Fabian Klostermann

The human thalamus processes syntactic and semantic language violations

Numerous linguistic operations have been assigned to cortical brain areas, but the contributions of subcortical structures to human language processing are still being discussed. Using simultaneous EEG recordings directly from deep brain structures and the scalp, we show that the human thalamus systematically reacts to syntactic and semantic parameters of auditorily presented language in a temporally interleaved manner in coordination with cortical regions. In contrast, two key structures of the basal ganglia, the globus pallidus internus and the subthalamic nucleus, were not found to be engaged in these processes. We therefore propose that syntactic and semantic language analysis is primarily realized within cortico-thalamic networks, whereas a cohesive basal ganglia network is not involved in these essential operations of language analysis.

Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: Final 12-month, open-label results

Motor complications in Parkinsons disease (PD) are associated with long‐term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l‐dopa‐carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG‐J), which reduces l‐dopa‐plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54‐week, open‐label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post‐LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary‐assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health‐related quality‐of‐life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG‐J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty‐seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIGs safety profile consisted primarily of AEs associated with the device/procedure, l‐dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks.

Effects of subthalamic deep brain stimulation on dysarthrophonia in Parkinson’s disease

Background: Motor deficits in Parkinson’s disease (PD) are reduced by deep brain stimulation (DBS) of the subthalamic nucleus (STN), but the impact of this therapy on dysarthrophonic problems in PD remains controversial. We therefore aimed to disentangle the effects of STN DBS on the speech skills of long-term treated patients. Methods: Under continued medication, speech and motor functions of 19 patients with PD with bilateral STN DBS were studied when their therapeutic stimulation was active (STIM-ON) versus switched off (STIM-OFF). Per condition, perceptual speech ratings were given by: (i) the patients themselves, (ii) the treating physician, and (iii) professional speech therapists. Furthermore, single speech parameters were measured with a battery of technical exams in both STIM-ON and STIM-OFF. Results: STN DBS significantly worsened speech performance according to all perceptual rating methods applied. In contrast, technical measures showed DBS-induced improvements of single speech dimensions affected by the PD-specific motor disorder. These changes occurred independently of the reduction of motor impairment, which was consistently effectuated by STN DBS. Conclusion: In parallel to the beneficial effects on the motor symptoms of PD, STN DBS reduces designated disease-inherent dysarthrophonic symptoms, such as glottic tremor. However, these actions on speech are predominantly outweighed by the general dysarthrogenic effects of STN DBS, probably based on a decline of complex (eg, prosodic) functions. Thus, stimulation-induced speech impairment should be considered a likely problem in the course of this treatment.

Task-related differential dynamics of EEG alpha- and beta-band synchronization in cortico-basal motor structures

Movement‐related processing results in the modulation of neuronal synchronization over several electroencephalography (EEG) frequency ranges, including alpha‐ (8–12 Hz) and beta‐band (14–30 Hz). Whether modulation patterns differ across sites within the motor system remains unclear, but could denote how information is conveyed across the cortico‐basal network. We therefore compared the event‐related synchronization/desynchronization (ERS/ERD) in recordings from the scalp, basal ganglia and thalamic structures during a motor task.

Peripheral neuropathy in Parkinson's disease: levodopa exposure and implications for duodenal delivery.

In advanced Parkinsons disease (PD) patients, continuous intra-duodenal infusion of levodopa/carbidopa intestinal gel (LCIG) is an established approach in the management of motor complications that cannot be further improved by conventional oral therapy. In general, tolerability of LCIG has resembled that of oral dopaminergic therapy; however, cases of symptomatic peripheral neuropathy (PN), sometimes severe, have been reported in patients receiving LCIG. Cases are generally a sensorimotor polyneuropathy with both subacute and chronic onsets, often associated with vitamin B12 and/or B6 deficiency. Rare cases clinically resemble Guillain-Barré syndrome. In the absence of prospectively collected data on possible associations between LCIG and PN, it is prudent to explore potential mechanisms that may explain a possible relationship. The PN may be linked to use of high-dose levodopa, promoting high levels of homocysteine and methylmalonic acid or reduced absorption of vitamins essential for homocysteine metabolism. Cases of LCIG-associated PN often have responded to vitamin supplementation without need for LCIG cessation, although LCIG cessation is sometimes necessary. It may be advisable to monitor vitamin B12/B6 status before and after patients start LCIG and be vigilant for signs of PN. Prospective, large-scale, long-term studies are needed to clarify whether vitamin supplementation and routine use of a catechol-O-methyltransferase inhibitor may help prevent PN in LCIG recipients and whether these measures should be routine practice in patients with PD on high-dose oral levodopa.

Spatiotemporal characteristics of human intrathalamic high-frequency (> 400 Hz) SEP components

Somatosensory evoked potentials (SEP) were recorded in 11 awake patients from intrathalamic electrodes implanted for tremor treatment. A brief (7ms) polyphasic SEP burst (mean frequency > 1000 Hz, with occasional drops to 600 Hz) was found to be superimposed onto the primary thalamic low-frequency response at 16 ms (tP16) and preceeded a scalp-derived 600 Hz burst by 4 ms. Thalamic burst and tP16 generators had a close intrathalamic co-localization. The thalamic burst strength varied more than and independently from tP16. High-frequency thalamic SEP bursts probably reflect a superposition of slightly asynchronously triggered population spikes, generated e.g. by bursting thalamocortical relay cells. The thalamic burst amplitude fluctuations independent from low-frequency responses suggest a peculiar role for thalamic burst coding in awake subjects.

Malnutritional neuropathy under intestinal levodopa infusion

Levodopa/Carbidopa intestinal gel infusion (LCIG) for Parkinson’s disease is under debate to provoke polyneuropathy (PNP). In our cohort of 20 thus treated patients, two developed debilitating axonal PNP with deficient pyridoxin and folate levels, and marginal cobalamin. Homocysteine was highly elevated. The neuropathies responded to vitamin replacement. We assume that LCIG can provoke PNP most likely of malnutritional origin. To avoid this side effect, the assessment of predisposing factors before treatment as well as neurophysiological and laboratory screenings appear necessary.

Intrathalamic non-propagating generators of high-frequency (1000 Hz) somatosensory evoked potential (SEP) bursts recorded subcortically in man

OBJECTIVES Recently, bursts of high-frequency (1000 Hz) median nerve somatosensory evoked potential (SEP) wavelets were recorded subcortically near and inside the thalamus from deep brain electrodes implanted for tremor therapy. This study aimed to clarify whether these subcortical SEP bursts reflect evoked axonal volleys running in the thalamocortical radiation or a locally restricted intrathalamic response. METHODS During deep brain electrode implantation, median nerve SEP were recorded in 7 patients sequentially along the subcortical stereotactic trajectory at sites +20 and +10 mm above the respective target nucleus (ventral intermediate thalamus or nucleus subthalamicus). Low- and high-frequency SEP components (corner frequency 430 Hz) were analyzed separately with respect to peak latency and amplitude as they changed along the recording trajectory. RESULTS Individual wavelets of the subcortical 1000 Hz SEP burst showed fixed peak latencies independent from the depth of the electrode penetration; they increased markedly in amplitude with decreasing distance to the thalamus. In contrast, the amplitude gradient between the two recording sites was shallower for the low-frequency SEP component, which peaked earlier at the lower recording site. CONCLUSIONS Subcortically recorded 1000 Hz SEP wavelet bursts predominantly reflect locally restricted near-field activity, presumably generated in the somatosensory relay nucleus. In contrast, the variable peak latency of the subcortical low-frequency component could reflect postsynaptic potentials sequentially evoked during passage of the lemniscal afferences curving through the thalamus and contributions from the thalamocortical radiation.

Differential influence of levodopa on reward-based learning in Parkinson's disease

The mesocorticolimbic dopamine (DA) system linking the dopaminergic midbrain to the prefrontal cortex and subcortical striatum has been shown to be sensitive to reinforcement in animals and humans. Within this system, coexistent segregated striato-frontal circuits have been linked to different functions. In the present study, we tested patients with Parkinsons disease (PD), a neurodegenerative disorder characterized by dopaminergic cell loss, on two reward-based learning tasks assumed to differentially involve dorsal and ventral striato-frontal circuits. 15 non-depressed and non-demented PD patients on levodopa monotherapy were tested both on and off medication. Levodopa had beneficial effects on the performance on an instrumental learning task with constant stimulus-reward associations, hypothesized to rely on dorsal striato-frontal circuits. In contrast, performance on a reversal learning task with changing reward contingencies, relying on ventral striato-frontal structures, was better in the unmedicated state. These results are in line with the “overdose hypothesis” which assumes detrimental effects of dopaminergic medication on functions relying upon less affected regions in PD. This study demonstrates, in a within-subject design, a double dissociation of dopaminergic medication and performance on two reward-based learning tasks differing in regard to whether reward contingencies are constant or dynamic. There was no evidence for a dose effect of levodopa on reward-based behavior with the patients’ actual levodopa dose being uncorrelated to their performance on the reward-based learning tasks.

Propofol narcosis dissociates human intrathalamic and cortical high-frequency (> 400 Hz) Sep components

Human somatosensory evoked potentials (SEP) contain a brief burst of high-frequency wavelets (> 400 Hz) presumably reflecting rapidly repeated population spikes of as-yet undetermined origin. To study state-dependent response changes, SEP after electric median nerve stimulation were recorded in six Parkinsons disease patients perioperatively from intrathalamic electrode implants, and in five non-implanted patients from scalp electrodes, before and under propofol narcosis. In all intrathalamic recordings burst amplitude and intraburst frequency (∼950 Hz) proved to be almost stable under propofol administration. In strong contrast, the scalp burst (640 Hz) was significantly slowed (480 Hz) under propofol narcosis, and its amplitude reduced to 28% of the pre-propofol baseline. Low-frequency SEP components which underly the burst at thalamic (P16) and cortical level (N20) did not change significantly. This dissociation of bursts indicates neuronal generators showing different sensitivities to propofol narcosis, with a robust thalamic response and a state-dependent cortical contribution, possibly from pyramidal chattering cells and/or inhibitory interneurons.