Characterization of Complex Pulse Shapes in Deep Brain Stimulation for Movement Disorders Using EEG and Local Field Potential Recordings
Characterization of Complex Pulse Shapes in Deep Brain Stimulation for Movement Disorders Using EEG and Local Field Potential Recordings
Parkinson's disease and essential tremor are chronic movement disorders for which there is no
 cure. When medication is no longer effective, deep brain stimulation (DBS) is recommended.
 Standard DBS is a neuromodulation method that uses a simple monophasic pulse, delivered from
 an electrode to stimulate neurons in a target brain area. This monophasic pulse spreads out
 from the electrode creating a broad, electric field that stimulates a large neural
 population. This can often effectively reduce motor symptoms. However, many DBS patients
 experience side effects - caused by stimulation of non-target neurons - and suboptimal
 symptom control - caused by inadequate stimulation of the correct neural target. The ability
 to carefully manipulate the stimulating electric field to target specific neural
 subpopulations could solve these problems and improve patient outcomes. The use of complex
 pulse shapes, specifically biphasic pulses and asymmetric pre-pulses, can control the
 temporal properties of the stimulation field. Evidence suggests that temporal manipulations
 of the stimulation field can exploit biophysical differences in neurons to target specific
 subpopulations. Therefore, our aim is to evaluate the direct neurophysiological effects of
 complex pulse shapes in DBS movement disorder patients. This will be achieved using a
 two-stage investigation: stage one will study the neural response to different pulse shapes
 using electroencephalography (EEG) recordings. Stage two will study the neural responses to
 different pulse shapes using intra-operative local field potential (LFP) recordings. This
 study only relates only to the collection of EEG and LFP recordings in DBS patients. The
 protocol does not cover any surgical procedures, which already take place as part of the
 patient's normal clinical care.
Parkinson's disease and essential tremor are chronic movement disorders for which there is no
 cure. When medication is no longer effective, deep brain stimulation (DBS) is recommended.
 Standard DBS is a neuromodulation method that uses a simple monophasic pulse, delivered from
 an electrode to stimulate neurons in a target brain area. This monophasic pulse spreads out
 from the electrode creating a broad, electric field that stimulates a large neural
 population. This can often effectively reduce motor symptoms. However, many DBS patients
 experience side effects - caused by stimulation of non-target neurons - and suboptimal
 symptom control - caused by inadequate stimulation of the correct neural target. The ability
 to carefully manipulate the stimulating electric field to target specific neural
 subpopulations could solve these problems and improve patient outcomes.

 It has been shown that modifying the electrical waveform (e.g. pulse duration, pulse
 polarity, etc.) determine the spatial selectivity in functional electrical stimulation. Also,
 a recent clinical study examined for the first time the acute effects of anodic compared to
 cathodic neurostimulation in 10 PD patients. They found that thresholds for anodic
 stimulation were significantly higher than thresholds for cathodic stimulation, which is in
 agreement with previous research in animal studies and model calculations. However, they also
 reported a better clinical effect of anodic compared to cathodic stimulation. Furthermore, a
 modeling study from Anderson et al. (2018) found that fiber orientations can be selectively
 targeted depending on the stimulus waveform (i.e. cathodic or anodic). Another recent study
 examined the effect of an active symmetric biphasic pulse in 8 PD and 3 ET patients. They
 found that this pulse shapes produced significant clinical improvements compared to the
 standard clinical pulse shape.

 Besides the symmetric biphasic pulse shape, the asymmetric pre-pulse shows great potential
 for the refinement of DBS therapy. If the pre-pulse is anodic, it has a hyperpolarizing
 effect and is therefore referred to as a hyperpolarizing pre-pulse. If it is cathodic, it has
 a depolarizing effect near the electrode and is therefore referred to as a depolarizing
 pre-pulse. Clinical studies focused on the use of asymmetric pulse shapes to improve the
 spatial selectivity by selectively exciting fibers in cochlear implant listeners13-16.
 Modeling studies indicate that a hyperpolarizing pre-pulse can actually decrease the
 threshold for axons and that the threshold is decreased more for axons close to the electrode
 than axons further away. This indicates that a hyperpolarizing pre-pulse may help focus the
 effects of stimulation to axons near the electrode, thus leading to an increase in the
 therapeutic window and potentially more efficient symptom control.

 Evidence suggests that temporal manipulations (i.e. the use of complex pulse shapes,
 specifically biphasic pulses and asymmetric pre-pulses) of the stimulation field can exploit
 biophysical differences in neurons to target specific subpopulations. Ultimately, this may
 lead to an increase in the therapeutic window and/or more efficient symptom control. In this
 study, we aim to understand the neural mechanism underpinning the clinical effects observed
 by manipulating the pulse shapes, by comparing neurophysiological responses to the standard
 clinical pulse shapes to the responses to the complex pulse shapes. This will be achieved
 using two approaches. The first approach will study neural responses to different pulse
 shapes using electroencephalography (EEG) recordings. The second approach will study neural
 responses to different pulse shapes using intra-operative local field potential (LFP)
 recordings. This study and research protocol relates only to the collection of EEG and LFP
 recordings in DBS patients. The protocol does not cover any surgical procedures, which will
 already take place as part of the patient's normal clinical care.
Inclusion Criteria for PD:

 -  Diagnosis of idiopathic Parkinson's disease where the diagnosis was made by a Movement
 Disorder Specialist according to the MDS criteria of 2015, with a Hoehn and Yahr scale
 (H&Y) of at least 2 (bilateral involvement).

 -  Onset of the symptoms more than five years ago.

 -  MDS-UPDRS-III score of ≥30 without medication or DBS.

 -  Electrodes are implanted in target area STN.

 Inclusion Criteria for ET:

 -  Patient is diagnosed with essential tremor by a Movement Disorder Specialist.

 -  Diagnosis since more than 3 years.

 -  Patient has a disabling medical-refractory upper extremity tremor without medication
 or DBS.

 -  Patient has a postural or kinetic tremor severity score of at least 3 out of 4 in the
 extremity intended for treatment on the Fahn-Tolosa-Marin Clinical Rating Scale for
 Tremor without medication or DBS.

 -  Electrodes are implanted in target area VIM.

 General Inclusion Criteria:

 Post-op the implanted electrodes pass an integrity check, i.e. no open or shorted
 electrodes.

 -  Stable medications

 -  Lack of dementia or depression.

 -  Patient is willing and able to comply with all visits and study related procedures

 -  Patient understands the study requirements and the treatment procedures and provides
 written informed consent before any study-specific tests or procedures are performed.

 -  Patient can tolerate at least 12 hours OFF medication and per clinical judgement be
 able to perform all study related procedures

 Exclusion Criteria:

 -  Any significant psychiatric problems, including unrelated clinically significant
 depression.

 -  Any current drug or alcohol abuse.

 -  Any history of recurrent or unprovoked seizures.

 -  Have any significant medical condition that is likely to interfere with study
 procedures or likely to confound evaluation of study endpoints, including any terminal
 illness with survival <12 months.