Adam Zaidel

Akineto-rigid vs. tremor syndromes in Parkinsonism

Purpose of reviewAkinesia, rigidity and low-frequency rest tremor are the three cardinal motor signs of Parkinsons disease and some Parkinsons disease animal models. However, cumulative evidence supports the view that akinesia/rigidity vs. tremor reflect different pathophysiological phenomena in the basal ganglia. Here, we review the recent physiological literature correlating abnormal neural activity in the basal ganglia with Parkinsons disease clinical symptoms. Recent findingsThe subthalamic nucleus of Parkinsons disease patients is characterized by oscillatory activity in the beta-frequency (∼15 Hz) range. However, Parkinsons disease tremor is not strictly correlated with the abnormal synchronous oscillations of the basal ganglia. On the other hand, akinesia and rigidity are better correlated with the basal ganglia beta oscillations. SummaryThe abnormal basal ganglia output leads to akinesia and rigidity. Parkinsons disease tremor most likely evolves as a downstream compensatory mechanism.

Delimiting Subterritories of the Human Subthalamic Nucleus by Means of Microelectrode Recordings and a Hidden Markov Model

Positive therapeutic response without adverse side effects to subthalamic nucleus deep brain stimulation (STN DBS) for Parkinsons disease (PD) depends to a large extent on electrode location within the STN. The sensorimotor region of the STN (seemingly the preferred location for STN DBS) lies dorsolaterally, in a region also marked by distinct beta (13–30 Hz) oscillations in the parkinsonian state. In this study, we present a real‐time method to accurately demarcate subterritories of the STN during surgery, based on microelectrode recordings (MERs) and a Hidden Markov Model (HMM). Fifty‐six MER trajectories were used, obtained from 21 PD patients who underwent bilateral STN DBS implantation surgery. Root mean square (RMS) and power spectral density (PSD) of the MERs were used to train and test an HMM in identifying the dorsolateral oscillatory region (DLOR) and nonoscillatory subterritories within the STN. The HMM demarcations were compared to the decisions of a human expert. The HMM identified STN‐entry, the ventral boundary of the DLOR, and STN‐exit with an error of −0.09 ± 0.35, −0.27 ± 0.58, and −0.20 ± 0.33 mm, respectively (mean ± standard deviation), and with detection reliability (error < 1 mm) of 95, 86, and 91%, respectively. The HMM was successful despite a very coarse clustering method and was robust to parameter variation. Thus, using an HMM in conjunction with RMS and PSD measures of intraoperative MER can provide improved refinement of STN entry and exit in comparison with previously reported automatic methods, and introduces a novel (intra‐STN) detection of a distinct DLOR‐ventral boundary.

Propofol decreases neuronal population spiking activity in the subthalamic nucleus of Parkinsonian patients.

BACKGROUND: Implantation of deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN) for the treatment of Parkinson disease is often performed using microelectrode recording (MER) of STN population spike activity. The extent to which sedative drugs interfere with MER is unknown. We recorded the population activity of STN neurons during propofol sedation and examined its effect on neuronal activity. METHODS: The procedure was performed during DBS surgery for Parkinson disease. We administered propofol (50 &mgr;g/kg/min) at a constant electrode location in the STN until stable sedation was achieved. We recorded the electrical activity, and calculated its root mean square (RMS) before, during, and after the propofol infusions. RESULTS: The activity of 24 electrode trajectories was recorded in 16 patients. The RMS of STN activity decreased significantly after propofol administration in 18 of the 24 trajectories. The average normalized RMS decreased by 23.2%± 9.1% (mean ± SD) during propofol administration (P < 0.001), and returned to baseline 9.3 ± 4.0 minutes after it was stopped. CONCLUSIONS: Propofol administration leads to a significant decrease of STN neuronal activity. Thus, it may interfere with MER identification of the STN borders. However, activity returns to baseline shortly after administration stops. Therefore, propofol can be safely used until shortly before MER for DBS.

Levodopa and subthalamic deep brain stimulation responses are not congruent

There is a consensus that in Parkinsons disease, the extent of preoperative levodopa responsiveness predicts the efficacy of subthalamic nucleus deep brain stimulation (STN DBS). However, this may be the result of statistical methods and primary assumptions. We were able to reproduce previously published correlation results on our data (N = 49 patients). Yet, these same results were demonstrated even after random shuffling of our data. Notably, we did not observe a correlation between STN DBS efficacy and preoperative levodopa responsiveness when using their respective baselines and fractional scores of motor improvement. Furthermore, postoperative responses were not limited by preoperative scores, with tremor demonstrating the greatest discrepancy. We conclude that preoperative levodopa responsiveness does not predict or limit the outcome of STN DBS. These results imply different therapeutic mechanisms for levodopa and STN DBS and therefore question the validity of using substantial preoperative levodopa responsiveness as a selection criterion for STN DBS.

Prior pallidotomy reduces and modifies neuronal activity in the subthalamic nucleus of Parkinson's disease patients

Parkinsons disease (PD) patients with prior radio‐frequency lesions in the internal segment of the globus pallidus (GPi, pallidotomy), whose symptoms have deteriorated, may be candidates for further invasive treatment such as subthalamic deep brain stimulation (STN DBS). Six patients with prior pallidotomy (five unilaterally; one bilaterally) underwent bilateral STN DBS. The microelectrode recordings (MERs, used intraoperatively for STN verification), ipsilateral and contralateral to pallidotomy, and MERs from 11 matched PD patients who underwent bilateral STN DBS without prior pallidotomy were compared. For each trajectory, average, variance and mean successive difference (MSD, a measure of irregularity) of the root mean square (RMS) of the STN MER were calculated. The RMS in trajectories ipsilateral to pallidotomy showed significant reduction of the mean average and MSD of STN activity when compared with trajectories from patients without prior pallidotomy. The RMS parameters contralateral to pallidotomy tend to lie between those ipsilateral to pallidotomy and those without prior pallidotomy. The average STN power spectral density of oscillatory activity was notably lower ipsilateral to pallidotomy than contralateral, or without prior pallidotomy. The finding that pallidotomy reduces STN activity and changes firing characteristics, in conjunction with the effectiveness of STN DBS despite prior pallidotomy, calls for reappraisal and modification of the current model of the basal ganglia (BG) cortical network. It highlights the critical role of direct projections from the BG to brain‐stem structures and suggests a possible GPi–STN reciprocal positive‐feedback mechanism.

Microelectrode Recording Duration and Spatial Density Constraints for Automatic Targeting of the Subthalamic Nucleus

Background: Accurate detection of the boundaries of the subthalamic nucleus (STN) in deep brain stimulation (DBS) surgery using microelectrode recording (MER) is considered to refine localization and may therefore improve clinical outcome. However, MER tends to extend operation time and its cost-utility balance has been debated. Objectives: To quantify the tradeoff between accuracy of STN localization and the spatial and temporal parameters of MER that effect the operation time using an automated detection method. Methods: We retrospectively estimated the accuracy of STN detection on data from 100 microelectrode trajectories. Our dense (average step = 0.12 mm) and long (average duration = 22.5 s) MER data was downsampled in the spatial and temporal domains. Then, the STN borders were detected automatically on both the downsampled and original data and compared to each other. Results: With a recording duration of 16 s, average accuracy for detecting STN entry ranged from 0.06 mm for a 0.1-mm step to 0.51 mm for a 1.0-mm step. Smaller effects were found along the temporal axis. For example, a 0.1-mm recording step yielded an STN entry average accuracy ranging from 0.06 mm for a 16-second recording duration to 0.16 mm for 0.1 s. Conclusions: STN entry detection error was about half of the step size. Sampling duration of STN activity can be minimized to 1 s/record without compromising accuracy. We conclude that bilateral DBS surgery time utilizing MER may be significantly shortened without compromising targeting accuracy.

The use of macroelectrodes in recording cellular spiking activity.

Microelectrode recording (MER) is an important navigational and investigational tool, specifically with regard to deep brain stimulation (DBS) surgery. MER is often utilized when targeting the subthalamic nucleus (STN) and other deep brain nuclei in the management of Parkinsons disease (PD), tremor, dystonia and other emerging applications. Microelectrodes are used to detect and measure cellular spiking activity while macroelectrodes are considered more suitable for measuring the collective sum of slow potentials from multiple cells near the electrode, the local field potential (LFP). Precisely how the characteristics of an electrode affect the data recorded is still unclear. Technical idiosyncrasies of some surgical cases allowed serendipitous data collection from a 250 to 6000 Hz bandpassed macroelectrode recording during DBS implantation for PD. Simultaneous recording from both a microelectrode and macroelectrode were compared along the same surgical trajectory. Audio, normalized root mean square of the recorded signal, and power spectrograms were used to analyze the data. The analyses demonstrate similar results in detecting cellular spiking activity when recording with macroelectrodes compared with microelectrodes. This has important implications for the standardization of recording electrophysiological data as well as for the development of next generation closed-loop deep brain stimulation systems.

Chapter 38 – Pathological Synchrony of Basal Ganglia-Cortical Networks in the Systemic MPTP Primate Model of Parkinson's Disease

Publisher Summary This chapter reviews that the core pathology of PD is degeneration of the dopamine neurons in the midbrain and the resulting depletion of striatal dopamine. The striatum is the major input stage of the basal ganglia, receiving input from the cerebral cortex and thalamus, and projecting directly and indirectly to the output stages of the basal ganglia – the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). The dopamine precursor l-DOPA remains the gold standard for the treatment of PD. However, long-term use of l-DOPA is associated with the development of motor complications. It discusses that the multi-stage therapy of Parkinsons disease (PD), from dopamine replacement methods to modulation of the activity of the basal ganglia structures using deep Brain Stimulation DBS, reinstates interest in identifying the critical features of abnormal basal ganglia activity that follow striatal dopamine depletion and lead to the symptoms. The chapter summarizes the main physiological findings in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) primate model of PD, and compares them to the recent physiological findings in human patients. There is an accumulation of data linking excessive synchrony at low frequencies in basal ganglia-thalamo-cortical loops to impaired motor processing in PD. Whether synchronization is an epiphenomenon or truly pathogenic in PD, it provides a clear biological marker for the disease process. Recent studies indicate the differential roles or correlates of the distinctive bands of oscillatory activity in the pathogenesis of PD. It suggests that amelioration of specific domains of basal ganglia-cortical synchronized oscillatory activity could form the basis for future closed-loop stimulation regimes for human PD patients.

Reduced and Modified Neuronal Activity in the Subthalamic Nucleus of Parkinson’s Disease Patients with Prior Pallidotomy

Parkinson’s disease (PD) patients with prior pallidotomy [radio-frequency lesions in the internal segment of the globus pallidus (GPi)], whose symptoms have deteriorated, may be candidates for subthalamic nucleus (STN) deep brain stimulation (STN-DBS). In this study we analyzed the microelectrode recordings (MER, used intra-operatively for target verification) from 7 patients with prior pallidotomy (6 unilaterally and 1 bilaterally) and MERs from 12 matched PD patients without prior pallidotomy who underwent bilateral STN-DBS. The MERs were divided into three groups for comparison: (a) ipsilateral and (b) contralateral to prior pallidotomy and (c) from patients with no prior pallidotomy. For each MER trajectory, average, variance and mean successive difference [(MSD), a measure of irregularity] of the root mean square (RMS) of the STN-MER were calculated. The RMS in trajectories ipsilateral to pallidotomy demonstrated significant reduction of the mean average and MSD of STN activity when compared with trajectories from patients without prior pallidotomy, while RMS parameters contralateral to pallidotomy tended to be in between the two. The average power spectral density of 10–20 Hz oscillatory activity in the somatosensory STN was notably lower ipsilateral to pallidotomy, compared with contralateral or without prior pallidotomy. These findings highlight the critical role of direct projections from the basal ganglia to brainstem structures and suggest a possible GPi-STN reciprocal positive-feedback mechanism.