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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - STOP-Beta (Selectively Targeting Oscillations in Parkinson\'s disease: Causal effects of the beta-rhythm on motor control)

Teaser

Summary

Parkinsonâ€™s disease is a common neurodegenerative disorder, which strongly affects patientsâ€™ ability to control movements. Electrical stimulation of a deep-seated brain region (the subthalamic nucleus) has been shown to significantly improve motor function and quality of life in Parkinsonâ€™s disease. This treatment, which is referred to as deep brain stimulation (DBS), is particularly helpful in patients, who developed side-effects to their Parkinson drug treatment. However, DBS also has unwanted effects, such as impairing patientsâ€™ ability to delay or slow down their responses when faced with difficult or conflicting choices.

Recent technological advances in DBS render it possible to adjust stimulation to ongoing brain activity so that stimulation is only turned on when brain activity is thought to be abnormal. This method, referred to as closed loop DBS, has been shown to be just as effective as conventional DBS that is turned on continuously, even though closed loop DBS only delivers electrical stimulation ~ 50% of the time. Given that stimulation is applied less frequently, it is conceivable that closed loop DBS might alleviate some of the side effects observed during conventional DBS. Indeed, it has recently been demonstrated that closed loop DBS has less negative effects on speech compared to conventional DBS. It remains, however, unknown whether closed loop DBS also preserves patientsâ€™ ability to slow down responses during difficult decisions.

In this project, we aimed to assess (i) what function is normally (i.e. in the absence of DBS) carried out by the subthalamic nucleus (ii) whether closed loop DBS changes how patients make responses during decision-making, and (iii) what â€˜mechanismsâ€™ are affected by DBS that interfere with physiological control of responses during decision-making.

Work performed

The project comprised two parts. First, we assessed what function is normally carried out by the subthalamic nucleus (the area that is stimulated during DBS) during decision-making in patients with Parkinsonâ€™s disease. To this end, we recorded neural activity from the subthalamic nucleus and interconnected areas at the surface of the brain (prefrontal cortex and motor cortex) while patients were making simple decisions in which they had to judge whether a cloud of moving dots was moving to the left or right side on a computer screen. We analysed data from an existing dataset of eleven patients and a newly acquired study with eleven patients. We found that activity in the subthalamic nucleus reflected the â€˜decision thresholdâ€™ determining the amount of evidence that people require before committing to a choice. Importantly, we detected two distinct correlates of such threshold adjustments; Oscillatory activity between 2-8 Hz (low frequency oscillations) was related to activity at the prefrontal cortex and predicted increased decision thresholds, but only if patients were cautious when making decision, not when they weighted speed over accuracy. Conversely, oscillations between 13-30 Hz (beta oscillations) were related to activity at the motor cortex and predicted decreased decision thresholds irrespective of patients emphasising speed or accuracy during decision-making. These findings indicate that distinct cortico-subthalamic connections are involved in determining whether people respond in haste or with caution. The results have been published in the journals Current Biology (doi: 10.1016/j.cub.2016.01.051) and eLife (doi: 10.7554/eLife.21481.). They have also been presented both as a poster and oral presentation (symposium â€˜Fronto-subthalamic circuits for control of action and cognitionâ€™) at the Society for Neuroscience meeting 2016 in San Diego, USA, the worldâ€™s largest Neuroscience conference with over 30 000 attendees.

In the second part of the project, we used the same task as above, but this time we repeated the task three times for each patient; with DBS turned off, with DBS turned continuously on, and with closed loop DBS. This design allowed us to test whether DBS altered how patients controlled their responses during decision-making. We have thus far included seven patients. Preliminary analysis indicates that, in contrast to our a-priori hypothesis, closed loop DBS does affect patientsâ€™ ability to slow down responses when decision are difficult. Interestingly, this effect seems to depend strongly on the exact timing when stimulation is applied: it was only present if stimulation was applied during a short period several hundred milliseconds after the cue (cloud of moving dots) appeared on the screen, but not during other time windows. This suggests that DBS could be applied without affecting patientsâ€™ ability to slow down responses, if stimulation was turned off during the detected task-related time window. The results will be presented at an upcoming conference on DBS and optogenetics (Opto-DBS 2017) in Geneva, Switzerland. We also expect to submit the results to a peer-reviewed journal soon.

Final results

In this project, we found the first direct evidence that the STN is involved in setting decision thresholds and can thereby contribute to switching between cautious and hasty decision-making. We showed that DBS only affects patientsâ€™ ability to slow down their responses (i.e. increase their decision thresholds) during difficult decisions when applied in a specific time window. This paves the way for future research testing whether stimulation, which is turned off during this â€˜criticalâ€™ time period but turned on during the remaining time might leave physiological adjustments of decision thresholds unaltered. Such advancements in closed loop stimulation protocols might benefit Parkinsonâ€™s disease patients in the future by alleviating motor impairment whilst avoiding unwanted side effects.