Stimulation Of Nucleus Research Articles

P 29 Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

Background: Deep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized. Objective: The objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr). Methods: Two microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for PD. Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. Results: Excitatory and inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .007). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation, but not SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). Interpretation: Persistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.

P 19 Auditory brainstem implants: Intraoperative electrophysiological measures and hearing outcome

Introduction: Auditory brainstem implants (ABI) are primarily designed for tumour related deafness in neurofibromatosis type 2 (NF2) patients. These neuro-prosthetic devices bypass the auditory nerve and produce hearing sensations by direct stimulation of the cochlear nuclei (CN). This study investigates the importance of intraoperative electrically evoked auditory brainstem responses (EABR) with regards to the auditory outcome. Patients & Methods: Out of a prospectively collected series of ABI implantations from 2005 to 2019, 22 patients (11 male, 11 female) fulfilled inclusion criteria (min. age of 15 y, NF2 diagnosis) and were analysed retrospectively for EABR and hearing outcome. EABR analysis relied on the presence and number of vertex positive peaks P1, P2 and P3 at brainstem stimulation. For post-operative hearing outcome a new Clinical ABI Outcome Classification was developed and applied at 6 to 12 months containing 4 categories: Category 1, Star Performer, with >80% speech understanding in auditory only MTP (mono- to polysyllabic) test and ability for continuous spoken conversation without any lip reading; Category 2, Good Performer, with >40 to 80% in auditory only MTP test and some speech understanding combined with lip reading; Category 3, Useful Performance, communication with some additional measures possible (hearing, lip-reading and written notes); Category 4, Non-useful Performance, no or only scarce sound reception. Results: In 22 patients, 146 EABR recordings at various sites of the implant were evaluated: A three-peak-formation was present in 7, a two-peek-formation in 115 (78,8%), and one-peak in 13 EABRs, while 11 remained without any reproducible responses. EABR waveforms showed some variation: Peak P1 developed just out of or after the stimulus artefact while peaks P2 and P3 sometimes showed melting and larger latency differences. P1 appears to correspond to wave III of the acoustically evoked ABR. Overall auditory outcome was useful (Categories 1, 2 or 3) in 95,5% of cases, with Star or Good Performance in about 77% of patients. EABR presence predicted auditory rehabilitation correctly in 95,5%. Conclusion: False positive EABR are rare and a matter of open discussion such as on lead dislocation or secondary brainstem nuclei degeneration. Overall, intra-operative reproducible EABR are highly predictive of adequate brainstem activation and useful hearing rehabilitation with ABI in deaf NF2 patients and appear indispensable for implant positioning. The most reliable peak P1 of EABR may represent immediate activity of cochlear nuclei. The importance of further peaks P2 and P3 and their anatomic correlation still need further evaluation and possibly correlation with more long-term auditory development. The presented ABI hearing classification includes the internationally accepted MTP test but goes beyond this and proves to be a universal tool to elucidate the patient's capacity for speech communication in real life.

Altered Interhemispheric Functional Connectivity Associated With Early Verbal Fluency Decline After Deep Brain Stimulation in Parkinson's Disease.

BackgroundPatients with Parkinson’s disease (PD) experience a decline in verbal fluency (VF) immediately after undergoing deep brain stimulation (DBS) of the subthalamic nucleus (STN). This phenomenon is thought to be related to surgical microlesions.PurposeWe investigated the alterations in interhemispheric functional connectivity after STN-DBS in PD patients. We also evaluated the correlation between these changes and decreased VF scores.MethodOverall, 30 patients with PD were enrolled in the study. Resting-state functional magnetic resonance imaging scans were performed twice, once before and once after DBS, in PD patients. Voxel-mirrored homotopic connectivity (VMHC) was applied in order to evaluate the synchronicity of functional connectivity between the hemispheres.ResultAfter undergoing STN-DBS, PD patients demonstrated reduced VMHC value in the posterior cerebellum lobe, angular gyrus, precuneus/posterior cingulate gyrus (PCC), supramarginal gyrus, superior frontal gyrus (SFG) (medial and dorsolateral) and middle frontal gyrus (MFG). In addition, we observed a significant positive correlation between the altered VMHC value in the SFG and MFG and the change of phonemic VF scores.ConclusionPD patients demonstrated an interhemispheric coordination disorder in the prefrontal cortex, cerebellum, supramarginal gyrus and DMN after undergoing STN-DBS. The positive correlation between reduced VMHC value in the SFG and MFG and the changes of VF scores provides a novel understanding with regard to the decline of VF after DBS.

Reverse Visually Guided Reaching in Patients with Parkinson's Disease.

In addition to motor symptoms such as difficulty in movement initiation and bradykinesia, patients with Parkinson's disease (PD) display nonmotor executive cognitive dysfunction with deficits in inhibitory control. Preoperative psychological assessments are used to screen for impulsivity that may be worsened by deep brain stimulation (DBS) of the subthalamic nucleus (STN). However, it is unclear whether anti-Parkinson's therapy, such as dopamine replacement therapy (DRT) or DBS, which has beneficial effects on motor function, adversely affects inhibitory control or its domains. The detrimental effects of STN-DBS are more apparent when tasks test the inhibition of habitual prepotent responses or involve complex cognitive loads. Our goal was to use a reverse visually guided reaching (RVGR) task, a hand-based version of the antisaccade task, to simultaneously measure motor performance and response inhibition in subjects with PD. We recruited 55 healthy control subjects, 26 PD subjects receiving treatment with DRTs, and 7 PD subjects receiving treatment with STN-DBS and DRTs. In the RVGR task, a cursor moved opposite to the subject's hand movement. This was compared to visually guided reaching (VGR) where the cursor moved in the same direction as the subject's hand movement. Reaction time, mean speed, and direction errors (in RVGR) were assessed. Reaction times were longer, and mean speeds were slower during RVGR compared to VGR in all three groups but worse in untreated subjects with PD. Treatment with DRTs, DBS, or DBS + DRT improved the reaction time and speed on the RVGR task to a greater extent than VGR. Additionally, DBS or DBS + DRT demonstrated an increase in direction errors, which was correlated with decreased reaction time. These results show that the RVGR task quantifies the benefit of STN-DBS on bradykinesia and the concomitant reduction of proactive inhibitory control. The RVGR task has the potential to be used to rapidly screen for preoperative deficits in inhibitory control and to titrate STN-DBS, to maximize the therapeutic benefits on movement, and minimize impaired inhibitory control.

Reliable cognitive change following unilateral deep brain stimulation in essential tremor

Objective: This retrospective analysis assessed regression-based reliable change (RC) of cognition in a sample of essential tremor (ET) patients who underwent unilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM-DBS). Method: Thirty patients (mean age at pre-evaluation = 70.4 ± 6.3 years) underwent neuropsychological evaluation pre- and post-unilateral VIM-DBS placement (mean time between pre and post-evaluation = 13.1 ± 4.0 months). Paired samples t-tests and RC analyses were employed. Results: No significant within-group differences were observed when cognitive scores were compared between evaluations. The vast majority of patients demonstrated stability across pre-and post-surgical evaluations (i.e. 29 out of 30); however, those with high-risk co-morbid medical conditions may be vulnerable to post-surgical cognitive decline as indicated by RC measures. Conclusions: The use of regression-based RC indices to assess individual cognitive changes between pre and post-surgical evaluations control for systematic and measurement errors that can occur over repeated evaluations, and may be able to identify cognitive changes that evade detection in traditional within-group comparisons.

Deep Brain Stimulation for Arm Tremor: A Randomized Trial Comparing Two Targets.

ObjectiveDeep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) effectively suppresses arm tremor. Uncontrolled studies suggest the posterior subthalamic area (PSA) may be superior. We compared the intra‐individual efficacy of VIM‐ versus PSA‐DBS on tremor suppression and arm function.MethodsWe performed a randomized, double‐blind, crossover trial at Oslo University Hospital in patients (18–80 years) with isolated or combined action tremor affecting at least one arm. Four‐contact DBS leads were implanted (bi‐ or unilaterally) with a trajectory to cover the VIM (upper two contacts) and PSA (lower two contacts). Patients were randomized (1:1 ratio) post‐surgery to: Group 1, VIM‐stimulation months 0–3 (period 1), then PSA‐stimulation months 4–6 (period 2); Group 2, PSA‐stimulation first, then VIM‐stimulation. Primary endpoint was the difference in improvement from baseline to the end of the VIM‐ versus PSA‐period in the sum of the dominant arm tremor scores of the Fahn‐Tolosa‐Marin Tremor Rating Scale (FTMTRS), items 5/6 + 10−14.ResultsForty‐five patients were randomized to Group 1 (n = 23) or 2 (n = 22). In the primary endpoint per‐protocol analysis (mixed model, n = 40), mean difference in the sum FTMTRS score improvement for the dominant arm was −2.65 points (95% CI −4.33 to −0.97; p = 0.002). The difference in favour of PSA stimulation was highly significant in period 2, but not period 1.InterpretationOur randomized trial demonstrated that PSA stimulation provided superior tremor suppression compared with VIM stimulation. A period effect reducing tremor for up to three months in both groups was most likely attributed to a post‐surgery stun effect. ANN NEUROL 2022;91:585–601

Vim-Thalamic Deep Brain Stimulation for Cervical Dystonia and Upper-Limb Tremor: Quantification by Markerless-3D Kinematics and Accelerometry.

Background:Deep Brain Stimulation (DBS) for dystonia is usually targeted to the globus pallidus internus (GPi), though stimulation of the ventral-intermediate nucleus of the thalamus (Vim) can be an effective treatment for phasic components of dystonia including tremor. We report on a patient who developed a syndrome of bilateral upper limb postural and action tremor and progressive cervical dystonia with both phasic and tonic components which were responsive to Vim DBS. We characterize and quantify this effect using markerless-3D-kinematics combined with accelerometry.Methods:Stereo videography was used to record our subject in 3D. The DeepBehavior toolbox was applied to obtain timeseries of joint position for kinematic analysis [1]. Accelerometry was performed simultaneously for comparison with prior literature.Results:Bilateral Vim DBS improved both dystonic tremor magnitude and tonic posturing. DBS of the hemisphere contralateral to the direction of dystonic head rotation (left Vim) had greater efficacy. Assessment of tremor magnitude by 3D-kinematics was concordant with accelerometry and was able to quantify tonic dystonic posturing.Discussion:In this case, Vim DBS treated both cervical dystonic tremor and dystonic posturing. Markerless-3D-kinematics should be further studied as a method of quantifying and characterizing tremor and dystonia.

Deep brain stimulation of the anterior nuclei of the thalamus can alleviate seizure severity and induce hippocampal GABAergic neuronal changes in a pilocarpine-induced epileptic mouse brain.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) has been widely used as an effective treatment for refractory temporal lobe epilepsy. Despite its promising clinical outcome, the exact mechanism of how ANT-DBS alleviates seizure severity has not been fully understood, especially at the cellular level. To assess effects of DBS, the present study examined electroencephalography (EEG) signals and locomotor behavior changes and conducted immunohistochemical analyses to examine changes in neuronal activity, number of neurons, and neurogenesis of inhibitory neurons in different hippocampal subregions. ANT-DBS alleviated seizure activity, abnormal locomotor behaviors, reduced theta-band, increased gamma-band EEG power in the interictal state, and increased the number of neurons in the dentate gyrus (DG). The number of parvalbumin- and somatostatin-expressing inhibitory neurons was recovered to the level in DG and CA1 of naïve mice. Notably, BrdU-positive inhibitory neurons were increased. In conclusion, ANT-DBS not only could reduce the number of seizures, but also could induce neuronal changes in the hippocampus, which is a key region involved in chronic epileptogenesis. Importantly, our results suggest that ANT-DBS may lead to hippocampal subregion-specific cellular recovery of GABAergic inhibitory neurons.

Signal-Induced Inhibition of Telomerase Activity in HL60 Cancer Cells by Signal Transduction Using the Biophysically Activated Regulative Molecule 31 (RM31): A Pilot Study.

In this pilot study, we report the use of a novel, patented biophysical technology, which enables intranuclear access and cell nucleus stimulation, via the signal of the biophysically activated regulative molecule 31 (RM31). RM31 is the name of an isolated natural molecule found in the human body and is involved in many cellular mechanisms. We used a specific low electromagnetic field frequency to activate the RM31 molecule, which leads to specific signal transduction, to investigate the effect of telomerase activity in HL60 cancer cells. Our results revealed a dramatic inhibition in telomerase activity, a 99.5% decrease within 72 hours, with avoidance of subsequent reactivation, due to the simultaneous inhibition of human telomerase reverse transcriptase (hTERT).

Dual Orexin Receptor Antagonist Attenuates Increases in IOP, ICP, and Translaminar Pressure Difference After Stimulation of the Hypothalamus in Rats.

PurposeIntraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. Our previous discovery that stimulation of nuclei within the hypothalamus can modulate IOP, intracranial pressure (ICP), and translaminar pressure difference (TLPD) fluctuations led us to investigate this pathway further. Our purpose was to determine the role of orexin neurons, primarily located in the dorsomedial hypothalamus (DMH) and perifornical (PeF) regions of the hypothalamus, in modulating these pressures.MethodsSprague Dawley rats were pretreated systemically with a dual orexin receptor antagonist (DORA-12) at 30 mg/Kg (n = 8), 10 mg/Kg (n = 8), or vehicle control (n = 8). The IOP, ICP, heart rate (HR), and mean arterial pressure (MAP) were recorded prior to and following excitation of the DMH/PeF using microinjection of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline methiodide (BMI).ResultsAdministration of the DORA at 30 mg/Kg significantly attenuated peak IOP by 5.2 ± 3.6 mm Hg (P = 0.007). During the peak response period (8–40 minutes), the area under the curve (AUC) for the 30 mg/Kg DORA cohort was significantly lower than the control cohort during the same period (P = 0.04). IOP responses for peak AUC versus DORA dose, from 0 to 30 mg/Kg, were linear (R2 = 0.18, P = 0.04). The ICP responses during the peak response period (4–16 minutes) versus DORA dose were also linear (R2 = 0.24, P = 0.014). Pretreatment with DORA significantly decreased AUC for the TLPD following stimulation of the DMH/PeF (10 mg/kg, P = 0.045 and 30 mg/kg, P = 0.015).ConclusionsDORAs have the potential to attenuate asynchronous changes in IOP and in ICP and to lessen the extent of TLPDs that may result from central nervous system (CNS) activation.

Switching and Combining Device-Aided Therapies in Advanced Parkinson's Disease: A Double Centre Retrospective Study.

Background: Device-aided therapies (DAT), such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel infusion (LCIG), and deep brain stimulation of the subthalamic nucleus (STN-DBS), have markedly changed the treatment landscape of advanced Parkinson’s disease (aPD). In some patients, it is necessary to switch or combine DATs for various reasons. The aim of this retrospective study was to explore the frequency and reasons for switching between or combining DATs in two movement disorders centres in Slovenia and Israel. Methods: We collected and analysed demographic and clinical data from aPD patients who switched between or combined DATs. Motor and non-motor reasons, adverse events for switching/combining, and their frequency were examined, as was the effect of DAT using the Global Improvement subscale of the Clinical Global Impression Scale, Movement Disorders Society Unified Parkinson’s Disease Rating Scale part III, Mini Mental State Examination, and Parkinson’s Disease Questionnaire 39. Descriptive statistics and non-parametric tests were used to analyse the data. Results: Of 505 aPD patients treated with DATs at both centres between January 2009 and June 2021, we identified in a total of 30 patients (6%) who either switched DAT (n = 24: 7 LCIG-to-STN−DBS, 1 LCIG-to-CSAI, 5 CSAI-to STN−DBS, 8 CSAI-to-LCIG, 1 STN−DBS-to-LCIG, 1 LCIG-to-CSAI-to-STN−DBS, and 1 STN−DBS-to-CSAI-to-LCIG) or combined DATs (n = 6:5 STN−DBS+LCIG and 1 STN−DBS+CSAI-to-STN−DBS+LCIG). In most of these patients, an inadequate control of motor symptoms was the main reason for switching or combining DATs, but non-motor reasons (related to the disease and/or DAT) were also identified. Conclusions: Switching between and combining DATs is uncommon, but in some patients brings substantial clinical improvement and should be considered in those who have either inadequate symptom control on DAT treatment or have developed DAT-related complications.

In vivo electrophysiological study of the targeting of 5-HT3 receptor-expressing cortical interneurons by the multimodal antidepressant, vortioxetine.

The antidepressant vortioxetine has high affinity for the ionotropic 5‐HT3 receptor (5‐HT3R) as well as other targets including the 5‐HT transporter. The procognitive effects of vortioxetine have been linked to altered excitatory:inhibitory balance in cortex. Thus, vortioxetine purportedly inhibits cortical 5‐HT3R‐expressing interneurons (5‐HT3R‐INs) to disinhibit excitatory pyramidal neurons. The current study determined for the first time the effect of vortioxetine on the in vivo firing of putative 5‐HT3R‐INs whilst simultaneously recording pyramidal neuron activity using cortical slow‐wave oscillations as a readout. Extracellular single unit and local field potential recordings were made in superficial layers of the prefrontal cortex of urethane‐anaesthetised rats. 5‐HT3R‐INs were identified by a short‐latency excitation evoked by electrical stimulation of the dorsal raphe nucleus (DRN). Juxtacellular‐labelling found such neurons had the morphological and immunohistochemical properties of 5‐HT3R‐INs: basket cell or bipolar cell morphology, expression of 5‐HT3R‐IN markers and parvalbumin‐immunonegative. Vortioxetine inhibited the short‐latency DRN‐evoked excitation of 5‐HT3R‐INs and simultaneously decreased cortical slow wave oscillations, indicative of pyramidal neuron activation. Likewise, the 5‐HT3R antagonist ondansetron inhibited the short‐latency DRN‐evoked excitation of 5‐HT3R‐INs. However unlike vortioxetine, ondansetron did not decrease cortical slow‐wave oscillations, suggesting a dissociation between this effect and inhibition of 5‐HT3R‐INs. The 5‐HT reuptake inhibitor escitalopram had no consistent effect on any electrophysiological parameter measured. Overall, the current findings suggest that vortioxetine simultaneously inhibits (DRN‐evoked) 5‐HT3R‐INs and excites pyramidal neurons, thereby changing the excitatory:inhibitory balance in cortex. However, under the current experimental conditions, these two effects were dissociable with only the former likely involving a 5‐HT3R‐mediated mechanism.

423 Efficacy of an Image-Based Programing Plan in Predicting the Final Stimulation Configuration and Directionality for Subthalamic Nucleus Deep Brain Stimulation

INTRODUCTION: Subthalamic nucleus stimulation (STN-DBS) is a well stablished therapy for Parkinson’s disease (PD). Initial programing of the DBS electrodes may take up to 2 hours in order to determine the contact(s) with the best and worse therapeutic response and thresholds for side effects. Furthermore novel directional electrodes have additional contacts that increase complexity and time to the selection. New image processing techniques allows reconstruction and visualisation of the DBS electrode and adjacent structures in a tridimensional space as well as modeling of the volume of tissue activation (VTA) which in turns helps to infer which contact(s) could be best for the stimulation. METHODS: Forty-four electrodes were evaluated; directional contacts were initially reviewed as a ring. The images were processed using two different methods 1) The spatial position and distance of each electrode contact was assessed in a normalized space with respect to the STN, motor portion of the STN (mSTN) and the corticospinal tract (CST) using the open source toolbox Lead-DBS; 2) The relation of the electrode contacts with the STN was visualized using the Boston Scientific GuideTM XT clinical software which is based on automatic anatomical segmentation. Both methods were independently used to select the best (positive) and worst (negative) stimulation contacts and then compared with the final stimulation plan. RESULTS: A chi-square analysis demonstrated a significant association between the IBP and the final therapeutic configuration (p&lt;0.05). The test sensitivity was 95%-97.3%, specificity 85.7%-83.87%, positive predictive value 86.3%-87.8%, negative predictive value 94.7%-96.3%, and accuracy 90.2%-91.2% using the research and clinical methods respectively. In a subsequent analysis the selection of the directional contact(s) was investigated in 5 patients (6 electrodes) using current steering. In 89%-78% of the cases the contact(s) selected based on the IBP was part of the final configuration. CONCLUSION: An Imaged-based programing plan could be used as an initial guide to predict the best electrode configuration in order to reduce the programing time, this may translate in better use of hospital resources, improve the patient comfort and may avoid further adjustments in programing.

Combined Subthalamic and Nigral Stimulation Modulates Temporal Gait Coordination and Cortical Gait-Network Activity in Parkinson's Disease.

BackgroundFreezing of gait (FoG) is a disabling burden for Parkinson’s disease (PD) patients with poor response to conventional therapies. Combined deep brain stimulation of the subthalamic nucleus and substantia nigra (STN+SN DBS) moved into focus as a potential therapeutic option to treat the parkinsonian gait disorder and refractory FoG. The mechanisms of action of DBS within the cortical-subcortical-basal ganglia network on gait, particularly at the cortical level, remain unclear.MethodsTwelve patients with idiopathic PD and chronically-implanted DBS electrodes were assessed on their regular dopaminergic medication in a standardized stepping in place paradigm. Patients executed the task with DBS switched off (STIM OFF), conventional STN DBS and combined STN+SN DBS and were compared to healthy matched controls. Simultaneous high-density EEG and kinematic measurements were recorded during resting-state, effective stepping, and freezing episodes.ResultsClinically, STN+SN DBS was superior to conventional STN DBS in improving temporal stepping variability of the more affected leg. During resting-state and effective stepping, the cortical activity of PD patients in STIM OFF was characterized by excessive over-synchronization in the theta (4–8 Hz), alpha (9–13 Hz), and high-beta (21–30 Hz) band compared to healthy controls. Both active DBS settings similarly decreased resting-state alpha power and reduced pathologically enhanced high-beta activity during resting-state and effective stepping compared to STIM OFF. Freezing episodes during STN DBS and STN+SN DBS showed spectrally and spatially distinct cortical activity patterns when compared to effective stepping. During STN DBS, FoG was associated with an increase in cortical alpha and low-beta activity over central cortical areas, while with STN+SN DBS, an increase in high-beta was prominent over more frontal areas.ConclusionsSTN+SN DBS improved temporal aspects of parkinsonian gait impairment compared to conventional STN DBS and differentially affected cortical oscillatory patterns during regular locomotion and freezing suggesting a potential modulatory effect on dysfunctional cortical-subcortical communication in PD.

Utilizing 7-Tesla Subthalamic Nucleus Connectivity in Deep Brain Stimulation for Parkinson Disease

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson disease (PD). Combining 7.0-Tesla (7T) T2- and diffusion-weighted imaging (DWI) sequences allows for selective segmenting of the motor part of the STN and, thus, for possible optimization of DBS. Materials and Methods7T T2 and DWI sequences were obtained, and probabilistic segmentation of motor, associative, and limbic STN segments was performed. Left- and right-sided motor outcome (Movement Disorders Society Unified Parkinson’s Disease Rating Scale) scores were used for evaluating the correspondence between the active electrode contacts in selectively segmented STN and the clinical DBS effect. The Bejjani line was reviewed for crossing of segments. ResultsA total of 50 STNs were segmented in 25 patients and proved highly feasible. Although the highest density of motor connections was situated in the dorsolateral STN for all patients, the exact partitioning of segments differed considerably. For all the active electrode contacts situated within the predominantly motor-connected segment of the STN, the average hemi-body Unified Parkinson’s Disease Rating Scale motor improvement was 80%; outside this segment, it was 52% (p < 0.01). The Bejjani line was situated in the motor segment for 32 STNs. ConclusionThe implementation of 7T T2 and DWI segmentation of the STN in DBS for PD is feasible and offers insight into the location of the motor segment. Segmentation-guided electrode placement is likely to further improve motor response in DBS for PD. However, commercially available DBS software for postprocessing imaging would greatly facilitate widespread implementation.

Personality Related to Quality-of-Life Improvement After Deep Brain Stimulation in Parkinson's Disease (PSYCHO-STIM II).

Deep brain stimulation of the sub-thalamic nucleus (DBS-STN) reduces symptoms in Parkinson's disease (PD) patients with motor fluctuations. However, some patients may not feel ameliorated afterwards, despite an objective motor improvement. It is thus important to find new predictors of patients' quality of life (QoL) amelioration after DBS-STN. We hypothesized that personality dimensions might affect QoL after DBS-STN. To evaluate associations between personality dimensions and QoL improvement one year after DBS-STN. DBS-STN-PD patients (n = 303) having answered the "Temperament and Character Inventory" (TCI) before surgery and the PDQ-39 before and one year after surgery were included, from the cohort study PREDI-STIM. Linear regression models were used to evaluate associations between TCI dimensions and change in PDQ-39 scores after DBS-STN. Novelty Seeking and Cooperativeness scores before surgery were positively associated with PDQ-39 scores improvement after DBS-STN (FDR-adjusted p < 0.01). Moreover, paradoxically unimproved patients with deterioration of their PDQ-39 scores after DBS-STN despite improvement of their MDS-UPDRS-IV scores had lower Cooperativeness scores, while paradoxically improved patients with amelioration of their PDQ-39 scores despite deterioration of their MDS-UPDRS-IV scores had higher Reward Dependence scores. Some presurgical personality dimensions were significantly associated with QoL amelioration and discrepancy between motor state and QoL changes after DBS-STN in PD. Educational programs before DBS-STN should take in account patient personality dimensions to better deal with their expectations.

Current-dependent ocular tilt reaction in deep brain stimulation of the subthalamic nucleus: Evidence for an incerto-interstitial pathway?

The aim was to characterize a combined vestibular, ocular motor and postural syndrome induced by deep brain stimulation (DBS) of the subthalamic nucleus in a patient with Parkinson's disease. In a systematic DBS programming session, eye, head and trunk position in roll and pitch plane were documented as a function of stimulation amplitude and field direction. Repeat ocular coherence tomography was used to estimate ocular torsion. The interstitial nucleus of Cajal (INC), zona incerta (ZI) and ascending vestibular fibre tracts were segmented on magnetic resonance imaging using both individual and normative structural connectomic data. Thresholded symptom-associated volumes of tissue activated (VTA) were calculated based on documented stimulation parameters. Ipsilateral ocular tilt reaction and body lateropulsion as well as contralateral torsional nystagmus were elicited by the right electrode in a current-dependent manner and subsided after DBS deactivation. With increasing currents, binocular tonic upgaze and body retropulsion were observed. Symptoms were consistent with an irritative effect on the INC. Symptom-associated VTA was found to overlap with the dorsal ZI and the ipsilateral vestibulothalamic tract, while lying rather distant to the INC proper. A ZI-to-INC 'incerto-interstitial' tract with contact to the medial-uppermost portion of the VTA could be traced. Unilateral stimulation of INC-related circuitry induces an ipsilateral vestibular, ocular motor and postural roll-plane syndrome, which converts into a pitch-plane syndrome when functional activation expands bilaterally. In this case, tractography points to an incerto-interstitial pathway, a tract previously only characterized in non-human primates. Directional current steering proved useful in managing this rare side effect.

Sleep and Body Temperature

Mammals and birds seek a warm environment prior to sleep, which triggers vasodilatation and body cooling. Ambient temperatures outside the thermoneutral zone suppress sleep, particularly rapid eye movement (REM) sleep. We discuss the neurocircuit interactions associated with thermal and sleep regulation that occur primarily in the hypothalamic areas. An increase in ambient temperature stimulates the median preoptic/medial preoptic area of the hypothalamus, decreases body temperature, and increases non-REM sleep. Similarly, optical stimulation of the ventrolateral preoptic nucleus, which contains galanin (VLPOGAL), results in body cooling and non-REM sleep. A decrease in VLPOGAL disrupts sleep in elderly individuals and may also be associated with reduced decline in core body temperature during sleep. However, stimulation of neurons that synthesize melanin-concentrating hormone in the lateral hypothalamus decreases body temperature and induces REM sleep. We also discussed the acute effect of light on sleep induction and decreased body temperature, implicated with gamma-aminobutyric acid-ergic neurons in the preoptic area. Further investigation is needed to determine the mechanisms that induce physiological responses in diurnal and nocturnal species. These studies will contribute to a better understanding of the association between sleep and thermoregulation.

Subthalamic deep brain stimulation versus best medical treatment: a 12-year follow-up

PurposeElectrical stimulation of the sub-thalamic nucleus (STN-DBS) is well established to alleviate motor fluctuations in advanced Parkinson’s disease but little is known about its very long-term efficacy.MethodsWe followed over 12 years 15 parkinsonian patients having undergone STN-DBS and compared them to a matched group of 14 patients with best medical drug therapy. All had been considered as good candidates for surgery. They were allocated to each group depending on their own decision.ResultsAfter 12 years, mortality rates were similar in both groups. In the DBS group, best “on” UPDRS III scores (on medications, on stimulation) remained significantly better and dyskinesia shorter and weaker than in the drug-treated group (on medication only). Yet, looking at independent life and quality of life (QoL) evaluated with PDQ39, no significant difference could be observed between groups at the end of follow-up, probably due to development of dopa- and stimulation-resistant motor and non-motor symptoms like falls, freezing, dementia, apathy and depression, the latter two more frequent in the DBS group.ConclusionDrug- and DBS-resistant symptoms and signs occur more often after long disease evolution and in elder patients. It might be why differences in QoL between both groups no longer existed after twelve years as, compared to other studies, our patients were older at inclusion.

People With Parkinson's Disease and Freezing of Gait Show Abnormal Low Frequency Activity of Antagonistic Leg Muscles.

ObjectiveFreezing of gait is detrimental to patients with idiopathic Parkinson’s disease (PD). Its pathophysiology represents a multilevel failure of motor processing in the cortical, subcortical, and brainstem circuits, ultimately resulting in ineffective motor output of the spinal pattern generator. Electrophysiological studies pointed to abnormalities of oscillatory activity in freezers that covered a broad frequency range including the theta, alpha, and beta bands. We explored muscular frequency domain activity with respect to freezing, and used deep brain stimulation to modulate these rhythms thereby evaluating the supraspinal contributions to spinal motor neuron activity.MethodsWe analyzed 9 PD freezers and 16 healthy controls (HC). We studied the patients after overnight withdrawal of dopaminergic medication with stimulation off, stimulation of the subthalamic nucleus (STN-DBSonly) or the substantia nigra pars reticulate (SNr-DBSonly), respectively. Patients performed a walking paradigm passing a narrow obstacle. We analyzed the frequency-domain spectra of the tibialis anterior (TA) and gastrocnemius (GA) muscles in ‘regular gait’ and during the ‘freezing’ episodes.ResultsIn stimulation off, PD freezers showed increased muscle activity of the alpha and low-beta band compared to HC in both TA and GA. This activity increase was present during straight walking and during the freezes to similar extent. STN- but not SNr-DBS decreased this activity and paralleled the clinical improvement of freezing.ConclusionWe found increased muscle activation of the alpha and lower beta band in PD freezers compared to HC, and this was attenuated with STN-DBS. Future studies may use combined recordings of local field potentials, electroencephalography (EEG), and electromyography (EMG) to interrogate the supraspinal circuit mechanisms of the pathological activation pattern of the spinal pattern generator.