Beyond Dopamine: GABA, Glutamate, and the Axial Symptoms of Parkinson Disease

Introduction: The axial symptoms of Parkinson disease (PD) include difficulties with balance, posture, speech, swallowing, and locomotion with freezing of gait, as well as axial rigidity. These axial symptoms impact negatively on quality of life for many patients, yet remain poorly understood. Dopaminergic treatments typically have little effect on the axial symptoms of PD, suggesting that disruptions in other neurotransmitter systems beyond the dopamine system may underlie these symptoms. The purpose of the present study was to examine the relationship between the axial symptoms of PD and GABA and glutamate levels quantified with magnetic resonance spectroscopy.Methods: The participant group included 20 patients with PD and 17 healthy control participants. Water-scaled GABA and Glx (glutamate + glutamine) concentrations were derived from GABA-edited MEGA-PRESS spectra acquired from the left basal ganglia and prefrontal cortex, and additional water-scaled Glx concentrations were acquired from standard PRESS spectra acquired from the pons. Spectra were analyzed with LCModel. The axial symptoms of PD were evaluated from subscales of the Unified Parkinson's Disease rating scale (MDS-UPDRS).Results: PD patients demonstrated significantly higher GABA levels in the basal ganglia, which correlated with the degree of gait disturbance. Basal ganglia Glx levels and prefrontal GABA and Glx levels did not differ significantly between patient and control groups, but within the PD group prefrontal Glx levels correlated negatively with difficulties turning in bed. Results from an exploratory subgroup analysis indicate that the associations between GABA, Glx, and axial symptoms scores are typically more prominent in akinetic-rigid patients than in tremor-dominant patients.Conclusion: Alterations in GABAergic and glutamatergic neurotransmission may contribute to some of the axial symptoms of PD

The Impact of Subthalamic Deep Brain Stimulation on Sleep–Wake Behavior: A Prospective Electrophysiological Study in 50 Parkinson Patients

Study objectives: This prospective observational study was designed to systematically examine the effect of subthalamic deep brain stimulation (DBS) on subjective and objective sleep-wake parameters in Parkinson patients. Methods: In 50 consecutive Parkinson patients undergoing subthalamic DBS, we assessed motor symptoms, medication, the position of DBS electrodes within the subthalamic nucleus (STN), subjective sleep-wake parameters, 2-week actigraphy, video-polysomnography studies, and sleep electroencepahalogram frequency and dynamics analyses before and 6 months after surgery. Results: Subthalamic DBS improved not only motor symptoms and reduced daily intake of dopaminergic agents but also enhanced subjective sleep quality and reduced sleepiness (Epworth Sleepiness Scale: -2.1 ± 3.8, p < .001). Actigraphy recordings revealed longer bedtimes (+1:06 ± 0:51 hours, p < .001) without shifting of circadian timing. Upon polysomnography, we observed an increase in sleep efficiency (+5.2 ± 17.6%, p = .005) and deep sleep (+11.2 ± 32.2 min, p = .017) and increased accumulation of slow-wave activity over the night (+41.0 ± 80.0%, p = .005). Rapid eye movement sleep features were refractory to subthalamic DBS, and the dynamics of sleep as assessed by state space analyses did not normalize. Increased sleep efficiency was associated with active electrode contact localization more distant from the ventral margin of the left subthalamic nucleus. Conclusion: Subthalamic DBS deepens and consolidates nocturnal sleep and improves daytime wakefulness in Parkinson patients, but several outcomes suggest that it does not normalize sleep. It remains elusive whether modulated activity in the STN directly contributes to changes in sleep-wake behavior, but dorsal positioning of electrodes within the STN is linked to improved sleep-wake outcomes

Stimulation sites in the subthalamic nucleus projected onto a mean 3-D atlas of the thalamus and basal ganglia

Background: In patients with severe forms of Parkinson's disease (PD), deep brain stimulation (DBS) commonly targets the subthalamic nucleus (STN). Recently, the mean 3-D Morel-Atlas of the basal ganglia and the thalamus was introduced. It combines information contained in histological data from ten post-mortem brains. We were interested whether the Morel-Atlas is applicable for the visualization of stimulation sites. Methods: In a consecutive PD patient series, we documented preoperative MRI planning, intraoperative target adjustment based on electrophysiological and neurological testing, and perioperative CT target reconstruction. The localization of the DBS electrodes and the optimal stimulation sites were projected onto the Morel-Atlas. Results: We included 20 patients (median age 62 years). The active contact had mean coordinates Xlat = ±12.1mm, Yap = −1.8mm, Zvert = −3.2mm. There was a significant difference between the initially planned site and the coordinates of the postoperative active contact site (median 2.2mm). The stimulation site was, on average, more anterior and more dorsal. The electrode contact used for optimal stimulation was found within the STN of the atlas in 38/40 (95%) of implantations. Conclusions: The cluster of stimulation sites in individual patients—as deduced from preoperative MR, intraoperative electrophysiology and neurological testing—showed a high degree of congruence with the atlas. The mean 3D Morel Atlas is thus a useful tool for postoperative target visualization. This represents the first clinical evaluation of the recently created atla

Der Stellenwert der tiefen Hirnstimulation bei der schwer behandelbaren sowie therapierefraktären Depression

Die tiefe Hirnstimulation («THS») ist ein minimalinvasives, neurochirurgisches und hypothesengeleitetes Therapieverfahren zur dauerhaften, lokalen Regulation pathologischer Regelkreise. Während die Depression ein heterogenes Syndrom mit multifaktorieller Ätiopathogenese darstellt, fördert die neurowissenschaftliche Forschung die Evidenz zur Identifikation von Mechanismen auf Netzwerkebene, die in der Pathophysiologie der Depression eine tragende Rolle spielen. Der folgende Beitrag gibt einen Überblick über den Stellenwert der THS bei der therapieresistenten oder schwer behandelbaren Depression. Dabei möchten wir praxisnah den Bekanntheitsgrad der THS fördern und die Herausforderungen bei Therapie und Implementierung diskutieren. The Value of Deep Brain Stimulation in Difficult-To-Treat and Treatment-Refractory Depression Abstract: Deep Brain Stimulation ("DBS") is a minimally invasive, neurosurgical and hypothesis-driven therapeutic procedure for permanent local regulation of pathological circuits. While depression represents a heterogeneous syndrome with multifactorial etiopathogenesis, neuroscience research is advancing evidence to identify network-level mechanisms that play an important role in the pathophysiology of depression. In the following article, we will review the role of DBS in treatment-resistant or difficult-to-treat depression. The aim is to increase the awareness of DBS and to discuss the challenges of its therapy and implementation

Reduced Regional NREM Sleep Slow-Wave Activity Is Associated With Cognitive Impairment in Parkinson Disease

Growing evidence implicates a distinct role of disturbed slow-wave sleep in neurodegenerative diseases. Reduced non-rapid eye movement (NREM) sleep slow-wave activity (SWA), a marker of slow-wave sleep intensity, has been linked with age-related cognitive impairment and Alzheimer disease pathology. However, it remains debated if SWA is associated with cognition in Parkinson disease (PD). Here, we investigated the relationship of regional SWA with cognitive performance in PD. In the present study, 140 non-demented PD patients underwent polysomnography and were administered the Montréal Cognitive Assessment (MoCA) to screen for cognitive impairment. We performed spectral analysis of frontal, central, and occipital sleep electroencephalography (EEG) derivations to measure SWA, and spectral power in other frequency bands, which we compared to cognition using linear mixed models. We found that worse MoCA performance was associated with reduced 1–4 Hz SWA in a region-dependent manner (F2, 687 =11.67, p < 0.001). This effect was driven by reduced regional SWA in the lower delta frequencies, with a strong association of worse MoCA performance with reduced 1–2 Hz SWA (F2, 687 =18.0, p < 0.001). The association of MoCA with 1–2 Hz SWA (and 1–4 Hz SWA) followed an antero-posterior gradient, with strongest, weaker, and absent associations over frontal (rho = 0.33, p < 0.001), central (rho = 0.28, p < 0.001), and occipital derivations, respectively. Our study shows that cognitive impairment in PD is associated with reduced NREM sleep SWA, predominantly in lower delta frequencies (1–2 Hz) and over frontal regions. This finding suggests a potential role of reduced frontal slow-wave sleep intensity in cognitive impairment in PD

Worsened Parkinson's Disease Progression: Impact of the COVID-19 Pandemic

Whilst some studies investigated the impact of viral infection or reduced access to medication during the COVID-19 pandemic in patients with Parkinson's disease (PD), data on the effects of pandemic restrictions are still scarce. We retrospectively analyzed motor symptoms of longitudinally followed PD patients (n = 264) and compared motor disease progression before and during the COVID-19 pandemic. Additionally, we performed a trend analysis of the yearly evolution of motor symptoms in 755 patients from 2016 until 2021. We observed a worsening of motor symptoms and a significantly increased motor disease progression during pandemic-related restrictions as compared to before the COVID-19 outbreak

Narcolepsy type 2: A rare, yet existing entity

Because of unspecific diagnostic criteria, there is much controversy around narcolepsy type 2, its existence and its frequency. With this retrospective and purely descriptive study, we aimed to compare the frequency of narcolepsy type 2 compared to the well-described narcolepsy type 1, in a large (n = 3,782) retrospective sample from a single tertiary sleep centre. After 2 weeks washout of sleep-wake active medication, all patients with excessive daytime sleepiness (n = 1,392) underwent 2 weeks actigraphy, polysomnography and multiple sleep latency test, and all diagnoses were made along current diagnostic criteria. Narcolepsy type 1 was diagnosed in 91 patients, and 191 patients without cataplexy had multiple sleep latency test (MSLT) results indicating narcolepsy. After exclusion of shift work syndrome (n = 19), suspected insufficient sleep syndrome (n = 128), delayed sleep phase syndrome (n = 4) and obstructive sleep apnea (n = 34), six patients were diagnosed with narcolepsy type 2, of whom two patients later developed narcolepsy type 1. Altogether, our observations suggest that narcolepsy type 2 exists, but its frequency may be much lower compared to narcolepsy type 1. In addition, they emphasize the importance of scrupulously excluding other potential causes of sleepiness, if possible, with 2-week actigraphy and polysomnography

Partners' view after subthalamic deep brain stimulation: Better relationships despite patients being less active

Introduction: After deep brain stimulation (DBS) of the subthalamic nucleus (STN), Parkinson patients report difficulties in the relationship with their partners. The partners' experience after DBS appears to be variable and complex. Purpose of this pilot study was to investigate the partners' perspective on the relationship following STN-DBS. Subjects and methods: We conducted a postoperative questionnaire assessment in 56 partners of Parkinson patients with STN-DBS, using questionnaires addressing partnership satisfaction, dyadic coping, and role allocation in duties and activities of daily living. Results: Regarding overall relationship satisfaction after surgery, 40% of partners were happier with their relationship than before DBS, and 14% were less satisfied. Partners reported that patients involved themselves distinctly less in duties and activities of daily living, leaving partners to take over. A need for more professional support for the relationship following surgery was noted by 27% of the partners. Conclusion: Although quality of relationship and dyadic coping improved or remained unchanged according to the majority of partners, patients became less prone to take over common duties and activities despite being in a better and more stable motor state. Potential conflicts and problems in role allocation in relationships following DBS need to be addressed in patients care

Extending sleep to confirm insufficient sleep syndrome is challenging

Insufficient sleep syndrome (ISS) is prevalent, but poorly studied. This descriptive study was performed to determine its diagnostic challenges and clinical characteristics in a large (n = 3,461) retrospective sample from a single sleep laboratory. Based on actigraphy, polysomnography and multiple sleep latency tests, we diagnosed "suspected insufficient sleep syndrome" in patients with chronic sleepiness, short time in bed, longer sleep duration during weekends or vacation, and without evidence of other causes of sleepiness. For the diagnosis of "definite insufficient sleep syndrome", we additionally required objectively confirmed resolution of sleepiness with actigraphy-documented extension of time in bed. We diagnosed "suspected insufficient sleep syndrome" in 300 subjects. In 94 subjects, extension of sleep time with consecutive relief of sleepiness was attempted, but only 37 subjects succeeded, often despite being offered several attempts. "Definite insufficient sleep syndrome" was confirmed in 36 patients. In these subjects, mean time in bed after sleep extension was above 8 hr per night and 84 min longer than at baseline. Narcolepsy-like findings were frequently observed before sleep extension, but no sleep onset rapid eye movement sleep on polysomnography. This study indicates that fulfilling the diagnostic criteria of ISS is challenging in clinical practice. It further corroborates the importance of actigraphy and polysomnography for correct diagnosis