Dejan Georgiev

Event-Related Potentials and Cognition in Parkinson's Disease: An Integrative Review.

Cognitive impairment is a common non-motor symptom of Parkinsons disease (PD), but the nature of cognitive changes varies considerably between individuals. According to the dual-syndrome hypothesis, one cluster of patients is characterized by deficits in executive function that may be related to fronto-striatal dysfunction. Other patients primarily show non-frontal cognitive impairments that progress rapidly to PD dementia (PDD). We provide a comprehensive review of event-related potential (ERP) studies to identify ERP measures substantiating the heterogeneity of cognitive impairment in PD. Our review revealed evidence for P3b and mismatch-negativity alterations in PDD, but not in non-demented PD, indicating that alterations of these ERPs constitute electrophysiological markers for PDD. In contrast, ERP correlates of executive functions, such as NoGo-P3, N2, and error(-related) negativity (Ne/ERN), appear to be attenuated in non-demented PD patients in a dopamine-dependent manner. Hence, ERP measures confirm and yield distinct electrophysiological markers for the heterogeneity of cognitive impairment in PD. We discuss limitations and open questions of the ERP approach and provide directions and predictions for future ERP research.

Different effects of dopaminergic medication on perceptual decision-making in Parkinson's disease as a function of task difficulty and speed-accuracy instructions.

When choosing between two options, sufficient accumulation of information is required to favor one of the options over the other, before a decision is finally reached. To establish the effect of dopaminergic medication on the rate of accumulation of information, decision thresholds and speed-accuracy trade-offs, we tested 14 patients with Parkinsons disease (PD) on and off dopaminergic medication and 14 age-matched healthy controls on two versions of the moving-dots task. One version manipulated the level of task difficulty and hence effort required for decision-making and the other the urgency, requiring decision-making under speed vs. accuracy instructions. The drift diffusion model was fitted to the behavioral data. As expected, the reaction time data revealed an effect of task difficulty, such that the easier the perceptual decision-making task was, the faster the participants responded. PD patients not only made significantly more errors compared to healthy controls, but interestingly they also made significantly more errors ON than OFF medication. The drift diffusion model indicated that PD patients had lower drift rates when tested ON compared to OFF medication, indicating that dopamine levels influenced the quality of information derived from sensory information. On the speed-accuracy task, dopaminergic medication did not directly influence reaction times or error rates. PD patients OFF medication had slower RTs and made more errors with speed than accuracy instructions compared to the controls, whereas such differences were not observed ON medication. PD patients had lower drift rates and higher response thresholds than the healthy controls both with speed and accuracy instructions and ON and OFF medication. For the patients, only non-decision time was higher OFF than ON medication and higher with accuracy than speed instructions. The present results demonstrate that when task difficulty is manipulated, dopaminergic medication impairs perceptual decision-making and renders it more errorful in PD relative to when patients are tested OFF medication. In contrast, for the speed/accuracy task, being ON medication improved performance by eliminating the significantly higher errors and slower RTs observed for patients OFF medication compared to the HC group. There was no evidence of dopaminergic medication inducing impulsive decisions when patients were acting under speed pressure. For the speed-accuracy instructions, the sole effect of dopaminergic medication was on non-decision time, which suggests that medication primarily affected processes tightly coupled with the motor symptoms of PD. Interestingly, the current results suggest opposite effects of dopaminergic medication on the levels of difficulty and speed-accuracy versions of the moving dots task, possibly reflecting the differential effect of dopamine on modulating drift rate (levels of difficulty task) and non-decision time (speed-accuracy task) in the process of perceptual decision making.

Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson's disease.

OBJECTIVES Firstly, to identify subthalamic region stimulation clusters that predict maximum improvement in rigidity, bradykinesia and tremor, or emergence of side-effects; and secondly, to map-out the cortical fingerprint, mediated by the hyperdirect pathways which predict maximum efficacy. METHODS High angular resolution diffusion imaging in twenty patients with advanced Parkinsons disease was acquired prior to bilateral subthalamic nucleus deep brain stimulation. All contacts were screened one-year from surgery for efficacy and side-effects at different amplitudes. Voxel-based statistical analysis of volumes of tissue activated models was used to identify significant treatment clusters. Probabilistic tractography was employed to identify cortical connectivity patterns associated with treatment efficacy. RESULTS All patients responded well to treatment (46% mean improvement off medication UPDRS-III [p < 0.0001]) without significant adverse events. Cluster corresponding to maximum improvement in tremor was in the posterior, superior and lateral portion of the nucleus. Clusters corresponding to improvement in bradykinesia and rigidity were nearer the superior border in a further medial and posterior location. The rigidity cluster extended beyond the superior border to the area of the zona incerta and Forel-H2 field. When the clusters where averaged, the coordinates of the area with maximum overall efficacy was X = -10(-9.5), Y = -13(-1) and Z = -7(-3) in MNI(AC-PC) space. Cortical connectivity to primary motor area was predictive of higher improvement in tremor; whilst that to supplementary motor area was predictive of improvement in bradykinesia and rigidity; and connectivity to prefrontal cortex was predictive of improvement in rigidity. INTERPRETATION These findings support the presence of overlapping stimulation sites within the subthalamic nucleus and its superior border, with different cortical connectivity patterns, associated with maximum improvement in tremor, rigidity and bradykinesia.

Continuous Theta Burst Stimulation Over the Dorsolateral Prefrontal Cortex and the Pre-SMA Alter Drift Rate and Response Thresholds Respectively During Perceptual Decision-Making

BACKGROUND The speed-accuracy trade-off (SAT) refers to the balancing of speed versus accuracy during decision-making. SAT is very commonly investigated with perceptual decision-making tasks such as the moving dots task (MDT). The dorsolateral prefrontal cortex (DLPFC) and the pre-supplementary motor area (pre-SMA) are two brain regions considered to be involved in the control of SAT. OBJECTIVES/HYPOTHESES The study tested whether the DLPFC and the pre-SMA play an essential role in the control of SAT. We hypothesized that continuous theta burst stimulation (cTBS) over the right DLPFC would primarily alter the rate of accumulation of evidence, whereas stimulation of the pre-SMA would influence the threshold for reaching a decision. METHODS Fifteen (5 females; mean age = 30, SD =5.40) healthy volunteers participated in the study. We used two versions of the MDT and cTBS over the right DLPFC, pre-SMA and sham stimulation. The drift diffusion model was fit to the behavioural data (reaction time and error rate) in order to calculate the drift rate, boundary separation (threshold) and non-decision time. RESULTS cTBS over the right DLPFC decreased the rate of accumulation of evidence (i.e. the drift rate from the diffusion model) in high (0.35 and 0.5) but not in low coherence trials. cTBS over the pre-SMA changed the boundary separation/threshold required to reach a decision on accuracy, but not on speed trials. CONCLUSIONS The results suggest for the first time that both the DLPFC and the pre-SMA make essential but distinct contributions to the modulation of SAT.

Connectivity derived thalamic segmentation in deep brain stimulation for tremor

The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinsons disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing.

Pyramidal tract activation due to subthalamic deep brain stimulation in Parkinson's disease

Background: Subthalamic deep brain stimulation (STN‐DBS) is an effective treatment for Parkinsons disease (PD), but can have side effects caused by stimulus spread to structures outside the target volume such as the pyramidal tract.

Movement-related potentials in Parkinson’s disease

To date, many different approaches have been used to study the impairment of motor function in Parkinsons disease (PD). Event-related potentials (ERPs) are averaged amplitude fluctuations of the ongoing EEG activity that are time locked to specific sensory, motor or cognitive events, and as such can be used to study different brain processes with an excellent temporal resolution. Movement-related potentials (MRPs) are ERPs associated with processes of voluntary movement preparation and execution in different paradigms. In this review we concentrate on MRPs in PD. We review studies recording the Bereitschaftspotential, the Contingent Negative Variation, and the lateralized readiness potential in PD to highlight the contributions they have made to further understanding motor deficits in PD. Possible directions for future research are also discussed.

Dopaminergic medication alters auditory distractor processing in Parkinson's disease

Parkinsons disease (PD) patients show signs of cognitive impairment, such as executive dysfunction, working memory problems and attentional disturbances, even in the early stages of the disease. Though motor symptoms of the disease are often successfully addressed by dopaminergic medication, it still remains unclear, how dopaminergic therapy affects cognitive function. The main objective of this study was to assess the effect of dopaminergic medication on visual and auditory attentional processing. 14 PD patients and 13 matched healthy controls performed a three-stimulus auditory and visual oddball task while their EEG was recorded. The patients performed the task twice, once on- and once off-medication. While the results showed no significant differences between PD patients and controls, they did reveal a significant increase in P3 amplitude on- vs. off-medication specific to processing of auditory distractors and no other stimuli. These results indicate significant effect of dopaminergic therapy on processing of distracting auditory stimuli. With a lack of between group differences the effect could reflect either 1) improved recruitment of attentional resources to auditory distractors; 2) reduced ability for cognitive inhibition of auditory distractors; 3) increased response to distractor stimuli resulting in impaired cognitive performance; or 4) hindered ability to discriminate between auditory distractors and targets. Further studies are needed to differentiate between these possibilities.

Gender differences in Parkinson's disease : a clinical perspective

Available data indicate that there are gender differences in many features of Parkinsons disease (PD). Precise identification of the gender differences is important to tailor treatment, predict outcomes, and meet other individual and social needs in women and men with PD. The aim of this study was to review the available clinical data on gender differences in PD. Original articles and meta‐analyses published between 1990 and 2016 systematically exploring gender differences in PD were reviewed. There is slight male preponderance in incidence and prevalence of PD. PD starts earlier in men. Women tend to be more prone to develop tremor‐dominant PD but are less rigid than men. Motor improvement after deep brain stimulation is equal in both sexes, but women tend to show better improvement in activities of daily living. Furthermore, women with PD show better results on tests for general cognitive abilities, outperform men in verbal cognitive tasks, show more pain symptoms, and score higher on depression scales. It seems, however, that the differences in cognition, mood, and pain perception are not disease specific as similar gender differences can be found in healthy subjects and in other neurological conditions. Despite PD being the most frequently studied movement disorder, studies investigating gender differences in PD are still scarce with most of the studies being cross‐sectional. Good‐quality, prospective, longitudinal studies analyzing gender differences in PD and comparing them to matched healthy controls are needed in order to properly address the issues of gender differences in PD.

Parkinson Check smart phone app

The paper introduces the Parkinson Check application. It is an app for smart phones based on spirography (spiral drawing) intended to detect signs of Parkinsons disease (PD) and essential tremor (ET), which is the main differential diagnosis from PD in the early stage of the disease. The app is equipped with an expert system and is the first such app to be completely automated. Its intended use is twofold: (a) to act as a standalone test for general population, advising potential patients to seek medical help as early as possible, and (b) to be used by neurologists as a portable and inexpensive fully digitalised clinical decision support system. Parkinson Check is currently freely available in Slovenia on four mobile platforms as a pilot study. After potentially upgrading its expert system with new learning data, the plan is for it to be translated into English and offered worldwide.