Heide Baumann-Vogel

Progressive dopamine and hypocretin deficiencies in Parkinson's disease: is there an impact on sleep and wakefulness?

Sleep–wake disturbances are frequent in patients with Parkinson’s disease, but prospective controlled electrophysiological studies of sleep in those patients are surprisingly sparse, and the pathophysiology of sleep–wake disturbances in Parkinson’s disease remains largely elusive. In particular, the impact of impaired dopaminergic and hypocretin (orexin) signalling on sleep and wakefulness in Parkinson’s disease is still unknown. We performed a prospective, controlled electrophysiological study in patients with early and advanced Parkinson’s disease, e.g. in subjects with presumably different levels of dopamine and hypocretin cell loss. We compared sleep laboratory tests and cerebrospinal fluid levels with hypocretin‐deficient patients with narcolepsy with cataplexy, and with matched controls. Nocturnal sleep efficiency was most decreased in advanced Parkinson patients, and still lower in early Parkinson patients than in narcolepsy subjects. Excessive daytime sleepiness was most severe in narcolepsy patients. In Parkinson patients, objective sleepiness correlated with decrease of cerebrospinal fluid hypocretin levels, and repeated hypocretin measurements in two Parkinson patients revealed a decrease of levels over years. This suggests that dopamine and hypocretin deficiency differentially affect sleep and wakefulness in Parkinson’s disease. Poorer sleep quality is linked to dopamine deficiency and other disease‐related factors. Despite hypocretin cell loss in Parkinson’s disease being only partial, disturbed hypocretin signalling is likely to contribute to excessive daytime sleepiness in Parkinson patients.

Interleaving deep brain stimulation for a patient with both Parkinson's disease and essential tremor†‡

Parkinson’s disease (PD) and essential tremor (ET) sometimes appear in the same patient, but the nature of this coexistence is a matter of ongoing debate. Although deep brain stimulation (DBS) is effective for both disorders, the targeted brain regions differ: the subthalamic nucleus (STN) or pars interna of the globus pallidus is preferred in PD patients and the nucleus ventralis intermedius of the thalamus (Vim) for ET patients. In addition, stimulation of the caudal zona incerta has been suggested for tremor control. In 1 reported patient with ET and PD, DBS in the STN improved both disorders. We present the case of a 50-year-old man who has suffered from ET since he was 5 years old. His mother and brother also suffered from ET. The Whiget Tremor Rating Scale score was 34 points (left, 14; right, 20) and improved to 16 (8/8) points after alcohol intake. Furthermore, he showed progressive signs of PD, which started 2 years ago. Both ET and PD were more dominant on the right side. Apart from the rest tremor, PD signs responded well to levodopa (motor part of the Unified Parkinson’s Disease Rating Scale score: 32 points off, 17 points on levodopa). Pharmacological treatment was difficult; treatment for ET was either insufficient (gabapentin, topiramate, alprazolam) or not well tolerated (primidone, propranolol). Dopaminergic drugs (pramipexole, ropinirole, levodopa) caused severe sleepiness. After careful evaluation, we recommended DBS. Although at this point the patient was still more affected by ET, PD symptoms were already significantly limiting the patient’s daily activities. Based on the above-mentioned case report, we selected as a target structure the medial STN, neighboring the caudal zona incerta in T2-weighted MRI (Suppl. Fig.; mid-commissural point [MCP]–based coordinates as x/y/z in millimeters: L, 10.72/ 5.75/ 4.08; R, 10.15/ 5.0/ 4.08). However, we aimed for an electrode trajectory that allowed the most dorsal poles of the quadripolar electrodes (Medtronic model 3389) to be located as close as possible to the Vim. After 5 microelectrode recordings and intraoperative macrostimulation, and after weighing benefits versus side effects, we implanted the electrodes in the anterior (left side) and lateral (right side) trajectory passing the thalamus and ending down in the STN, but not in proximity of the zona incerta. Fusion of intraoperative stereotactic computed tomography images with preoperative MRI revealed the following MCPbased positions (Suppl. Fig.): c0, 11.18/ 2.85/ 3.50; c8, 11.21/ 2.97/ 4.24; c3, 13.17/ 0.50/1.70; c11, 14.01/ 0.70/ 0.56. Projection of the electrodes on a 3-D atlas confirmed the localization of the most ventral poles (c0/c8) in the STN and the most dorsal poles (c3/c11) in the ventrolateral anterior thalamus (Fig. 1 and Suppl. Fig.). After bilateral electrode implantation, we first stimulated the left STN to alleviate right-sided symptoms of both PD and ET. However, this did not improve ET (unipolar stimulation of the most ventral pole; amplitude up to 3.5 V; impulse width, 60 ls; frequency, 130 Hz). Conversely, unipolar stimulation of the most dorsal pole (up to 4.2 V/60 ls/ 130 Hz) only improved ET. Thereafter, we programmed simultaneous unipolar stimulation at both extreme poles (up to 4.2 V/60 ls/130 Hz), but this strategy improved neither PD nor ET. Finally, we employed an interleaving stimulation of the same extreme poles (ventral: 3.3 V, dorsal: 4.3 V, both 60 ls/125 Hz). For the first time, symptoms of both PD and ET were significantly improved (Video). In contrast to an earlier case report, stimulation of the STN alone was not beneficial for ET in this patient. And simultaneous unipolar stimulation at both extreme poles was not efficacious for any symptom. However, an interleaving stimulation strategy, that is, alternating unipolar impulses with different amplitudes for the extreme poles in the STN and the ventrolateral anterior thalamic region near the Vim was successful in improving both PD and ET. The importance of pulse timing (simultaneous vs interleaving) may be related to temporal integration in the receiving brain areas.

Impulse control disorders in Parkinson's disease: don't set your mind at rest by self-assessments

Impulse control disorders (ICDs) and related conditions in Parkinsons disease (PD) patients are frequent, disabling and sometimes devastating neuropsychiatric behaviors. Current knowledge on the prevalence of ICDs in PD is mainly based on assessments with questionnaires or patient interviews. This study was designed to evaluate the reliability of self‐assessed ICDs and related conditions in PD by exploring the agreement between self‐assessment of ICDs and related conditions in PD patients on the one hand and the estimation of their caregivers on the other hand.

Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson's disease.

&NA; Subthalamic deep brain stimulation is superior to best medication for improvement of Parkinson’s‐related pain. This treatment effect can be predicted by pre‐operative l‐dopa challenge tests. &NA; Pain is a frequently observed non‐motor symptom of patients with Parkinson’s disease. In some patients, Parkinson’s‐related pain responds to dopaminergic treatment. In the present study, we aimed to elucidate whether subthalamic deep brain stimulation has a similar beneficial effect on pain in Parkinson’s disease, and whether this effect can be predicted by a pre‐operative l‐dopa challenge test assessing pain severity. We prospectively analyzed 14 consecutive Parkinson’s patients with severe pain who underwent subthalamic deep brain stimulation. In 8 of these patients, pain severity decreased markedly with high doses of l‐dopa, irrespective of the type and localization of the pain symptoms. In these patients, subthalamic deep brain stimulation provided an even higher reduction of pain severity than did dopaminergic treatment, and the majority of this group was pain‐free after surgery. This effect lasted for up to 41 months. In the remaining 6 patients, pain was not improved by dopaminergic treatment nor by deep brain stimulation. Thus, we conclude that pain relief following subthalamic deep brain stimulation is superior to that following dopaminergic treatment, and that the response of pain symptoms to deep brain stimulation can be predicted by l‐dopa challenge tests assessing pain severity. This diagnostic procedure could contribute to the decision on whether or not a Parkinson’s patient with severe pain should undergo deep brain stimulation for potential pain relief.

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.

Adaptive grip force is modulated by subthalamic beta activity in Parkinson's disease patients.

Introduction Healthy subjects scale grip force to match the load defined by physical object properties such as weight, or dynamic properties such as inertia. Patients with Parkinsons disease (PD) show an elevated grip force in dynamic object handling, but temporal aspects of anticipatory grip force control are relatively preserved. In PD patients, beta frequency oscillatory activity in the basal ganglia is suppressed prior to externally paced movements. However, the role of the subthalamic nucleus (STN) in anticipatory grip force control is not known. Methods After implantation of deep brain stimulation (DBS) electrodes in the STN, PD patients performed adaptive and voluntary grip force tasks, while we recorded subthalamic local field potentials (LFP) and scalp EEG. Results During adaptive grip force control (Shake), we found event related desynchronization (ERD) in the beta frequency band, which was time-locked to the grip force. In contrast, during voluntary grip force control (Press) we recorded a biphasic ERD, corresponding to peak grip force and grip force release. Beta synchronization between STN and cortical EEG was reduced during adaptive grip force control. Conclusion The time-locked suppression of beta oscillatory activity in the STN is in line with previous reports of beta ERD prior to voluntary movements. Our results show that the STN is involved in anticipatory grip force control in PD patients. The difference in the phasic beta ERD between the two tasks and the reduction of cortico-subthalamic synchronization suggests that qualitatively different neuronal network states are involved in different grip force control tasks.

Functionally separated networks for self-paced and externally-cued motor execution in Parkinson's disease: Evidence from deep brain recordings in humans

&NA; Spatially segregated cortico‐basal ganglia networks have been proposed for the control of goal‐directed and habitual behavior. In Parkinsons disease, selective loss of dopaminergic neurons regulating sensorimotor (habitual) behavior might therefore predominantly cause deficits in habitual motor control, whereas control of goal‐directed movement is relatively preserved. Following this hypothesis, we examined the electrophysiology of cortico‐basal ganglia networks in Parkinson patients emulating habitual and goal‐directed motor control during self‐paced and externally‐cued finger tapping, respectively, while simultaneously recording local field potentials in the subthalamic nucleus (STN) and surface EEG. Only externally‐cued movements induced a pro‐kinetic event‐related beta‐desynchronization, whereas beta‐oscillations were continuously suppressed during self‐paced movements. Connectivity analysis revealed higher synchronicity (phase‐locking value) between the STN and central electrodes during self‐paced and higher STN to frontal phase‐locking during externally‐cued movements. Our data provide direct electrophysiological support for the existence of functionally segregated cortico‐basal ganglia networks controlling motor behavior in Parkinson patients, and corroborate the assumption of Parkinson patients being shifted from habitual towards goal‐directed behavior.

Hyperkeratotic cutaneous vascular malformation associated with familial cerebral cavernous malformations (FCCM) with KRIT1/CCM1 mutation

We report the case of a 40-year-old male patient with a history of seizures due to multiple cerebral cavernomas since the age of 14, treated by oxycarbamazepine and lamotrigine. Familial history for cerebral cavernomas was negative. The patient was referred to the department of Dermatology by his neurologist for the evaluation of an asymptomatic dark-blue spot on the left heel, which had been present for many years. The lesion was an isolated well-delimited dark-blue hyperkeratotic plaque with an [...]

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 Parkinsons 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.