Stimulation Off Research Articles

Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes.

It has been proposed that estrogen regulates the mechanosensitivity of osteocytes; however, the effects of estrogen deficiency that arises during postmenopausal osteoporosis on mechanical stimulation-induced calcium signaling in osteocytes remain elusive. Here, we pretreated MLO-Y4 osteocytes with 10 nM E2 for 2, 3 and 5 d, then simulated postmenopausal conditions either by estrogen withdrawal (EW) from culture medium, or by inhibiting the estrogen receptor by using fulvestrant and estrogen (FE; ICI 182,780) in vitro We investigated [Ca2+]i oscillations and mechanobiologic responses of osteocytes (EW and FE) that were exposed to oscillatory fluid flow (OFF; 1 Pa, 0.5 Hz). We demonstrated that estrogen treatment enhanced OFF-induced [Ca2+]i oscillations and that this effect was abrogated both by FE and EW. Moreover, osteocytes in both estrogen-depleted groups (EW and FE) had reduced levels of NO and prostaglandin E2 release, down-regulated dentin matrix protein-1, sclerostin, osteopontin, osteocalcin, and alkaline phosphatase mRNA expression, and reduced F-actin fiber formation after OFF stimulation compared with estrogen-treated cells. We propose a link between estrogen deficiency and alterations in [Ca2+]i-mediated mechanosensitivity of osteocytes, which ultimately alter osteocyte function and differentiation.-Deepak, V., Kayastha, P., McNamara, L. M. Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes.

Focused stimulation of dorsal subthalamic nucleus improves reactive inhibitory control of action impulses

Frontal-basal ganglia circuitry dysfunction caused by Parkinson's disease impairs important executive cognitive processes, such as the ability to inhibit impulsive action tendencies. Subthalamic Nucleus Deep Brain Stimulation in Parkinson's disease improves the reactive inhibition of impulsive actions that interfere with goal-directed behavior. An unresolved question is whether this effect depends on stimulation of a particular Subthalamic Nucleus subregion. The current study aimed to 1) replicate previous findings and additionally investigate the effect of chronic versus acute Subthalamic Nucleus stimulation on inhibitory control in Parkinson's disease patients off dopaminergic medication 2) test whether stimulating Subthalamic Nucleus subregions differentially modulate proactive response control and the proficiency of reactive inhibitory control. In the first experiment, twelve Parkinson's disease patients completed three sessions of the Simon task, Off Deep brain stimulation and medication, on acute Deep Brain Stimulation and on chronic Deep Brain Stimulation. Experiment 2 consisted of 11 Parkinson's disease patients with Subthalamic Nucleus Deep Brain Stimulation (off medication) who completed two testing sessions involving of a Simon task either with stimulation of the dorsal or the ventral contact in the Subthalamic Nucleus. Our findings show that Deep Brain Stimulation improves reactive inhibitory control, regardless of medication and regardless of whether it concerns chronic or acute Subthalamic Nucleus stimulation. More importantly, selective stimulation of dorsal and ventral subregions of the Subthalamic Nucleus indicates that especially the dorsal Subthalamic Nucleus circuitries are crucial for modulating the reactive inhibitory control of motor actions.

Sensory trigeminal ULF-TENS stimulation reduces HRV response to experimentally induced arithmetic stress: A randomized clinical trial

Ultra Low Frequency Transcutaneous Electric Nervous Stimulation (ULF-TENS) is extensively used for pain relief and for the diagnosis and treatment of temporomandibular disorders (TMD). In addition to its local effects, ULF-TENS acts on the autonomic nervous system (ANS), with particular reference to the periaqueductal gray (PAG), promoting the release of endogenous opioids and modulating descending pain systems. It has been suggested that the PAG participates in the coupling between the emotional stimulus and the appropriate behavioral autonomic response. This function is successfully investigated by HRV. Therefore, our goal is to investigate the effects of trigeminal ULF-TENS stimulation on autonomic behavior in terms of HRV and respiratory parameters during an experimentally-induced arithmetic stress test in healthy subjects.Thirty healthy women between 25 and 35years of age were enrolled and randomly assigned to either the control (TENS stimulation off) or test group (TENS stimulation on). Heart (HR, LF, HF, LF/HF ratio, DET, RMSSD, PNN50, RR) and respiratory (BR) rate were evaluated under basal, T1 (TENS off/on), and stress (mathematical task) conditions. Results showed that HRV parameters and BR significantly changed during the arithmetic stress paradigm (p<0.01). Independently of stress conditions, TENS and control group could be discriminated only by non-linear HRV data, namely RR and DET (p=0.038 and p=0.027, respectively). During the arithmetic task, LF/HF ratio was the most sensitive parameter to discriminate between groups (p=0.019).Our data suggest that trigeminal sensory ULF-TENS reduces the autonomic response in terms of HRV and BR during acute mental stress in healthy subjects. Future directions of our work aim at applying the HRV and BR analysis, with and without TENS stimulation, to individuals with dysfunctional ANS among those with TMD.

The elicitation of steady-state visual evoked potentials during sleep.

This study confirmed the hypothesis that it is possible to elicit SSVEPs through closed eyelids during NREM sleep. To test this hypothesis, SSVEP amplitudes were measured in eight subjects across two conditions of stimulation (stimulation on and stimulation off) and three brain states (waking, light sleep, and deep sleep). Results showed a significant interaction between stimulation and brain state. In particular, EEG activity at the frequency of stimulation was higher during both light sleep and deep sleep in the stimulation on condition than in the stimulation off condition. The fact that it is possible to elicit SSVEPs during sleep may provide a new way to study how SSVEPs are generated in the brain-one that might help resolve open questions such as identifying the SSVEP activation sequence or deciding if SSVEPs derive from evoked or oscillatory neural processes.

Occipital Nerve Stimulation for Refractory Chronic Migraine: Results of a Long-Term Prospective Study

Refractory chronic migraine affects approximately 4% of the population worldwide and results in severe pain, lifestyle limitations, and decreased quality of life. Occipital nerve stimulation (ONS) refers to the electric stimulation of the distal branches of greater and lesser occipital nerves; the surgical technique has previously been described and has demonstrated efficacy in the treatment of a wide variety of headache disorders. The aim of this study is to evaluate the long-term efficacy and tolerability of ONS for medically intractable chronic migraine. Prospective, long-term, open-label, uncontrolled observational study. Single public university hospital. Patients who met the International Headache Society criteria for chronic migraine, all of them having been previously treated with other therapeutic alternatives, and who met all inclusion and exclusion criteria for neurostimulation, received the implantation of an ONS system after a positive psychological evaluation and a positive response to a preliminary occipital nerve blockage. The implantation was performed in 2 phases: a 10 day trial with implanted occipital leads connected to an external stimulator and, if more than 50% pain relief was obtained, permanent pulse generator implantation and connection to the previously implanted leads. After the surgery, the patients were thoroughly evaluated annually using different scales: pain Visual Analogue Scale (VAS), number of migraine attacks per month, sleep quality, functionality in social and labor activities, reduction in pain medication, patient satisfaction, tolerability, and reasons for termination. The average follow-up time was 9.4 ± 6.1 years, and 31 patients completed a 7-year follow-up period. Thirty-seven patients were enrolled and classified according to the location and quality of their pain, accompanying symptoms, work status, and psychological effects. Substantial pain reduction was obtained in most patients, and the VAS decreased by 4.9 ± 2.0 points. These results remained stable over the follow-up period. Five of the 35 permanently implanted patients with migraine attacks at baseline were free from these attacks at their last visits, whereas the pain severity decreased 3.8 ± 2.5 (according to the VAS) in the remaining patients. Seven of the 35 permanent implanted devices were definitively removed: 2 devices because of treatment inefficacy, and 5 devices because the patients were asymptomatic and considered to be cured from their pain, even with the stimulation off. Systemic side effects were not observed. Limitations of the current study include its uncontrolled and open-label design. Additionally, not all patients completed the 7-year follow-up period. We consider that the trigemino-cervical autonomous and cervical connection may explain why ONS might relieve chronic migraine pain, but this is just a theoretical explanation which should be demonstrated in future studies. The results achieved in this study suggest that ONS may provide long-term benefits for patients with medically intractable chronic migraine. These outcomes are slightly better than previous reports and were maintained over the 7-year follow-up. We believe that an accurate selection of patients, realization of diagnostic occipital nerve blocks, psychological evaluations, rigorous surgical technique, and appropriate parameter programming helped us achieve these outcomes. Key words: Refractory chronic migraine, headache, occipital nerve stimulatino, peripheral nerve stimulation, occipital nerve block.

Feasibility of magnetoencephalographic source imaging in patients with thalamic deep brain stimulation for epilepsy

SummarySource localization of interictal spikes in patients with medically refractory epilepsy is the most common clinical application of magnetoencephalography (MEG). In recent decades, many patients with intractable epilepsy have been treated with various forms of neurostimulation, including thalamic deep brain stimulation (DBS). Patients with suboptimal seizure control after DBS might in some cases benefit from further investigations for resective epilepsy surgery, including MEG source imaging (MSI). We sought to determine the feasibility and accuracy of MSI in the setting of active thalamic DBS. Simultaneous EEG/MEG was obtained in a patient using an Elekta 306‐channel MEG system, with high‐frequency (100 Hz) DBS of the thalamic anterior nuclei cycling between on and off states. Magnetic artifacts associated with the DBS apparatus were successfully suppressed using the spatiotemporal signal space separation (tSSS) method. Electrical stimulation artifact was removed by standard digital low‐pass filtering. Dipole source modeling results for spike foci in frontal and posterior temporal regions were comparable between stimulation on and stimulation off states, and the source solutions corresponded well to the localization of spikes documented by intracranial EEG. MSI is thus feasible and source solutions can be accurate when performed in patients with active thalamic DBS for epilepsy.

Acute Slow Wave Responses to High-Frequency Gastric Electrical Stimulation in Patients With Gastroparesis Defined by High-Resolution Mapping

High-frequency gastric electrical stimulation (GES) has emerged as a therapy for gastroparesis, but the mechanism(s) of action remain unclear. There is a need to refine stimulation protocols for clinical benefit, but a lack of accurate techniques for assessing mechanisms in clinical trials, such as slow wave modulation, has hindered progress. We thereby aimed to assess acute slow wave responses to GES in gastroparesis patients using high-resolution (HR) (multi-electrode) mapping, across a range of stimulation doses achievable by the Enterra stimulation device (Medtronic Inc., MN, USA). Patients with medically refractory gastroparesis (n = 8) undergoing device implantation underwent intraoperative HR mapping (256 electrodes). Baseline recordings were followed by four protocols of increasing stimulation intensity, with washout periods. Slow wave patterns, frequency, velocity, amplitude, and dysrhythmia rates were quantified by investigators blinded to stimulation settings. There was no difference in slow wave pattern, frequency, velocity, or amplitude between baseline, washout, and stimulation periods (all p > 0.5). Dysrhythmias included ectopic pacemakers, conduction blocks, retrograde propagation, and colliding wavefronts, and dysrhythmia rates were unchanged with stimulation off vs. on (31% vs. 36% duration dysrhythmic; p > 0.5). Symptom scores and gastric emptying were improved at 5.8 month follow-up (p < 0.05). High-frequency GES protocols achievable from a current commercial device did not acutely modulate slow wave activity or dysrhythmias. This study advances clinical methods for identifying and assessing therapeutic GES parameters, and can be applied in future studies on higher-energy protocols and devices.

Stimulation of subgenual cingulate area decreases limbic top-down effect on ventral visual stream: A DBS-EEG pilot study

Deep brain stimulation (DBS) of the subgenual cingulate gyrus (area CG25) is beneficial in treatment resistant depression. Though the mechanisms of action of Cg25 DBS remain largely unknown, it is commonly believed that Cg25 DBS modulates limbic activity of large networks to achieve thymic regulation of patients. To investigate how emotional attention is influenced by Cg25 DBS, we assessed behavioral and electroencephalographic (EEG) responses to an emotional Stroop task in 5 patients during ON and OFF stimulation conditions. Using EEG source localization, we found that the main effect of DBS was a reduction of neuronal responses in limbic regions (temporal pole, medial prefrontal and posterior cingulate cortices) and in ventral visual areas involved in face processing. In the dynamic causal modeling (DCM) approach, the changes of the evoked response amplitudes are assumed to be due to changes of long range connectivity induced by Cg25 DBS. Here, using a simplified neural mass model that did not take explicitly into account the cytoarchitecture of the considered brain regions, we showed that the remote action of Cg25 DBS could be explained by a reduced top-down effective connectivity of the amygdalo-temporo-polar complex. Overall, our results thus indicate that Cg25 DBS during the emotional Stroop task causes a decrease of top-down limbic influence on the ventral visual stream itself, rather than a modulation of prefrontal cognitive processes only. Tuning down limbic excitability in relation to sensory processing might be one of the biological mechanisms through which Cg25 DBS produces positive clinical outcome in the treatment of resistant depression.

An exploratory study of gait and functional outcomes after neuroprosthesis use in children with hemiplegic cerebral palsy

Purpose: To evaluate the immediate orthotic, total and therapeutic effects of functional electrical stimulation (FES) neuroprosthesis use on clinic based measures of gait and function in children with hemiplegic cerebral palsy.Methods: Eleven children (mean 9 years 11 months) participated in an FES neuroprosthesis (Ness L300) intervention (4 week accommodation period followed by 12 weeks of daily use) and were assessed at baseline and post in stimulation off and stimulation on conditions. Measures included clinic based outcomes of gait and function.Results: No significant immediate orthotic effects were observed. Significant (p < 0.01) total effects were noted for dorsiflexion at initial contact, Six-Minute Walk Test (6MWT), and walking speed. A significant therapeutic effect was found for steps off path on the Standardized Walking Obstacle Course (SWOC).Conclusions: Results support previous findings of neuroprosthesis total effects on gait and provide some evidence for effects on function. Therapeutic effects remain unclear.Implications for RehabilitationIn this study, children with hemiplegic CP did not demonstrate immediate improvements in gait or function at their first clinic visit using the FES neuroprosthesis device suggesting one visit using the device is not sufficient to determine potential benefits.Over time with daily use of the FES neuroprosthesis, ankle dorsiflexion in swing and at initial contact, walking speed and endurance increased with the device worn.Overtime, no carryover effects in ankle dorsiflexion in swing and at initial contact were noted at the end of the intervention period with the device off.Clinicians should consider purchasing units to loan or rent to individuals to trial a device at home before determining long-term potential for benefit.

EP 14. Clinical experiences with long term thalamic deep brain stimulation in severe Tourette Syndrome

Introduction Thalamic deep brain stimulation is effective in reducing tics in patients with severe Tourette syndrome at the short-term. Here, we report on the long-term outcome. Methods Seven patients with refractory Tourette syndrome were referred to the Maastricht University Medical Centre and underwent bilateral thalamic deep brain stimulation between 2001 and 2008. The target was the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus cross point of the thalamus. During the visits to the outpatient clinic, effects on tics, side-effects and stimulations parameters were evaluated. The follow-up duration varied between 12 to 78 months. Results Patient 1 showed an improvement on tics of 81.6% after 60 months, but due to higher voltage stimulation after some years needed to suppress the tics, side-effects became more severe and the target was changed to the anterior part of the internal pallidum. Patient 2 showed a tic improvement of 50% after 36 months, but due to increasing side-effects, he switched the stimulator permanently off. In patient 3 the stimulator is still active and showed satisfying results with an improvement on tics of 88.9% after 78 months. Patient 4 experienced a tic improvement of 34% after 16 months. However, side-effects became more severe, and when the whole system had to be removed due to a persisting hardware infection after six years, the target was changed to the anterior part of the internal pallidum. Patient 5 showed a minor tic improvement of 27.5% after 12 months. He was unsatisfied and went to abroad for stimulation of the external globus pallidus. Patient 6 developed cerebral atrophy due to a neurodegenerative disease and experienced several non-stimulation related side-effects. His tic improvement was 34% on the YGTSS after 26 months and he decided to turn the stimulator off. The positive effect on tics in patient 7 decreased over time until an improvement of only 9% at 60 months of follow-up. The target was changed to the anterior part of the internal pallidum. Conclusion Thalamic deep brain stimulation in patients with severe Tourette syndrome is effective in reducing tics, at least at the short-term. At the long-term only in one patient the stimulator is still active, in three patients the target was changed to the anterior part of the internal pallidum due to side-effects and three were unsatisfied and turned off their stimulator. There seems to be an increasing disbalance of effects versus side effects leading to either switching off the stimulator or re-surgery changing the target. These clinical cases reflect the strong heterogeneity of the disease, with serious comorbity, interfering with effects and side-effects of deep brain stimulation.

EP 65. DBS-induced alpha desynchronization in the subthalamic nucleus of PD patients

Question Deep brain stimulation of the subthalamic nucleus (STN DBS) has developed into a standard therapy for treatment refractory stages of Parkinson’s disease (PD). Oscillatory components play an important role in the functioning of the brain through the control of neuronal firing ( Engel and Fries, 2010 ). The power of the beta-band (12–30 Hz) in the STN is an informative biomarker for PD. It is reduced under L-Dopa medication and DBS ( [Kuhn et al., 2008] , [Bronte-Stewart et al., 2009] ). However, the impact of DBS onto other oscillatory components and their relevance as PD biomarkers is less explored ( [Rosa et al., 2014] , [Beudel and Brown, 2016] ). In the present contribution, we investigate the effect of DBS upon the power of the alpha-band (8–12 Hz). Methods For three PD patients (S1–S3), intraoperative microelectrode recordings were acquired as part of the implantation procedure for DBS. For one hemisphere three MER electrodes were lowered into the target region simultaneously (anterior, central, lateral) over a Ben’s gun approach (FHC, USA). Stimulating on a singular macro-tip of the telescopic FHC electrode (FHC, USA) with increasing currents allowed to record signals with 5 kHz sampling rate from two other MER positions. Overall, seven recording constellations were measured. Starting with stimulation off, stimulation intensity was ramped up in steps of 0.5 mA and 1 mA. Each intensity was delivered for at least 20 s at a rate of 130 Hz. Five out of seven recording constellations showed a clear alpha baseline activity prior to stimulation onset. These were used for an offline bandpower analysis. The analyzed frequency band was centered onto the individual alpha frequency of each patient and had a width of 3 Hz. The log-bandpower intensity was extracted from 10 non-overlapping consecutive time windows of one second duration each, overall covering the interval of [0,10]s relative to the onset of a novel stimulation intensity. To represent baseline activity, ten values were extracted from the interval [−15, −5]s relative to the stimulus onset. Results For 2 out of 3 patients and 2 out of 5 recording constellations (see plots for S2 left and S3 right in Fig. 1 ), DBS onset caused a significant reduction of the alpha power relative to the baseline activity. Increasing the stimulation current (and overall stimulation time) beyond 2 mA for S2 and beyond 5 mA for S3 lead to a rebound effect. The resulting higher alpha power of higher stimulation intensities, however, still remained significantly below the baseline level. For recordings of S1 [left] and S3 [left], an alpha reduction was observed after stimulation onset as well, but it did not reach significance over all levels of stimulation intensity. Conclusions Alpha band power of the STN may represent a biomarker for PD, which is sensitive to DBS and deserves further investigation along with the classical biomarkers beta and gamma. The rebound effect observed in this pilot study, however, suggests to test nonlinear analysis methods to assess the alpha activity.

Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis

Electrical neuromodulation by spinal cord stimulation (SCS) is a well-established method for treatment of neuropathic pain. However, the mechanism behind the pain relieving effect in patients remains largely unknown. In this study, we target the human cerebrospinal fluid (CSF) proteome, a little investigated aspect of SCS mechanism of action. Two different proteomic mass spectrometry protocols were used to analyze the CSF of 14 SCS responsive neuropathic pain patients. Each patient acted as his or her own control and protein content was compared when the stimulator was turned off for 48 hours, and after the stimulator had been used as normal for three weeks. Eighty-six proteins were statistically significantly altered in the CSF of neuropathic pain patients using SCS, when comparing the stimulator off condition to the stimulator on condition. The top 12 of the altered proteins are involved in neuroprotection (clusterin, gelsolin, mimecan, angiotensinogen, secretogranin-1, amyloid beta A4 protein), synaptic plasticity/learning/memory (gelsolin, apolipoprotein C1, apolipoprotein E, contactin-1, neural cell adhesion molecule L1-like protein), nociceptive signaling (neurosecretory protein VGF), and immune regulation (dickkopf-related protein 3). Previously unknown effects of SCS on levels of proteins involved in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity are demonstrated. These findings, in the CSF of neuropathic pain patients, expand the picture of SCS effects on the neurochemical environment of the human spinal cord. An improved understanding of SCS mechanism may lead to new tracks of investigation and improved treatment strategies for neuropathic pain.

Subthalamic Stimulation Reduces Vowel Space at the Initiation of Sustained Production: Implications for Articulatory Motor Control in Parkinson's Disease.

Background: Stimulation of the subthalamic nuclei (STN) is an effective treatment for Parkinson’s disease, but complaints of speech difficulties after surgery have been difficult to quantify. Speech measures do not convincingly account for such reports.Objective: This study examined STN stimulation effects on vowel production, in order to probe whether DBS affects articulatory posturing. The objective was to compare positioning during the initiation phase with the steady prolongation phase by measuring vowel spaces for three “corner” vowels at these two time frames.Methods: Vowel space was measured over the initial 0.25 sec of sustained productions of high front (/i/), high back (/u/) and low vowels (/a/), and again during a 2 sec segment at the midpoint. Eight right-handed male subjects with bilateral STN stimulation and seven age-matched male controls were studied based on their participation in a larger study that included functional imaging. Mean values: age = 57±4.6 yrs; PD duration = 12.3±2.7 yrs; duration of DBS = 25.6±21.2 mos, and UPDRS III speech score = 1.6±0.7. STN subjects were studied off medication at their therapeutic DBS settings and again with their stimulators off, counter-balanced order.Results: Vowel space was larger in the initiation phase compared to the midpoint for both the control and the STN subjects off stimulation. With stimulation on, however, the initial vowel space was significantly reduced to the area measured at the mid-point. For the three vowels, the acoustics were differentially affected, in accordance with expected effects of front versus back position in the vocal tract.Conclusions: STN stimulation appears to constrain initial articulatory gestures for vowel production, raising the possibility that articulatory positions normally used in speech are similarly constrained.

Centromedian-Parafascicular Complex Deep Brain Stimulation for Tourette Syndrome: A Retrospective Study

Deep brain stimulation (DBS) of the thalamic centromedian/parafascicular (CM-Pf) complex has been reported as a promising treatment for patients with severe, treatment-resistant Tourette syndrome (TS). In this study, safety and clinical outcomes of bilateral thalamic CM-Pf DBS were reviewed in a series of 12 consecutive patients with medically refractory TS, 11 of whom met the criteria of postsurgical follow-up at our institution for at least 2 months. Five patients were followed for a year or longer. Consistent with many patients with TS, all patients had psychiatric comorbidities. Tic severity and frequency were measured by using the Yale Global Tic Severity Scale (YGTSS) over time (average, 26 months) in 10 subjects. One patient was tested at 2-week follow-up only and thus was excluded from group YGTSS analysis. Final YGTSS scores differed significantly from the preoperative baseline score. The average (n=10) improvement relative to baseline in the total score was 54% (95% CI, 37-70); average improvement relative to baseline in the YGTSS Motor tic, Phonic tic, and Impairment subtests was 46% (95% CI, 34-64), 52% (95% CI, 34-72), and 59% (95% CI, 39-78), respectively. There were no intraoperative complications. After surgery, 1 subject underwent wound revision because of a scalp erosion and wound infection; the implanted DBS system was successfully salvaged with surgical revision and combined antibiotic therapy. Stimulation-induced adverse effects did not prevent the use of the DBS system, although 1 subject is undergoing a trial period with the stimulator off. This surgical series adds to the literature on CM-Pf DBS and supports its use as an effective and safe therapeutic option for severe refractory TS.

Distinct effects of dopamine vs STN stimulation therapies in associative learning and retention in Parkinson disease

Evidence has been provided in Parkinson’s disease patients of cognitive impairments including visual memory and learning which can be partially compensated by dopamine medication or subthalamic nucleus stimulation. The effects of these two therapies can differ according to the learning processes involving the dorsal vs ventral part of the striatum. Here we aimed to investigate and compare the outcomes of dopamine vs stimulation treatment in Parkinson patient’s ability to acquire and maintain over successive days their performance in visual working memory. Parkinson patients performed conditional associative learning embedded in visual (spatial and non spatial) working memory tasks over two consecutive days either ON or OFF dopaminergic drugs or STN stimulation depending on the group of patients studied. While Parkinson patients were more accurate and faster in memory tasks ON vs OFF stimulation independent of the day of testing, performance in medicated patients differed depending on the medication status during the initial task acquisition. Patients who learnt the task ON medication the first day were able to maintain or even improve their memory performance both OFF and ON medication on the second day after consolidation. These effects were observed only in patients with dopamine replacement with or without motor fluctuations. This enhancement in memory performance after having learnt under dopamine medication and not under STN stimulation was mostly significant in visuo-spatial working memory tasks suggesting that dopamine replacement in the depleted dorsal striatum is essential for retention and consolidation of learnt skill.

Rapid assessment of gait and speech after subthalamic deep brain stimulation.

Background:Describe a rapid assessment for patients with idiopathic Parkinson's disease (PD) and deep brain stimulation of the subthalamic nucleus reporting worsening speech and/or gait problems.Methods:We retrospectively reviewed 29 patients that had improvement in gait and/or speech within 30 min after turning stimulation off. Clinical data analyzed include unified PD rating scale motor scores and stimulation parameters before and after adjusting stimulation. All patients received electrode efficacy and side effect threshold testing. Stimulation parameters were adjusted to maximize efficacy, avoid side effects, and maximize battery longevity.Results:Turning stimulation off revealed reversible speech and/or gait stimulation side effects within 30 min. Focusing on six factors revealed stimulation modifications that improved motor symptoms, eliminated stimulation side effects, and reduced battery drain. Primary stimulation parameters modified were cathode selection and pulse width reduction.Conclusions:Stimulation-induced side effects impacting gait and speech can be identified within 30 min. A systematic evaluation can distinguish disease progression from reversible stimulation side effects and improve motor outcomes over the long term.

Effect of Spinal Cord Stimulation on Gait in a Patient with Thalamic Pain.

Thalamic pain is a central neuropathic pain disorder which occurs after stroke. Its severe chronic pain is often intractable to pharmacotherapies and affects the patients' activities of daily living (ADL) and quality of life (QOL). Recently, spinal cord stimulation (SCS) has been reported to be effective in relieving the pain of thalamic pain; however, the effect of SCS on gait performance in patients is unknown. Therefore, we evaluated the gait performance before and after SCS in a case with thalamic pain. A 73-year-old male with thalamic pain participated in this study. We evaluated the gait of the patient two times: before SCS insertion and after 6 days of SCS. At the second evaluation, we measured the gait in three conditions: stimulation off, comfortable stimulation, and strong stimulation. SCS succeeded in improving the pain from 7 to 2 on an 11-point numerical rating scale. Step frequency and the velocity of gait tended to increase between pre- and poststimulation periods. There were no apparent differences in gait among the three stimulation conditions (off, comfortable, and strong) at the poststimulation period. SCS may be effective on gait in patients with thalamic pain.

Anatomical and functional relationships between deep cerebellar nuclei and cerebellar cortical Crus II in vivo in mice

We previously reported that an air-puff stimulation on the ipsilateral whisker pad evoked responses in molecular layer (ML) and Purkinje cell (PC) layer in cerebellar cortex folium Crus II. We used anterograde tracing and electrophysiological methods to investigate the anatomical and functional relationships between the trigeminal tactile response area in the cerebellar cortex Crus II and deep cerebellar nuclei (DCN) in living mice. We found that the axons of tactile activated PCs projected in anterior part (IntA) and posterior part (IntP), and dorsolateral hump (IntDL) of ipsilateral interposed cerebellar nucleus (ICN). In ICN, the tactile stimulus evoked-field potential expressed a sequence of two negative components N1 and N2, while extracellular recordings from ICN neurons revealed that an increase in spike frequency in response to tactile stimulus. When the duration of facial air-puff stimulus were ≥30ms, stimulation off response (Roff) were observed in the ICN, but an increase in the duration of facial air-puff stimulation did not significantly affect the amplitude of Ron (N1 and N2) and Roff. The latency and time to peak of N1 in ICN were significantly shorter than that of N1 in the ML, but the latency and time to peak of N2 in ICN were significantly later than that of P1 in the ML. The present results suggest that the facial sensory information, at least in part, is transferred to ICN by PC axons from Crus II, which evokes excitation in ICN neurons.

Effect of Deep Brain Stimulation on Sympathetic outflow in humans

Electric deep brain stimulation (DBS) in midbrain nuclei in humans alters cardiovascularparameters, presumably by modulating autonomic and baroreflex function. Baroreflex modulation of sympathetic outflow is crucial for cardiovascular regulation and is hypothesized to occur at two distinct brain locations. This study aimed to evaluate sympathetic outflow in humans with DBS electrodes during ON and OFF stimulation of specific midbrain nuclei known to regulate cardiovascular function. Muscle sympathetic nerve activity (MSNA) was recorded during DBS ON and OFF in patients with chronic neuropathic pain (n=7) and Parkinson’s disease (n=10). Arterial blood pressure (ABP), heart rate and respiration were monitored during the recording session and spontaneous vasomotor and cardiac baroreflex sensitivity (BRS) were assessed. Head-up tilt testing was performed separately in the Parkinson’s patients post-operatively. Stimulation of the dorsal most part of the subthalamic nucleus (STN) and ventrolateral periaqueducta...

Effects of vagus nerve stimulation on pupillary function

BackgroundChronic vagus nerve stimulation (VNS) is a recognized treatment for refractory epilepsy and depression. The vagus nerve projects to several brainstem autonomic structures. As pupillary measures are an easy and non-invasive method to evaluate autonomic functioning, we used resting diameter and light reflex measures to investigate the influence of VNS on the human central autonomic nervous system. MethodWe studied 21 patients (7 with major depression, 14 with epilepsy) treated with chronic VNS (30s ON, 5min OFF stimulation trains). Resting pupil size and light reflex measures were compared in consecutive intervals with (ON) and without stimulation (OFF). ResultsCompared to the OFF condition, the ON condition was associated with a significant increase in resting pupil diameter, but did not affect light reflex measures. There was no group difference between the two populations of patients (depression and epilepsy) on any of the pupil measures. ConclusionVNS at clinically significant levels increases resting pupil diameter.