatric side effects. We hypothesize that stimulation of the STN motor area will provide the optimal effect on the motor symptoms without inducing these side effects, and expect that motor cortex stimulation (MCS) evokes a spatially specific response within the STN, which identifies the STN motor area. We previously showed that MCS evokes responses in the unit activity specifically within certain areas of the STN. Unit activity is generally considered a measure of the output activity. To gain more insight into the neuronal input into the STN, we describe the results of cortically evoked subthalamic local field potentials (LFPs). We show that the cortically evoked LFPs follow a certain temporal and spatial pattern. The significant peaks of the evoked LFPs coincide with the timing of some of the inhibitions and excitations present in the unit responses. The spatial resolution of responses measured in the LFP to MCS is not high enough to identify the STN motor region. However, we believe that optimizing targeting techniques and the development of novel DBS electrodes will improve STN DBS therapy for PD patients.
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http://dx.doi.org/10.1016/j.neulet.2013.01.036DOI Listing
February 2013

Neuromodulation in psychiatric disorders.

Int Rev Neurobiol 2012 ;107:283-314

Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands.

Psychiatric disorders are worldwide a common cause of severe and long-term disability and socioeconomic burden. The management of patients with psychiatric disorders consists of drug therapy and/or psychotherapy. However, in some patients, these treatment modalities do not produce sufficient therapeutic effects or induce intolerable side effects. For these patients, neuromodulation has been suggested as a potential treatment modality. Neuromodulation includes deep brain stimulation, vagal nerve stimulation, and transcranial magnetic and electrical stimulation. The rationale for neuromodulation is derived from the research identifying neurobiologically localized substrates for refractory psychiatric symptoms. Here, we review the clinical data on neuromodulation in the major psychiatric disorders. Relevant data from animal models will also be discussed to explain the neurobiological basis of the therapy.
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http://dx.doi.org/10.1016/B978-0-12-404706-8.00015-2DOI Listing
September 2013
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