Subthalamic nucleus physiology is correlated with deep brain stimulation motor and non-motor outcomes

Abstract Subthalamic nucleus deep brain stimulation is commonly indicated for symptomatic relief of idiopathic Parkinson’s disease. Despite the known improvement in motor scores, affective, cognitive, voice and speech functions might deteriorate following this procedure. Recent studies have correlated motor outcomes with intraoperative microelectrode recordings. However, there are no microelectrode recording–based tools with predictive values relating to long-term outcomes of integrative motor and non-motor symptoms. We conducted a retrospective analysis of the outcomes of patients with idiopathic Parkinson’s disease who had subthalamic nucleus deep brain stimulation at Tel Aviv Sourasky Medical Centre (Tel Aviv, Israel) during 2015–2016. Forty-eight patients (19 women, 29 men; mean age, 58 ± 8 years) who were implanted with a subthalamic nucleus deep brain stimulation device underwent pre- and postsurgical assessments of motor, neuropsychological, voice and speech symptoms. Significant improvements in all motor symptoms (except axial signs) and levodopa equivalent daily dose were noted in all patients. Mild improvements were observed in more posterior-related neuropsychological functions (verbal memory, visual memory and organization) while mild deterioration was observed in frontal functions (personality changes, executive functioning and verbal fluency). The concomitant decline in speech intelligibility was mild and only partial, probably in accordance with the neuropsychological verbal fluency results. Acoustic characteristics were the least affected and remained within normal values. Dimensionality reduction of motor, neuropsychological and voice scores rendered six principal components that reflect the main clinical aspects: the tremor-dominant versus the rigidity–bradykinesia-dominant motor symptoms, frontal versus posterior neuropsychological deficits and acoustic characteristics versus speech intelligibility abnormalities. Microelectrode recordings of subthalamic nucleus spiking activity were analysed off-line and correlated with the original scores and with the principal component results. Based on 198 microelectrode recording trajectories, we suggest an intraoperative subthalamic nucleus deep brain stimulation score, which is a simple sum of three microelectrode recording properties: normalized neuronal activity, the subthalamic nucleus width and the relative proportion of the subthalamic nucleus dorsolateral oscillatory region. A threshold subthalamic nucleus deep brain stimulation score >2.5 (preferentially composed of normalized root mean square >1.5, subthalamic nucleus width >3 mm and a dorsolateral oscillatory region/subthalamic nucleus width ratio >1/3) predicts better motor and non-motor long-term outcomes. The algorithm presented here optimizes intraoperative decision-making of deep brain stimulation contact localization based on microelectrode recording with the aim of improving long-term (>1 year) motor, neuropsychological and voice symptoms.

Attention shifting and cognitive flexibility were evaluated with the Trail-Making Test Part B (TMT-B).In addition, the Wisconsin Card Sorting Test (WCST) was used to evaluate executive functions, including problem-solving skills and cognitive flexibility ("set shifting"wiscat, wicsom, wispersv). 3onemic verbal fluency (an anterior faculty) was examined by a non-formal Hebrew 3-letter phonemic fluency task (FAS) and a one-category semantic fluency task (ANIMALSa posterior faculty) developed at the Hebrew University of Jerusalem. 4sterior neuropsychological scores Visuospatial functions and organization were evaluated with the Rey-Osterrieth Complex Figure copy test (ROCFcopy) and the Hooper test (hooper), respectively. 5In addition, Digit Symbol (digitsym), a subtest of the WAIS-III, was used to evaluate visuospatial functioning and processing speed. 2 Immediate and delayed Visual Memory were evaluated with ROCF-STM (short-term memory) and ROCF-LTM (long-term memory), respectively. 5rbal learning and memory were evaluated with the Hebrew version of the Rey Auditory Verbal Learning Test (RAVLT).6 The test includes verbal information encoding, verbal proactive interference (RAVLT6), immediate and delayed verbal memory recall, and verbal learning (RAVLTlearn).

Supplementary Appendix 2. Detailed voice and speech scores
Physical properties of the voice Acoustic characteristics of voice parameters of sustained vowels /a/, repetitions of /pataka/, and sentence production were evaluated with the PRAAT voice analysis program. 7as follows.All of these parameters are gender-independent.Fundamental Frequency (~Median Pitch) is a measure of the number of cycles the vocal folds could make in one second.Normal ranges differ between men (85-180 Hz) and women (165-255 Hz).Jitter is a measure of the variability or perturbation of the fundamental frequency.Diadochokinetic Rate is a measure of the structural and physiological changes in the central nervous system and the peripheral components of the oral and speech production mechanism.It is evaluated by /PTK/ repetition.The normal rate in adults is PTK*10 ≤5sec.Maximal Phonation Time (MPT) is a measure of glottic efficiency, that is, the ability to close (adduct) the vocal folds efficiently and easily and to vibrate them strongly through rapid opening and closing cycles.It determines the maximum time (in seconds) a person can sustain a vowel sound (/ah/, /ee/, /oo/) on a single deep breath at a relatively comfortable pitch and loudness.The final score is the best score of 3 'ah' attempts.The normal MPT range is 25-35 seconds in adult males and 15-25 seconds in adult females.A time of <7 seconds is definitively pathological.Speech intensity is evaluated using a computerized acoustic analysis of the intensity of normal /a/ (normal ~ 60 dB), loud /a/ (normal ~ 90 dB), spontaneous speech (normal ~ none), and reading (normal ~ none).Voice Quality is evaluated with the GRBAS scale, a widely used perceptual instrument 8 that covers 5 parameters: grade (of hoarseness), roughness, breathiness, asthenia, and strain.Each parameter is graded on a scale of 0 to 3. The instrument is completed by trained clinical staff.The final score indicates the severity of dysphonia.The f GRBAS is also used to evaluate the presence (yes/no) of tremor/pitch variation/loudness variation/voice interruption/other. 9ch intelligibility Patient, caregiver, and clinician perceptions of speech intelligibility were evaluated with the Voice Handicap Index (VHI), Speech Visual Analog Scale (VAS), 6-Point Scale, and UPDRS-Speech subscale.8 The VHI assesses self-perceived impact/interference of an individual's "voice disorder" on the social aspects of his or her life.It contains 30 statements relating to functional (VHI-F), physical (VHI-P), and emotional (VHI-E) issues of a voice disorder.Each is scored from 0 to 4. In addition, the VHI includes 2 independent items on the degree of disturbance rated from 1 to 7 and the quantity of communication/speech during the day (rated from 7 to 1).The Speech VAS is a nine-item form completed independently by the patient's caregiver and clinician to evaluate voice quality (item 1-4), intelligibility (items 5-7), and pragmatics (items 8, 9).All are scored on a scale of 1 (normal) to 10. Tse scales can be rearranged and grouped to assess functionality as follows: Voice Properties = VAS1-4 (+ VHI/P); Speech Intelligibility = VAS 5-7 (+ VHI/F+E); Pragmatic Function = VAS 8-9 (+ VHI/F+E) The 6-Point-Scale is a one-item instrument measuring speech intelligibility intended to be completed independently by the patient, the patient's caregiver, and the clinician.The responder is asked to select which statement out of 6 best describes the patient's current status (6 is normal).The UPDRS-Speech subscale comprises UPDRS items 5+18.10  Supplementary -Table 3: The distribution of neuropsychological symptoms are differed into dominantly anterior, posterior or mixed faculties.Overall, the cohort's scores distributed evenly and with no significant abnormalities before STN-DBS.

Speech-Voice Neuropsychological
An overall homogenous distribution of motor symptoms, good LDOPA responsiveness and normal neuropsychological and speech.
• ON/OFF/UPDRS IV had the highest correlation with ADL compared to all specific symptom.
• LEDD had a significant positive impact.
• Patients presented with normal speech and voice scores pre-DBS, except 3 scores (VHI E,F,P).
• Speech and voice scores given by patients, caregivers, and clinicians did not differ.
• Patients presented with normal neuropsychology scores pre-DBS.

•
Patients did not mention any significant neuropsychological differences between ON/OFF states.

Motor Speech-Voice Neuropsychological
Significant improvement in all motor scores (except axial signs) and mildly accepted deterioration in neuropsychological (personality, attention & language) and speech (intelligibility) scores.Axial symptoms and voice physical properties seem indifferent DBS.

•
The improvement of ON/OFF-UPDRS IV best predicted ADL outcomes, compared to any other symptoms.
• All MER properties predict improved motor outcomes except axial signs which are DBS resistant.
• β-oscillation best correlated with better ON/OFF improvement.
• Drugs maintain an independent positive effect, irreplaceable by DBS.
• Mild deterioration in speech intelligibility with much less significant changed voice physical properties.
• Drugs' positive impact is dominant and irreplaceable by DBS.
• Post-DBS there is a significant variability of patients/caregivers/clinicians scores.
• Mild deterioration in anterior faculties vs undetermined trend in posterior ones.
• Post-DBS there is a significant variability of patients/caregivers/clinicians scores.
Abbreviations: DBS, deep-brain stimulation; LEDD: levodopa equivalent daily dose; SD, standard deviation; STN, subthalamic nucleus; UPDRS: unified Parkinson's disease rating scale It is affected mainly by lack of control of vocal-fold vibrations.Values range from 0 to 200%, with >1.04% considered pathological.Higher scores indicate worse clinical status.Shimmer is the variability or perturbation of the amplitude of the sound wave or intensity of the vocal emission.It is affected by a reduction of glottic resistance and mass lesions in the vocal folds.Values >3.08% are considered pathological.Higher scores indicate worse clinical status.Harmonics-to-Noise-Ratio defines the degree of acoustic periodicity.It is determined by calculating the energy of the signal and noise [10*log 10 (harmonics/noise)].A value of 0 means there is equal energy in the harmonics and the noise.No threshold exists.Higher ratios indicate worse status.

Table 2 :
Except VHI F,E and P all voice and speech properties were normal pre STN-DBS.(