Martijn Beudel

Bilateral adaptive deep brain stimulation is effective in Parkinson's disease

Introduction & objectives Adaptive deep brain stimulation (aDBS) uses feedback from brain signals to guide stimulation. A recent acute trial of unilateral aDBS showed that aDBS can lead to substantial improvements in contralateral hemibody Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and may be superior to conventional continuous DBS in Parkinson’s disease (PD). We test whether potential benefits are retained with bilateral aDBS and in the face of concurrent medication. Methods We applied bilateral aDBS in 4 patients with PD undergoing DBS of the subthalamic nucleus. aDBS was delivered bilaterally with independent triggering of stimulation according to the amplitude of β activity at the corresponding electrode. Mean stimulation voltage was 3.0±0.1 volts. Motor assessments consisted of double-blinded video-taped motor UPDRS scores that included both limb and axial features. Results UPDRS scores were 43% (p=0.04; Cohen’s d=1.62) better with aDBS than without stimulation. Motor improvement with aDBS occurred despite an average time on stimulation (ToS) of only 45%. Levodopa was well tolerated during aDBS and led to further reductions in ToS. Conclusion Bilateral aDBS can improve both axial and limb symptoms and can track the need for stimulation across drug states.

Cerebral representations of space and time

A link between perception of time and spatial change is particularly revealed in dynamic conditions. By fMRI, we identified regional segregation as well as overlap in activations related to spatial and temporal processing. Using spatial and temporal anticipation concerning movements of a ball provided a balanced paradigm for contrasting spatial and temporal conditions. In addition, momentary judgments were assessed. Subjects watched a monitor-display with a moving ball that repeatedly disappeared. Ordered in 4 conditions, they indicated either where or when the ball would hit the screen bottom, where it actually disappeared or what its speed was. Analysis with SPM showed posterior parietal activations related to both spatial- and temporal predictions. After directly contrasting these two conditions, parietal activations remained robust in spatial prediction but virtually disappeared in temporal prediction, while additional left cerebellar-right prefrontal and pre-SMA activations in temporal prediction remained unchanged. Speed contrasted to the location of disappearance showed similar parietal decrease with maintained cerebellar-prefrontal activations, but also increased caudate activation. From these results we inferred that parietal-based spatial information was a prerequisite for temporal processing, while prefrontal-cerebellar activations subsequently reflected working memory and feedforward processing for the assessment of differences between past and future spatial states. We propose that a temporal component was extracted from speed, i.e. approximated momentary time, which demarcated minimal intervals of spatial change (defined by neuronal processing time). The caudate association with such interval demarcation provided an argument to integrate concepts of space-referenced time processing and a clock-like processing model.

Subthalamic nucleus phase-amplitude coupling correlates with motor impairment in Parkinson's disease

Highlights • We obtained invasive subthalamic nucleus recordings in 33 Parkinson’s disease patients.• Phase–amplitude coupling between beta band and high-frequency oscillations correlates with severity of motor impairments.• Parkinsonian pathophysiology is more closely linked with low-beta band frequencies.

Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson’s disease

Oswal et al . characterise the effect of deep brain stimulation (DBS) on STN–cortical synchronisation in Parkinson–s disease. They propose that cortical driving of the STN in beta frequencies is subdivided anatomically and spectrally, corresponding to the hyperdirect and indirect pathways. DBS predominantly suppresses the former.

The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson's disease

Pilot studies suggest that adaptive deep brain stimulation (DBS) may be more effective than conventional DBS for the treatment of Parkinsons disease. Tinkhauser et al. show that adaptive DBS regulates pathological beta synchronisation in the subthalamic nucleus by selectively limiting long duration beta bursts, which are related to clinical impairment.

Adaptive deep brain stimulation in Parkinson's disease

Although Deep Brain Stimulation (DBS) is an established treatment for Parkinsons disease (PD), there are still limitations in terms of effectivity, side-effects and battery consumption. One of the reasons for this may be that not only pathological but also physiological neural activity can be suppressed whilst stimulating. For this reason, adaptive DBS (aDBS), where stimulation is applied according to the level of pathological activity, might be advantageous. Initial studies of aDBS demonstrate effectiveness in PD, but there are still many questions to be answered before aDBS can be applied clinically. Here we discuss the feedback signals and stimulation algorithms involved in adaptive stimulation in PD and sketch a potential road-map towards clinical application.

Adaptive deep brain stimulation for Parkinson's disease demonstrates reduced speech side effects compared to conventional stimulation in the acute setting

Deep brain stimulation (DBS) for Parkinsons disease (PD) is currently limited by costs, partial efficacy and surgical and stimulation-related side effects. This has motivated the development of adaptive DBS (aDBS) whereby stimulation is automatically adjusted according to a neurophysiological biomarker of clinical state, such as β oscillatory activity (12–30 Hz). aDBS has been studied in parkinsonian primates and patients and has been reported to be more energy efficient and effective in alleviating motor symptoms than conventional DBS (cDBS) at matched amplitudes.1 ,2 However, these studies have not considered whether side effects can also be avoided with clinically effective stimulation. In PD, it is well recognised that a significant proportion of patients develop speech deterioration following DBS of the subthalamic nucleus (STN), which may be reversible.3 Here we test bilateral stimulation, optimising parameters for aDBS, and evaluate speech intelligibility. We hypothesised that acute aDBS would be more effective and more efficient than cDBS at matched stimulation parameters while causing less speech impairment. We recruited 10 patients with advanced idiopathic PD following implantation of DBS electrodes into the STN.2 Recordings took place 3–6 days following electrode placement during a temporary period of externalisation. All participants gave informed written consent, and were tested following overnight withdrawal of dopaminergic medication (see online supplementary material). Two patients were excluded due to external stimulator failure leading to no voltage delivery under aDBS and cDBS conditions. ### supplementary data [jnnp-2016-313518supp.pdf] aDBS stimulation was delivered bilaterally, only when β amplitude exceeded a threshold as previously described.2 aDBS contacts, voltages and trigger thresholds were independently set for the two sides according to motor benefit versus induced paraesthesiae, with the same contacts/voltages used for cDBS. Stimulation in each block continued for 15 min prior to evaluation. Participants were assessed …

Tremor Reduction by Deep Brain Stimulation Is Associated With Gamma Power Suppression in Parkinson's Disease

Rest tremor is a cardinal symptom of Parkinsons disease (PD), and is readily suppressed by deep brain stimulation (DBS) of the subthalamic nucleus (STN). The therapeutic effect of the latter on bradykinesia and rigidity has been associated with the suppression of exaggerated beta (13–30 Hz) band synchronization in the vicinity of the stimulating electrode, but there is no correlation between beta suppression and tremor amplitude. In the present study, we investigate whether tremor suppression is related to suppression of activities at other frequencies.

Oscillatory Beta Power Correlates With Akinesia-Rigidity in the Parkinsonian Subthalamic Nucleus

In Parkinson’s disease (PD), dopaminergic treatment-driven changes in akinesia and rigidity (AR), but not tremor, are associated with changes in local field potential (LFP) beta (1330 Hz) power spectral density (PSD). The PSD of these oscillations has recently successfully been applied as a biomarker for adaptive deep brain stimulation. However, it remains unclear whether beta PSD also correlates with OFFdopaminergic AR. In their recent study Neumann and colleagues report a strong correlation between OFF total Unified Parkinson’s Disease Rating Scale (UPDRS) III score and the LFP PSD over a broad 8 to 35 Hz band and more specifically in a narrow 10 to 14 Hz range. The following 3 questions arise: (1) What was the rational for using the total UPDRS scores (including tremor and bilaterality)? (2) Are the correlations in this narrow 10 to 14 Hz band reproducible? (3) Does it relate to a particular symptom complex? For this reason, we replicated the study of Neumann and colleagues but also investigated the contributions of AR, tremor, and axial symptoms. We investigated 39 PD patients (35 male, mean age 58.6 6 7.2 y.o., average disease duration 11.3 6 5.2 years, mean OFF UPDRS 42.3 6 12.8) with bilaterally implanted STN-DBS contacts. OFF UPDRS scores were obtained from the preoperative levodopa challenge. From these total scores, (contralateral) AR (items 22-26), tremor (items 20-21), and axial symptom (items 27-31) scores were obtained. LFPs were analyzed as described by Neumann and colleagues. This included the rejection of epochs with artefacts and normalization to 5 to 45 Hz and 55 to 95 Hz. However, to assess lateralized items we used the PSD LFP average per STN and not across both STNs. We were not able to reproduce the highly significant correlation between the 8 to 35 Hz PSD and total UPDRS score (rho 5 0.28, P 5 .07), nor between this and LFP PSD over 10 to 14 Hz (rho 5 0.23, P 5 .14). We only found an uncorrected significant correlation between total UPDRS and the 19 Hz PSD bin and between the 17 to 22 Hz PSD bins for AR. No significant correlation was found for either tremor or axial symptoms. However, when correlating maximum LFP beta peak PSD over 13 to 30 Hz in each STN (regardless of precise frequency), a highly significant correlation (rho 5 0.40, P< .0005) with contralateral AR UPDRS items was present (Fig. 1). Given the undifferentiated motor profile of the population enrolled in the study of Neumann and colleagues, it is difficult to pinpoint the reason why we were not able to replicate their precise findings. However, it is possible that it is the degree of neural synchronization (as indexed by PSD) rather than any specific frequency over the 8 to 35 Hz band that is most important. Moreover, our data suggest that PSD correlations may be strongest with AR. Other factors that might underlie the differences are the lower UPDRS score in the Neumann and colleagues study and the distribution of recording sites within the STN.

Electroencephalographic Findings in Posthypoxic Myoclonus

The physical examination findings of early posthypoxic myoclonus (PHM) are associated with poor prognosis. Recent findings indicate that patients with multifocal PHM, assumed to have a cortical origin, have a comparable outcome to resuscitated patients without PHM. Generalized PHM, assumed to have a subcortical myoclonus origin, is still associated with a bad clinical outcome. It is not known whether the electroencephalographic (EEG) findings differ between the multifocal and generalized myoclonus groups nor is the clinical significance clearly defined. Forty-three patients with PHM were retrospectively derived from an EEG database. Patients were categorized as having multifocal (i), generalized (ii), or undetermined (iii) PHM. Outcome was expressed in cerebral performance category scores. The EEG background was categorized into isoelectric (I), low voltage (II), burst suppression (III), status epilepticus (SE; IV), diffuse slowing (V), and mild encephalopathic or normal (VI). 17 patients had generalized PHM and 23 had multifocal PHM (3 undetermined). The EEG showed more SE in generalized compared to multifocal PHM (64% vs 13%, P < .001). Diffuse slowing was more often present in multifocal PHM (52% vs 17%, P < .05). Early-onset myoclonus occurred significantly more often in generalized PHM, and early generalized PHM was invariantly associated with poor outcome. In conclusion, patients with generalized PHM showed more SE. These EEG findings might be either subcortical corollaries or primarily cortical phenomena. Our retrospective results conflict with currently used clinical criteria for myoclonus classification, and we suggest that more refined difference may be needed for accurate assessment of PHM. To better understand PHM, prospective research with standardized clinical assessment and quantitative EEG analysis is needed.