Parkinson's Disease Tremor Differentially Responds to Levodopa and Subthalamic Stimulation.

Background: Tremor in Parkinson's disease (PD) has an inconsistent response to levodopa and subthalamic deep brain stimulation (STN-DBS). Objectives: To identify predictive factors of PD tremor responsiveness to levodopa and STN-DBS. Material and Methods: PD patients with upper limb tremor who underwent STN-DBS were included. The levodopa responsiveness of tremor (overall, postural, and rest sub-components), was assessed using the relevant Unified Parkinson's Disease Rating Scale-III items performed during the preoperative assessment. Post-surgical outcomes were similarly assessed ON and OFF stimulation. A score for the rest/postural tremor ratio was used to determine the influence of rest and postural tremor severity on STN-DBS outcome. Factors predictive of tremor responsiveness were determined using multiple linear regression modeling. Volume of tissue activated measurement coupled to voxel-based analysis was performed to identify anatomical clusters associated with motor symptoms improvement. Results: One hundred and sixty five patients were included in this study. Male gender was negatively correlated with tremor responsiveness to levodopa, whereas the ratio of rest/postural tremor was positively correlated with both levodopa responsiveness and STN-DBS tremor outcome. Clusters corresponding to improvement of tremor were in the subthalamic nucleus, the zona incerta and the thalamus, whereas clusters corresponding to improvement for akinesia and rigidity were located within the subthalamic nucleus. Conclusion: More severe postural tremor and less severe rest tremor were associated with both poorer levodopa and STN-DBS response. The different locations of clusters associated with best correction of tremor and other parkinsonian features suggest that STN-DBS effect on PD symptoms is underpinned by the modulation of different networks.

Accuracy, precision, and safety of stereotactic, frame-based, intraoperative MRI-guided and MRI-verified deep brain stimulation in 650 consecutive procedures.

OBJECTIVE: Suboptimal lead placement is one of the most common indications for deep brain stimulation (DBS) revision procedures. Confirming lead placement in relation to the visible anatomical target with dedicated stereotactic imaging before terminating the procedure can mitigate this risk. In this study, the authors examined the accuracy, precision, and safety of intraoperative MRI (iMRI) to both guide and verify lead placement during frame-based stereotactic surgery. METHODS: A retrospective analysis of 650 consecutive DBS procedures for targeting accuracy, precision, and perioperative complications was performed. Frame-based lead placement took place in an operating room equipped with an MRI machine using stereotactic images to verify lead placement before removing the stereotactic frame. Immediate lead relocation was performed when necessary. Systematic analysis of the targeting error was calculated. RESULTS: Verification of 1201 DBS leads with stereotactic MRI was performed in 643 procedures and with stereotactic CT in 7. The mean ± SD of the final targeting error was 0.9 ± 0.3 mm (range 0.1-2.3 mm). Anatomically acceptable lead placement was achieved with a single brain pass for 97% (n = 1164) of leads; immediate intraoperative relocation was performed in 37 leads (3%) to obtain satisfactory anatomical placement. General anesthesia was used in 91% (n = 593) of the procedures. Hemorrhage was noted after 4 procedures (0.6%); 3 patients (0.4% of procedures) presented with transient neurological symptoms, and 1 experienced delayed cognitive decline. Two bleeds coincided with immediate relocation (2 of 37 leads, 5.4%), which contrasts with hemorrhage in 2 (0.2%) of 1164 leads implanted on the first pass (p = 0.0058). Three patients had transient seizures in the postoperative period. The seizures coincided with hemorrhage in 2 of these patients and with immediate lead relocation in the other. There were 21 infections (3.2% of procedures, 1.5% in 3 months) leading to hardware removal. Delayed (> 3 months) retargeting of 6 leads (0.5%) in 4 patients (0.6% of procedures) was performed because of suboptimal stimulation benefit. There were no MRI-related complications, no permanent motor deficits, and no deaths. CONCLUSIONS: To the authors' knowledge, this is the largest series reporting the use of iMRI to guide and verify lead location during DBS surgery. It demonstrates a high level of accuracy, precision, and safety. Significantly higher hemorrhage was encountered when multiple brain passes were required for lead implantation, although none led to permanent deficit. Meticulous audit and calibration can improve precision and maximize safety.

Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson's Disease Dementia: A 36 Months Follow Up Study.

Background: Degeneration of the nucleus basalis of Meynert (NBM) and cortical cholinergic dysfunction are hallmarks of Parkinson's disease dementia (PDD). There is no effective therapy for PDD. Deep brain stimulation of the NBM (NBM-DBS) has been trialed as a potential treatment. Objective: Our primary aim was to evaluate the sustained tolerability of NBM-DBS in PDD, and its impact on global cognition, behavioral symptoms, quality of life and caregiver burden and distress. Second, we aimed to determine whether baseline measures of arousal, alertness, and attention were predictive of the three year response to NBM-DBS in PDD patients. Methods: Five of the six PDD patients who completed the baseline assessment participated in a 3 year follow up assessment. We assessed the participants after three years of NBM-DBS on the Mini Mental State Examination, Dementia Rating Scale-2, Blessed Dementia Rating Scale, Neuropsychiatric Inventory, and the SF36. Results: The five patients showed varying trajectories of cognitive decline, with two showing a slower progression over the three-year follow-up period. A slower progression of decline on global cognition was associated with higher baseline accuracy on the Posner covert orienting of attention test, and less daytime sleepiness. Conclusions: Whether slower progression of cognitive decline in two patients was in any way related to individual variability in responsiveness to NBM-DBS requires confirmation in a larger series including an unoperated PDD control group. Higher accuracy in covertly orienting attention and better sleep quality at baseline were associated with better cognitive outcomes at 36 months assessment. These results require validation in future studies with larger samples.

Long-term success of low-frequency subthalamic nucleus stimulation for Parkinson's disease depends on tremor severity and symptom duration.

Patients with Parkinson's disease can develop axial symptoms, including speech, gait and balance difficulties. Chronic high-frequency (>100 Hz) deep brain stimulation can contribute to these impairments while low-frequency stimulation (<100 Hz) may improve symptoms but only in some individuals. Factors predicting which patients benefit from low-frequency stimulation in the long term remain unclear. This study aims to confirm that low-frequency stimulation improves axial symptoms, and to go further to also explore which factors predict the durability of its effects. We recruited patients who developed axial motor symptoms while using high-frequency stimulation and objectively assessed the short-term impact of low-frequency stimulation on axial symptoms, other aspects of motor function and quality of life. A retrospective chart review was then conducted on a larger cohort to identify which patient characteristics were associated with not only the need to trial low-frequency stimulation, but also those which predicted its sustained use. Among 20 prospective patients, low-frequency stimulation objectively improved mean motor and axial symptom severity and quality of life in the short term. Among a retrospective cohort of 168 patients, those with less severe tremor and those in whom axial symptoms had emerged sooner after subthalamic nucleus deep brain stimulation were more likely to be switched to and remain on long-term low-frequency stimulation. These data suggest that low-frequency stimulation results in objective mean improvements in overall motor function and axial symptoms among a group of patients, while individual patient characteristics can predict sustained long-term benefits. Longer follow-up in the context of a larger, controlled, double-blinded study would be required to provide definitive evidence of the role of low-frequency deep brain stimulation.

The sensitivity to change of the cluster headache quality of life scale assessed before and after deep brain stimulation of the ventral tegmental area.

BACKGROUND: Cluster headache (CH) is a trigeminal autonomic cephalalgia (TAC) characterized by a highly disabling headache that negatively impacts quality of life and causes limitations in daily functioning as well as social functioning and family life. Since specific measures to assess the quality of life (QoL) in TACs are lacking, we recently developed and validated the cluster headache quality of life scale (CH-QoL). The sensitivity of CH-QoL to change after a medical intervention has not been evaluated yet. METHODS: This study aimed to test the sensitivity to change of the CH-QoL in CH. Specifically we aimed to (i) assess the sensitivity of CH-QoL to change before and following deep brain stimulation of the ventral tegmental area (VTA-DBS), (ii) evaluate the relationship of changes on CH-QoL with changes in other generic measures of quality of life, as well as indices of mood and pain. Ten consecutive CH patients completed the CH-QoL and underwent neuropsychological assessment before and after VTA-DBS. The patients were evaluated on headache frequency, severity, and load (HAL) as well as on tests of generic quality of life (Short Form-36 (SF-36)), mood (Beck Depression Inventory, Hospital Anxiety and Depression Rating Scale), and pain (McGill Pain Questionnaire, Headache Impact Test, Pain Behaviour Checklist). RESULTS: The CH-QoL total score was significantly reduced after compared to before VTA-DBS. Changes in the CH-QoL total score correlated significantly and negatively with changes in HAL, the SF-36, and positively and significantly with depression and the evaluative domain on the McGill Pain Questionnaire. CONCLUSIONS: Our findings demonstrate that changes after VTA-DBS in CH-QoL total scores are associated with the reduction of frequency, duration, and severity of headache attacks after surgery. Moreover, post VTA-DBS improvement in CH-QoL scores is associated with an amelioration in quality of life assessed with generic measures, a reduction of depressive symptoms, and evaluative pain experience after VTA-DBS. These results support the sensitivity to change of the CH-QoL and further demonstrate the validity and applicability of CH-QoL as a disease specific measure of quality of life for CH.

Differential responses to breath-holding, voluntary deep breathing and hypercapnia in left and right dorsal anterior cingulate.

NEW FINDINGS: What is the central question of this study? What is the role of dorsal anterior cingulate cortex (ACC) in respiration control in humans? What is the main finding and its importance? Direct evidence is provided for a role of the ACC in respiratory control in humans. The neurophysiological responses in dorsal ACC to different breathing tasks varied and were different between left and right ACC. ABSTRACT: The role of subcortical structures and cerebral cortex in the maintenance of respiratory homeostasis in humans remains poorly understood. Emerging evidence suggests an important role of the anterior cingulate cortex (ACC) in respiratory control. In this study, local field potentials (LFPs) from dorsal ACC were recorded in humans through implanted deep brain electrodes during several breathing activities, including voluntary activities of breath-holding and deep breathing, and involuntary activities of inspiration of varying concentrations of carbon dioxide (1%, 3%, 5% and 7%). We found that the breath-holding task induced significant unilateral left-sided ACC changes in LFP power, including an increased activity in lower frequency bands (3-5 Hz) and decreased activity in higher frequency bands (12-26 Hz). The respiratory task involving reflex increase in ventilation due to hypercapnia (raised inspired CO2 ) was associated with bilateral changes in activity of the ACC (again with increased activity in lower frequency bands and reduced activity in higher frequency bands). The voluntary breathing task with associated hypocapnia (deep breathing) induced bilateral changes in activity within low frequency bands. Furthermore, probabilistic diffusion tractography analysis showed left-sided connection of the ACC with the insula and frontal operculum, and bilateral connections within subsections of the cingulate gyrus and the thalamus. This electrophysiological analysis provides direct evidence for a role of the ACC in respiratory control in humans.

Pedunculopontine Nucleus Deep Brain Stimulation for Parkinsonian Disorders: A Case Series.

BACKGROUND: Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been investigated for the treatment of levodopa-refractory gait dysfunction in parkinsonian disorders, with equivocal results so far. OBJECTIVES: To summarize the clinical outcomes of PPN-DBS-treated patients at our centre and elicit any patterns that may guide future research. MATERIALS AND METHODS: Pre- and post-operative objective overall motor and gait subsection scores as well as patient-reported outcomes were recorded for 6 PPN-DBS-treated patients, 3 with Parkinson's disease (PD), and 3 with progressive supranuclear palsy (PSP). Electrodes were implanted unilaterally in the first 3 patients and bilaterally in the latter 3, using an MRI-guided MRI-verified technique. Stimulation was initiated at 20-30 Hz and optimized in an iterative manner. RESULTS: Unilaterally treated patients did not demonstrate significant improvements in gait questionnaires, UPDRS-III or PSPRS scores or their respective gait subsections. This contrasted with at least an initial response in bilaterally treated patients. Diurnal cycling of stimulation in a PD patient with habituation to the initial benefit reproduced substantial improvements in freezing of gait (FOG) 3 years post-operatively. Among the PSP patients, 1 with a parkinsonian subtype had a sustained improvement in FOG while another with Richardson syndrome (PSP-RS) did not benefit. CONCLUSIONS: PPN-DBS remains an investigational treatment for levodopa-refractory FOG. This series corroborates some previously reported findings: bilateral stimulation may be more effective than unilateral stimulation; the response in PSP patients may depend on the disease subtype; and diurnal cycling of stimulation to overcome habituation merits further investigation.

Entraining Stepping Movements of Parkinson's Patients to Alternating Subthalamic Nucleus Deep Brain Stimulation.

Patients with advanced Parkinson's can be treated by deep brain stimulation (DBS) of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson's patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients' stepping movements as evidence of the STN's involvement in stepping control. Group analyses of 10 Parkinson's patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study suggests that the STN is causally involved in dynamic control of step timing and motivates further exploration of this biomimetic stimulation pattern as a potential basis for the development of DBS strategies to ameliorate gait impairments.SIGNIFICANCE STATEMENT We tested whether the subthalamic nucleus (STN) in humans is causally involved in controlling stepping movements. To this end, we studied patients with Parkinson's disease who have undergone therapeutic deep brain stimulation (DBS), as in these individuals we can stimulate the STNs in a controlled manner. We developed an alternating pattern of stimulation that mimics the pattern of activity modulation recorded in this nucleus during stepping. The alternating DBS (altDBS) could entrain patients' stepping rhythm, suggesting a causal role of the STN in dynamic gait control. This type of stimulation may potentially form the basis for improved DBS strategies for gait.

Bilateral nucleus basalis of Meynert deep brain stimulation for dementia with Lewy bodies: A randomised clinical trial.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common form of dementia. Current symptomatic treatment with medications remains inadequate. Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a potential new treatment option in dementias. OBJECTIVE: To assess the safety and tolerability of low frequency (20 Hz) NBM DBS in DLB patients and explore its potential effects on both clinical symptoms and functional connectivity in underlying cognitive networks. METHODS: We conducted an exploratory randomised, double-blind, crossover trial of NBM DBS in six DLB patients recruited from two UK neuroscience centres. Patients were aged between 50 and 80 years, had mild-moderate dementia symptoms and were living with a carer-informant. Patients underwent image guided stereotactic implantation of bilateral DBS electrodes with the deepest contacts positioned in the Ch4i subsector of NBM. Patients were subsequently assigned to receive either active or sham stimulation for six weeks, followed by a two week washout period, then the opposite condition for six weeks. Safety and tolerability of both the surgery and stimulation were systematically evaluated throughout. Exploratory outcomes included the difference in scores on standardised measurements of cognitive, psychiatric and motor symptoms between the active and sham stimulation conditions, as well as differences in functional connectivity in discrete cognitive networks on resting state fMRI. RESULTS: Surgery and stimulation were well tolerated by all six patients (five male, mean age 71.33 years). One serious adverse event occurred: one patient developed antibiotic-associated colitis, prolonging his hospital stay by two weeks. No consistent improvements were observed in exploratory clinical outcome measures, but the severity of neuropsychiatric symptoms reduced with NBM DBS in 3/5 patients. Active stimulation was associated with functional connectivity changes in both the default mode network and the frontoparietal network. CONCLUSION: Low frequency NBM DBS can be safely conducted in DLB patients. This should encourage further exploration of the possible effects of stimulation on neuropsychiatric symptoms and corresponding changes in functional connectivity in cognitive networks. TRIAL REGISTRATION NUMBER: NCT02263937.

Globus pallidal deep brain stimulation for Tourette syndrome: Effects on cognitive function.

INTRODUCTION: In a double-blind randomized crossover trial, we previously established that bilateral deep brain stimulation of the anteromedial globus pallidus internus (GPiam-DBS) is effective in significantly reducing tic severity in patients with refractory Tourette syndrome (TS). Here, we report the effects of bilateral GPiam-DBS on cognitive function in 11 of the 13 patients who had participated in our double-blind cross-over trial of GPi-DBS. METHODS: Patients were assessed at baseline (4 weeks prior to surgery) and at the end of each of the three-month blinded periods, with stimulation either ON or OFF. The patients were evaluated on tests of memory (California Verbal Learning Test-II (CVLT-II); Corsi blocks; Short Recognition Memory for Faces), executive function (D-KEFS Stroop color-word interference, verbal fluency, Trail-making test, Hayling Sentence Completion test), and attention (Paced Auditory Serial Addition Test, Numbers and Letters Test). RESULTS: GPiam-DBS did not produce any significant change in global cognition. Relative to pre-operative baseline assessment verbal episodic memory on the CVLT-II and set-shifting on the Trail-making Test were improved with DBS OFF. Performance on the cognitive tests were not different with DBS ON versus DBS OFF. GPiam-DBS did not alter aspects of cognition that are impaired in TS such as inhibition on the Stroop interference task or the Hayling Sentence Completion test. CONCLUSIONS: This study extends previous findings providing data showing that GPiam-DBS does not adversely affect cognitive domains such as memory, executive function, verbal fluency, attention, psychomotor speed, and information processing. These results indicate that GPiam-DBS does not produce any cognitive deficits in TS.

Cardiovascular autonomic responses in patients with Parkinson disease to pedunculopontine deep brain stimulation.

PURPOSE: Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result in changes in autonomic performance. METHODS: To determine whether pedunculopontine nucleus stimulation improves cardiovascular responses to autonomic challenges of postural tilt and Valsalva manoeuver, eight patients with pedunculopontine nucleus deep brain stimulation were recruited to the study; two were excluded for technical reasons during testing. Participants underwent head up tilt and Valsalva manoeuver with stimulation turned ON and OFF. Continuous blood pressure and ECG waveforms were recorded during these tests. In a single patient, local field potential activity was recorded from the implanted electrode during tilt. RESULTS: The fall in systolic blood pressure after tilt was significantly smaller with stimulation ON (mean - 8.3% versus - 17.2%, p = 0.044). Valsalva ratio increased with stimulation from median 1.15 OFF to 1.20 ON (p = 0.028). Baroreflex sensitivity increased during Valsalva compared to rest with stimulation ON versus OFF (p = 0.028). The increase in baroreflex sensitivity correlated significantly with the mean depth of PPN stimulating electrode contacts. This accounted for 89% of its variance (r = 0.943, p = 0.005). CONCLUSION: PPN stimulation can modulate the cardiovascular system in patients with PD. In this study, it reduced the postural fall in systolic blood pressure during head-up tilt and improved the cardiovascular response during Valsalva, presumably by altering the neural control of baroreflex activation.

The pedunculopontine region and breathing in Parkinson's disease.

OBJECTIVE: Respiratory abnormalities such as upper airway obstruction are common in Parkinson's disease (PD) and are an important cause of mortality and morbidity. We tested the effect of pedunculopontine region (PPNr) stimulation on respiratory maneuvers in human participants with PD, and separately recorded PPNr neural activity reflected in the local field potential (LFP) during these maneuvers. METHODS: Nine patients with deep brain stimulation electrodes in PPNr, and seven in globus pallidus interna (GPi) were studied during trials of maximal inspiration followed by forced expiration with stimulation OFF and ON. Local field potentials (LFPs) were recorded in the unstimulated condition. RESULTS: PEFR increased from 6.41 ± 0.63 L/sec in the OFF stimulation state to 7.5 L ± 0.65 L/sec in the ON stimulation state (z = -2.666, df = 8, P = 0.024). Percentage improvement in PEFR was strongly correlated with proximity of the stimulated electrode contact to the mesencephalic locomotor region in the rostral PPN (r = 0.814, n = 9, P = 0.008). Mean PPNr LFP power increased within the alpha band (7-11 Hz) during forced respiratory maneuvers (1.63 ± 0.16 µV2/Hz) compared to resting breathing (0.77 ± 0.16 µV2/Hz; z = -2.197, df = 6, P = 0.028). No changes in alpha activity or spirometric indices were seen with GPi recording or stimulation. Percentage improvement in PEFR was strongly positively correlated with increase in alpha power (r = 0.653, n = 14 (7 PPNr patients recorded bilaterally), P = 0.0096). INTERPRETATION: PPNr stimulation in PD improves indices of upper airway function. Increased alpha-band activity is seen within the PPNr during forced respiratory maneuvers. Our findings suggest a link between the PPNr and respiratory performance in PD.

Beta synchrony in the cortico-basal ganglia network during regulation of force control on and off dopamine.

Beta power suppression in the basal ganglia is stronger during movements that require high force levels and high movement effort but it has been difficult to dissociate the two. We recorded scalp EEG and basal ganglia local field potentials in Parkinson's disease patients (11 STN, 7 GPi) ON and OFF dopaminergic medication while they performed a visually-guided force matching task using a pen on a force-sensitive graphics tablet. Force adjustments were accompanied by beta power suppression irrespective of whether the force was increased or reduced. Before the adjustment was completed, beta activity returned. High beta power was specifically associated with slowing of the force adjustment. ON medication, the peak force rate was faster and cortico-basal ganglia beta phase coupling was more readily modulated. In particular, phase decoupling was stronger during faster adjustments. The results suggest that beta power in the basal ganglia does not covary with force per se, but rather with a related factor, the absolute force rate, or a more general concept of movement effort. The results also highlight that beta activity reappears during stabilization of isometric contractions, and that dopamine-related suppression of cortico-basal ganglia beta coupling is linked to faster force adjustments.

Direct neurophysiological evidence for a role of the human anterior cingulate cortex in central command.

INTRODUCTION: The role of the anterior cingulate cortex (ACC) is still controversial. The ACC has been implicated in such diverse functions as cognition, arousal and emotion in addition to motor and autonomic control. Therefore the ACC is the ideal candidate to orchestrate cardiovascular performance in anticipation of perceived skeletal activity. The aim of this experiment was to investigate whether the ACC forms part of the neural network of central command whereby cardiovascular performance is governed by a top-down mechanism. METHODS & RESULTS: Direct local field potential (LFP) recordings were made using intraparenchymal electrodes in six human ACC's to measure changes in neuronal activity during performance of a motor task in which anticipation of exercise was uncoupled from skeletal activity itself. Parallel cardiovascular arousal was indexed by electrocardiographic changes in heart rate. During anticipation of exercise, ACC LFP power within the 25-60 Hz frequency band increased significantly by 21% compared to rest (from 62.7 µV2/Hz (±SE 4.94) to 76.0µV2/Hz (±SE 7.24); p = 0.004). This 25-60 Hz activity increase correlated with a simultaneous heart rate increase during anticipation (Pearson's r = 0.417, p = 0.016). CONCLUSIONS/SIGNIFICANCE: We provide the first invasive electrophysiological evidence to support the role of the ACC in both motor preparation and the top-down control of cardiovascular function in exercise. This further implicates the ACC in the body's response to the outside world and its possible involvement in such extreme responses as emotional syncope and hyperventilation. In addition we describe the frequency at which the neuronal ACC populations perform these tasks in the human.

Effect of Low versus High Frequency Subthalamic Deep Brain Stimulation on Speech Intelligibility and Verbal Fluency in Parkinson's Disease: A Double-Blind Study.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is an established treatment for late stage Parkinson's disease (PD). Speech intelligibility (SI) and verbal fluency (VF) have been shown to deteriorate following chronic STN-DBS. It has been suggested that speech might respond favourably to low frequency stimulation (LFS). OBJECTIVE: We examined how SI, perceptual speech characteristics, phonemic and semantic VF and processes underlying it (clustering and switching) respond to LFS of 60 and 80 Hz in comparison to high frequency stimulation (HFS) (110, 130 and 200 Hz). METHODS: In this double-blind study, 15 STN-DBS PD patients (mean age 65, SD = 5.8, 14 right handed, three females), were assessed at five stimulation frequencies: 60 Hz, 80 Hz, 110 Hz, 130 Hz and 200 Hz. In addition to the clinical neurological assessment of speech, VF and SI were assessed. RESULTS: SI and in particular articulation, respiration, phonation and prosody improved with LFS (all p < 0.05). Phonemic VF switching improved with LFS (p = 0.005) but this did not translate to an improved phonemic VF score. A trend for improved semantic VF was found. A negative correlation was found between perceptual characteristics of speech and duration of chronic stimulation (all p < 0.05). CONCLUSIONS: These findings highlight the need for meticulous programming of frequency to maximise SI in chronic STN-DBS. The findings further implicate stimulation frequency in changes to specific processes underlying VF, namely phonemic switching and demonstrate the potential to address such deficits through advanced adjustment of stimulation parameters.

Alternating Modulation of Subthalamic Nucleus Beta Oscillations during Stepping.

Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20-30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait.SIGNIFICANCE STATEMENT Gait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20-30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies.

The Effect of Short Pulse Width Settings on the Therapeutic Window in Subthalamic Nucleus Deep Brain Stimulation for Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for selected Parkinson's disease (PD) patients, but therapy is often limited by side effects. Previous studies indicate an inverse relationship of the therapeutic window (TW) to pulse width (PW) settings down to 60µs, but there is limited data available on the effect of shorter PWs. OBJECTIVE: To define the TW of STN-DBS in PD at PW of 30µs (PW30) relative to standard PW settings at 60µs (PW60), and to compare speed of gait and speech intelligibility on the two PW conditions. METHODS: Monopolar review data of 15 consecutive PD patients who had screening of contacts performed at PW60 and PW30 was used to calculate the TW at each contact. We compared the TWs of the most efficacious contact per STN, and a secondary analysis was performed comparing all contacts. Speed of gait with a timed 10 metre walk test, speech intelligibility, and perceptual characteristics of speech were also compared at the efficacy thresholds for PW60 and PW30. RESULTS: The TW was significantly greater at PW30 [3.8±1.6mA] than at PW60 [1.7±1.1mA]. In the secondary analysis, 110 TWs could be calculated and these remained significantly higher at PW30. The timed 10 metre walk at PW30 was faster than at PW60, and perceptual rating scores of speech were significantly improved at PW30. CONCLUSIONS: STN-DBS in PD patients using a PW of 30µs significantly increases the TW compared to standard PW settings, and this effect is consistent across all contacts of an electrode. Speed of gait and perceptual speech scores are also improved at 30µs settings.

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 Parkinson's 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.

Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia: A Randomized Clinical Trial.

Importance: Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a treatment option for Parkinson disease dementia. Objective: To evaluate the safety and potential symptomatic effects of NBM DBS in patients with Parkinson disease dementia. Design, Setting, and Participants: A randomized, double-blind, crossover clinical trial evaluated the results of 6 patients with Parkinson disease dementia who were treated with NBM DBS at a neurosurgical referral center in the United Kingdom from October 26, 2012, to July 31, 2015. Eligible patients met the diagnostic criteria for Parkinson disease dementia, had motor fluctuations, were appropriate surgical candidates aside from the coexistence of dementia, were age 35 to 80 years, were able to give informed consent, had a Mini-Mental State Examination score of 21 to 26, had minimal atrophy seen on results of brain magnetic resonance imaging, and lived at home with a caregiver-informant. Interventions: After surgery, patients were assigned to receive either active stimulation (bilateral, low-frequency [20 Hz] NBM DBS) or sham stimulation for 6 weeks, followed by the opposite condition for 6 weeks. Main Outcomes and Measures: The primary outcome was the difference in scores on each item of an abbreviated cognitive battery (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale-III digit span, verbal fluency, Posner covert attention test, and simple and choice reaction times) between the 2 conditions. Secondary outcomes were exploratory and included differences in scores on standardized measurements of cognitive, psychiatric, and motor symptoms and resting state functional magnetic resonance imaging. Results: Surgery and stimulation were well tolerated by all 6 patients (all men; mean [SD] age, 65.2 [10.7] years), with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional magnetic resonance imaging. An improvement in scores on the Neuropsychiatric Inventory was observed with NBM DBS (8.5 points [range, 4-26 points]) compared with sham stimulation (12 points [range, 8-38 points]; median difference, 5 points; 95% CI, 2.5-8.5 points; P = .03) and the preoperative baseline (13 points [range, 5-25 points]; median difference, 2 points; 95% CI, -8 to 5.5 points; P = .69). Conclusions and Relevance: Low-frequency NBM DBS was safely conducted in patients with Parkinson disease dementia; however, no improvements were observed in the primary cognitive outcomes. Further studies may be warranted to explore its potential to improve troublesome neuropsychiatric symptoms. Trial Registration: clinicaltrials.gov Identifier: NCT01701544.