Aging suppresses subthalamic neuronal activity in patients with Parkinson's disease.

Age is a primary risk factor for Parkinson's disease (PD); however, the effects of aging on the Parkinsonian brain remain poorly understood, particularly for deep brain structures. We investigated intraoperative micro-electrode recordings from the subthalamic nucleus (STN) of PD patients aged between 42 and 76 years. Age was associated with decreased oscillatory beta power and non-oscillatory high-frequency power, independent of PD-related variables. Single unit firing and burst rates were also reduced, whereas the coefficient of variation and the structure of burst activity were unchanged. Phase synchronization (debiased weighed phase lag index [dWPLI]) between sites was pronounced in the beta band between electrodes in the superficial STN but was unaffected by age. Our results show that aging is associated with reduced neuronal activity without changes to its temporal structure. We speculate that the loss of activity in the STN may mediate the relationship between PD and age.

Invasive neurophysiological recordings in human basal ganglia. What have we learned about non-motor behaviour?

Research into the function of deep brain structures has benefited greatly from microelectrode recordings in animals. This has helped to unravel physiological processes in the healthy and malfunctioning brain. Translation to the human is necessary for improving basic understanding of subcortical structures and their implications in diseases. The use of microelectrode recordings as a standard component of deep brain stimulation surgery offers the most viable route for studying the electrophysiology of single cells and local neuronal populations in important deep structures of the human brain. Most of the studies in the basal ganglia have targeted the motor loop and movement disorder pathophysiology. In recent years, however, research has diversified to include limbic and cognitive processes. This review aims to provide an overview of advances in neuroscience made using intraoperative and post-operative recordings with a focus on non-motor activity in the basal ganglia.

Reference values for nerve conduction studies of the peroneal, tibial, and sural nerve derived from a large population-based cohort: Associations with demographic and anthropometric characteristics-The Maastricht study.

INTRODUCTION/AIMS: Nerve conduction studies (NCSs) are widely used to support the clinical diagnosis of neuromuscular disorders. The aims of this study were to obtain reference values for peroneal, tibial, and sural NCSs and to examine the associations with demographic and anthropometric factors. METHODS: In 5099 participants (aged 40-79 years) without type 2 diabetes of The Maastricht Study, NCSs of peroneal, tibial, and sural nerves were performed. Values for compound muscle action potential (CMAP) and sensory nerve action potential amplitude, nerve conduction velocity (NCV), and distal latency were acquired. The association of age, sex, body mass index (BMI), and height with NCS values was determined using uni- and multivariate linear regression analyses. RESULTS: Detailed reference values are reported per decade for men and women. Significantly lower NCVs and longer distal latencies were observed in all nerves in older and taller individuals as well as in men. In these groups, amplitudes of the tibial and sural nerves were significantly lower, whereas a lower peroneal nerve CMAP was only significantly associated with age. BMI showed a multidirectional association. After correction for anthropometric factors in the multivariate analysis, the association between sex and NCS values was less straightforward. DISCUSSION: These values from a population-based dataset could be used as a reference for generating normative values. Our findings show the association of NCS values with anthropometric factors. In clinical practice, these factors can be considered when interpreting NCS values.

Spatiotemporal patterns of sleep spindle activity in human anterior thalamus and cortex.

Sleep spindles (8 - 16 Hz) are transient electrophysiological events during non-rapid eye movement sleep. While sleep spindles are routinely observed in the cortex using scalp electroencephalography (EEG), recordings of their thalamic counterparts have not been widely studied in humans. Based on a few existing studies, it has been hypothesized that spindles occur as largely local phenomena. We investigated intra-thalamic and thalamocortical spindle co-occurrence, which may underlie thalamocortical communication. We obtained scalp EEG and thalamic recordings from 7 patients that received bilateral deep brain stimulation (DBS) electrodes to the anterior thalamus for the treatment of drug resistant focal epilepsy. Spindles were categorized into subtypes based on their main frequency (i.e., slow (10±2 Hz) or fast (14±2 Hz)) and their level of thalamic involvement (spanning one channel, or spreading uni- or bilaterally within the thalamus). For the first time, we contrasted observed spindle patterns with permuted data to estimate random spindle co-occurrence. We found that multichannel spindle patterns were systematically coordinated at the thalamic and thalamocortical level. Importantly, distinct topographical patterns of thalamocortical spindle overlap were associated with slow and fast subtypes of spindles. These observations provide further evidence for coordinated spindle activity in thalamocortical networks.

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

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.

Surgical and Hardware-Related Adverse Events of Deep Brain Stimulation: A Ten-Year Single-Center Experience.

INTRODUCTION: Although deep brain stimulation (DBS) is effective for treating a number of neurological and psychiatric indications, surgical and hardware-related adverse events (AEs) can occur that affect quality of life. This study aimed to give an overview of the nature and frequency of those AEs in our center and to describe the way they were managed. Furthermore, an attempt was made at identifying possible risk factors for AEs to inform possible future preventive measures. MATERIALS AND METHODS: Patients undergoing DBS-related procedures between January 2011 and July 2020 were retrospectively analyzed to inventory AEs. The mean follow-up time was 43 ± 31 months. Univariate logistic regression analysis was used to assess the predictive value of selected demographic and clinical variables. RESULTS: From January 2011 to July 2020, 508 DBS-related procedures were performed including 201 implantations of brain electrodes in 200 patients and 307 implantable pulse generator (IPG) replacements in 142 patients. Surgical or hardware-related AEs following initial implantation affected 40 of 200 patients (20%) and resolved without permanent sequelae in all instances. The most frequent AEs were surgical site infections (SSIs) (9.95%, 20/201) and wire tethering (2.49%, 5/201), followed by hardware failure (1.99%, 4/201), skin erosion (1.0%, 2/201), pain (0.5%, 1/201), lead migration (0.52%, 2/386 electrode sites), and hematoma (0.52%, 2/386 electrode sites). The overall rate of AEs for IPG replacement was 5.6% (17/305). No surgical, ie, staged or nonstaged, electrode fixation, or patient-related risk factors were identified for SSI or wire tethering. CONCLUSIONS: Major AEs including intracranial surgery-related AEs or AEs requiring surgical removal or revision of hardware are rare. In particular, aggressive treatment is required in SSIs involving multiple sites or when Staphylococcus aureus is identified. For future benchmarking, the development of a uniform reporting system for surgical and hardware-related AEs in DBS surgery would be useful.

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

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 (n = 145 in noise-exposed group, n = 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 ß 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.NEW & NOTEWORTHY 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 ß and γ oscillations as a mechanism of tinnitus suppression by MGB DBS.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Central Aspects of Tinnitus: Advances in Mechanisms and Neuromodulation.

Tinnitus is a complex neuro-otologic disorder with a significant global impact, affecting approximately 14% of adults, with 2% experiencing severe forms [...].

A Prospective Self-Report Survey-Based Cohort Study on Factors That Have an Influence on Tinnitus.

Background: Limited information is available on factors that affect the burden tinnitus. The aim of this study is to investigate the association between tinnitus burden and demographic, patient-specific and tinnitus characteristics. Secondly, it was examined which variables could predict a change in tinnitus burden after 12 months. Method: In a prospective Dutch cohort of 383 tinnitus patients seeking medical help, tinnitus complaints, demographics, tinnitus characteristics, psychological wellbeing and quality of life were assessed using an online self-report survey at three timepoints (start, 6 months, 12 months). The main outcome variables for tinnitus burden are the Tinnitus Questionnaire (TQ) and Visual Analog Scale (VAS) for tinnitus burden and loudness. Results: Several variables (time, sex, education level, life events, anxiety and depression, sleep issues, tinnitus loudness, hearing impairment and treatment) were significantly associated with tinnitus burden. Additionally, tinnitus burden after 12 months was associated with anxiety, following treatment, sleep issues, negative life events and hearing impairment (increase) and anxiety, total of life events and environmental quality of life (decrease) predicted the tinnitus burden after 12 months. Conclusions: Several factors, such as education level, life events, psychological factors and sleep quality, are related to tinnitus burden and can predict tinnitus burden over time.

Parallel EEG assessment of different sound predictability levels in tinnitus.

Tinnitus denotes the perception of a non-environmental sound and might result from aberrant auditory prediction. Successful prediction of formal (e.g., type) and temporal sound characteristics facilitates the filtering of irrelevant information, also labelled as 'sensory gating' (SG). Here, we explored if and how parallel manipulations of formal prediction violations and temporal predictability affect SG in persons with and without tinnitus. Age-, education- and sex-matched persons with and without tinnitus (N = 52) participated and listened to paired-tone oddball sequences, varying in formal (standard vs. deviant pitch) and temporal predictability (isochronous vs. random timing). EEG was recorded from 128 channels and data were analyzed by means of temporal spatial principal component analysis (tsPCA). SG was assessed by amplitude suppression for the 2nd tone in a pair and was observed in P50-like activity in both timing conditions and groups. Correspondingly, deviants elicited overall larger amplitudes than standards. However, only persons without tinnitus displayed a larger N100-like deviance response in the isochronous compared to the random timing condition. This result might imply that persons with tinnitus do not benefit similarly as persons without tinnitus from temporal predictability in deviance processing. Thus, persons with tinnitus might display less temporal sensitivity in auditory processing than persons without tinnitus.

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

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.

[Current diagnostics and treatment options for tinnitus]. / Diagnostiek en behandelopties voor tinnitus.

Tinnitus is a common condition with great variability in the intensity of symptomatology. In recent years, more and more insights have been gained into the mechanism of tinnitus and its relationship with hearing loss and other factors such as stress. Depending on the symptoms and clinical findings, a patient may be referred to an ENT specialist or audiologist. For the majority of patients, re-assurance and providing good information is sufficient. For others improving hearing and possibly cognitive behavioral therapy remains the most important pillars for treatment of tinnitus. A number of experimental treatments are currently underway which offer hope for the future.

Validation of the Dutch Sensory Gating Inventory (D-SGI): Psychometric properties and a Confirmatory factor analysis.

The Sensory Gating Inventory (SGI) is an established self-report questionnaire that is used to assess the capacity for filtering redundant or irrelevant environmental stimuli. Translation and cross-cultural validation of the SGI are necessary to make this tool available to Dutch speaking populations. This study, therefore, aimed to design and validate a Dutch Sensory Gating Inventory (D-SGI). To this end, a forward-backward translation was performed and 469 native Dutch speakers filled in the questionnaire. A confirmatory factor analysis assessed the psychometric properties of the D-SGI. Additionally, test-retest reliability was measured. Results confirmed satisfactory similarity between the original English SGI and the D-SGI in terms of psychometric properties for the factor structure. Internal consistency and discriminant validity were also satisfactory. Overall test-retest reliability was excellent (ICC = 0.91, p < 0.001, 95% CI [0.87-0.93]). These findings confirm that the D-SGI is a psychometrically sound self-report measure that allows assessing the phenomenological dimensions of sensory gating in Dutch. Moreover, the D-SGI is publicly available. This establishes the D-SGI as a new tool for the assessment of sensory gating dimensions in general- and clinical Dutch speaking populations.

Sensory gating functions of the auditory thalamus: Adaptation and modulations through noise-exposure and high-frequency stimulation in rats.

The medial geniculate body (MGB) of the thalamus is an obligatory relay for auditory processing. A breakdown of adaptive filtering and sensory gating at this level may lead to multiple auditory dysfunctions, while high-frequency stimulation (HFS) of the MGB might mitigate aberrant sensory gating. To further investigate the sensory gating functions of the MGB, this study (i) recorded electrophysiological evoked potentials in response to continuous auditory stimulation, and (ii) assessed the effect of MGB HFS on these responses in noise-exposed and control animals. Pure-tone sequences were presented to assess differential sensory gating functions associated with stimulus pitch, grouping (pairing), and temporal regularity. Evoked potentials were recorded from the MGB and acquired before and after HFS (100 Hz). All animals (unexposed and noise-exposed, pre- and post-HFS) showed gating for pitch and grouping. Unexposed animals also showed gating for temporal regularity not found in noise-exposed animals. Moreover, only noise-exposed animals showed restoration comparable to the typical EP amplitude suppression following MGB HFS. The current findings confirm adaptive thalamic sensory gating based on different sound characteristics and provide evidence that temporal regularity affects MGB auditory signaling.