Deep Brain Stimulation ON Conditions Research Articles

Mixed anxiety-depressive disorder in Parkinson's disease associated with worse resting state functional response to deep brain stimulation of subthalamic nucleus

BackgroundParkinson's disease (PD), even though generally perceived as a dominantly motor disorder, is associated with a wide range of non-motor symptoms, including mixed anxiety-depressive disorder (MADD). ObjectivesThe aim of the presented study was to determine whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) brings the functional characteristics of non-motor networks closer to the condition detected in healthy population and whether pre-DBS presence of MADD in PD patients was associated with different reaction to this therapeutic modality. MethodsResting-state fMRI signature elicited by STN DBS activation and deactivation in 81 PD patients was compared against healthy controls, with the focus on measures of efficiency of information processing and localised subnetwork differences. ResultsWhile all the MRI metrics showed statistically significant differences between PD patients in DBS OFF condition and healthy controls, none were detected in such a comparison against DBS ON condition. Furthermore, in the post-DBS evaluation, PD patients with MADD in the pre-DBS stage showed no differences in depression scales compared to pre-DBS psychiatrically intact PD patients, but still exhibited lower DBS-related connectivity in a subnetwork encompassing anterior and posterior cingulate, dorsolateral prefrontal and medial temporal cortices. ConclusionsSTN DBS improved all the metrics of interest towards the healthy state, normalising the resting-state MRI signature of PD. Furthermore, pre-DBS presence of MADD, even though clinically silent at post-DBS MRI acquisition, was associated with lower DBS effect in areas highly relevant for depression. This finding points to a possibly latent nature of post-DBS MADD, calling for caution in further follow-up of these patients.

Evaluation of the effects of DBS in the caudal Zona incerta on brain activity during a working memory task in patients with essential tremor

Essential tremor (ET) is characterized by bilateral upper limb postural and/or kinetic tremor, but also cognitive deficits. Tremor in ET, as well as aspects of cognitive deficits associated with ET, have been suggested to be linked to dysfunction in the cerebello-thalamo-cerebral circuit. In ET patients with disabling and medically intractable motor symptoms, Deep Brain Stimulation (DBS) is effective in reducing tremor. DBS in the caudal Zona incerta (cZi) has been shown to modulate the activity of the sensorimotor cerebello-cerebral circuit during motor tasks. Whether the activity in the cerebello-cerebral circuit is modulated by DBS during tasks involving working memory is unknown. The present study therefore aimed to investigate the possible effects of cZi DBS on working-memory processing in ET patients by means of task-based blood oxygen level-dependent (BOLD) fMRI.Thirteen ET patients completed a working-memory task during DBS OFF and ON conditions. The task involved three conditions: maintenance, manipulation, and control. Behaviorally, there was no significant effect from DBS on accuracy, but a marginally significant Task x DBS interaction was detected for response times (RTs). However, post hoc comparisons for each condition failed to reach statistical significance. FMRI analyses revealed that DBS did not alter BOLD signal in regions of interest (lateral prefrontal cortex, parietal cortex, and the cerebellum), or in a complementary whole-brain analysis.The present study indicates that DBS in the cZi in patients with ET has at most marginal effects on working memory, which is consistent with the results of pre- and post-DBS neuropsychological assessment showing minimal cognitive effects of surgery.

Deep brain stimulation of the anterior nucleus of the thalamus increases slow wave activity in NREM sleep.

Previous studies suggest that intermittent deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) affects physiological sleep architecture. Here, we investigated the impact of continuous ANT-DBS on sleep in epilepsy patients in a multicenter cross-over study in ten patients. We assessed sleep stage distribution, delta power, delta energy, and total sleep time (TST) in standardized 10/20 polysomnography (PSG) investigations before and 12 months after DBS lead implantation. In contrast to previous studies, we found no disruption of sleep architecture or alterations of sleep stage distribution under active ANT-DBS (P = 0.76). On the contrary, we observed more consolidated and deeper slow wave sleep (SWS) under continuous high frequency DBS as compared to baseline sleep prior to DBS lead implantation. In particular, biomarkers of deep sleep (delta power and delta energy) showed a significant increase post-DBS as compared to baseline (36.67 ± 13.68 μV2 and 799.86 ± 407.56 μV2 *s, P < 0.001). Furthermore, the observed increase in delta power was related to the location of the active stimulation contact within the ANT: we found higher delta power and higher delta energy in patients with active stimulation in more superior contacts as compared to inferior ANT stimulation. We also observed significantly less nocturnal EEG discharges in DBS ON condition. In conclusion, our findings suggest that continuous ANT-DBS in the most cranial part of the target region leads to more consolidated SWS. From a clinical perspective, these findings suggest that patients with sleep disruption under cyclic ANT-DBS could benefit from an adaptation of stimulation parameters to more superior contacts and continuous mode stimulation.

P 33 Changes in functional connectivity relate to modulation of cognitive control by subthalamic stimulation

Introduction Using cognitive control, humans can flexibly influence behavior based on set goals, which includes overriding impulses by inhibiting automatic responses in a conflicting environment. The basal ganglia have been hypothesized as an integral part in a cortico-subcortical network that modulates inhibitory control in both motor and non-motor domains. Subthalamic (STN) deep brain stimulation (DBS) in Parkinson‘s disease (PD) patients not only improves kinematic parameters of movement but also modulates cognitive control in the motor and non-motor domain, especially in situations of high conflict. Materials & Methods During DBS ON and OFF conditions, we conducted a visuomotor task in 14 PD patients who previously underwent resting-state functional MRI (rs-fMRI) acquisitions DBS ON and OFF. In the task, participants had to move a cursor with a pen on a digital tablet either towards (automatic condition) or in the opposite direction (controlled condition) of a target. Behaviorally, the first main outcome parameter was reaction time, and specifically, the difference in reaction time between automatic and controlled condition that reflects the additional time associated with engagement of cognitive control. Furthermore, average movement velocity ON vs. OFF DBS in automatic and controlled trials was assessed. Analysis of the imaging data focused on STN DBS induced modulation of rs-fMRI connectivity as a function of changes in behavior ON vs. OFF DBS and was estimated using link-wise network-based statistics within an a-priori defined network parcellation with 7 bihemispheric regions of interest (STN, internal/external pallidum (GPi and GPe), striatum, motor thalamus (VAn, VAp, VLd/VLv nuclei combined), motor and premotor cortices, supplementary motor area (SMA) and pre-SMA). Results Behavioral results showed diminished reaction time adaptation under DBS, i.e., PD patients ON DBS slowed down significantly less in the controlled condition compared to the automatic condition than they did OFF DBS. Additionally, pen-to-target movement velocity was increased under DBS in both automatic and controlled condition. Resting-state imaging data analysis revealed that DBS-induced reaction time reduction was associated with attenuated functional connectivity between cortical motor areas, basal ganglia and thalamus. On the other hand, increased movement velocity ON DBS was associated with stronger pallido-thalamic connectivity. Conclusion These findings suggest that DBS-induced decoupling of a motor cortico-basal ganglia network underlies impaired inhibitory control in PD patients undergoing subthalamic DBS and highlight the concept of functional network modulation through DBS. Understanding the connectivity basis of nonmotor changes in PD patients treated with DBS has a high clinical relevance, since network modulation may be fine-tuned with advancing therapeutic developments such as adaptive stimulation.

F151. Sensorimotor cortex plasticity correlates with effectiveness of pallidal stimulation in dystonia

Introduction Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective symptomatic treatment of farmacoresistant dystonic syndromes. The sensorimotor cortex of dystonia patients exhibits an exaggerated responsiveness to the TMS (transcranial magnetic stimulation) in conditioning protocols. The aim of our study was to analyse the excitability of the primary motor cortex (MI) in relation to modulation of input from the primary somatosensory cortex (SI) in dystonia patients treated by GPi DBS. Methods We examined 21 patients (mean age 51 ± (SD)17 years) with dystonia treated by GPi DBS. The SI was modulated in DBS ON and OFF conditions by a 2-min series of paired associative stimulation (PAS) with 5 Hz frequency, consisting of electrical stimulation of the median nerve followed by 20 ms of subthreshold TMS pulse. The excitability of the MI was tested by motor evoked potentials (MEP) applied before and after the PAS. The clinical effect (CE) was expressed as a change in the dystonic score between DBS ON condition and the preoperative state. Results The SI PAS caused a decrease of the MEP amplitude in dystonia patients with the GPi DBS ON state in comparison with GPi DBS OFF state ( p p N = 8, p p N = 13, >25% CE) had the MEP amplitude unchanged after the SI PAS in both of the GPi DBS conditions. Conclusion The SI PAS intervention applied over SI cortex affected motor cortex excitability in dystonia patients but not in healthy controls. The GPi DBS reduced the sensorimotor cortex plasticity of dystonia patients under level seen in the GPi DBS off state and even under the level seen in healthy controls. Surprisingly, only poor responders to GPi DBS therapy showed a loss of an inhibitory effect of the SI on the MI immediately after switching stimulation off in comparison with good responders and healthy controls. This may suggest, that the GPi DBS normalizes the excitability of MI through strengthening of the sensorimotor interaction and causes long lasting cortical plasticity changes in good responders which may contribute to better suppression of the dystonic symptoms. Supported by the grants GACR 16-13323S, PROGRES Q27/LF1 and MJFF11362.

F60. Acute and chronic changes of motor network excitability in relation to the clinical benefit of pallidal stimulation in dystonia: A combined TMS and VBM study

Introduction Dystonia patients express less effective intracortical inhibition, which can potentially be restored with pallidal deep brain stimulation (DBS). The DBS-related clinical benefit in dystonia increases relatively slowly, suggesting an induction of slow plastic processes in regions involved with motor control. In our study, we explored the relationship between intracortical inhibition of the motor cortex, brain morphology, and DBS-related clinical effects. Methods Twenty-two patients (mean age 51 ± (SD)17 years) with dystonia of various distribution and etiology treated by chronic pallidal DBS and 22 healthy subjects were included in the study. Voxel-based morphometry of postoperative T1-weighted images (MPRAGE, 1 × 1 × 1 mm) was calculated for gray matter (GM) density in each voxel using CAT12/SPM12 software. Paired TMS with subthreshold conditioning stimulus followed by a supratreshold testing stimulus were applied to the motor cortex to elicit short-latency intracortical inhibition (SICI) of the motor evoked potential. The clinical effect of DBS was expressed as a change in the dystonic score (BFMDS or TWSTRS) between actual DBS ON condition and the preoperative state. Results Dystonia patients showed increased GM density in the supplementary motor area (SMA) and middle cingulate in comparison with healthy controls (p Conclusion Good responders to pallidal DBS treatment exhibited a similar level of SICI as healthy controls but non-responders were unable to increase it. Brain changes of treated patients possibly underwent grey matter rebuilding with cerebellar hypertrophy quantitatively related to the improvement of intracortical inhibition and with hypertrophy in the cortex involved in motor act preparation. All these results support the multilevel impact of effective DBS on motor networks in dystonia. Supported by the grants GACR 16-13323S.

O19 Abnormal interaction between somatosensory and the motor cortex in dystonia not responding to pallidal stimulation

Objectives To analyse the influence of the primary somatosensory cortex (SI) on the motor cortex (MI) in dystonia in regards to the effectiveness of deep brain stimulation (DBS) of the globus pallidus interna (GPi). Methods We examined 21 patients (mean age 51 ± (SD)17 years) with dystonia treated by GPi DBS. The SI was modulated in DBS ON and OFF conditions by a 2-min series of paired associative stimulation (PAS) with 5 Hz frequency, consisting of electrical stimulation of the median nerve followed by 20 ms of TMS pulse. The excitability of the MI was tested by motor evoked potentials (MEP) applied before and after the PAS. The clinical effect (CE) was expressed as a change in the dystonic score between DBS ON condition and the preoperative state. Results The SI PAS caused a decrease of the MEP amplitude in responders ( N = 8, >50% CE) and in partial responders ( N = 5, 25–50% CE) during both conditions which was indistinguishable from controls. In non-responders ( N = 8, p Discussion Non-responders showed a quick suppression of an inhibitory effect of the SI on the MI after switching stimulation off than when compared with the group of responders and controls. Conclusion GPi DBS normalizes the excitability of MI probably due to strengthening of the sensorimotor interaction, suggesting a longer lasting cortical plasticity in the responders. Significance The SI PAS reduces the excitability of the MI in dystonia according to effectiveness of GPi DBS. Supported by the grants GACR 16-13323S and PROGRES Q27/LF1 .

EP 45. Emotional valence and arousal gradient along the anterior–posterior axis within the subthalamic nucleus in Parkinson’s disease

Introduction Changes in emotional processes have been reported after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson’s disease (PD). The STN DBS increased activity of the aversive motivational system: the fearful stimuli were experienced as more salient with the DBS switched on. The STN is organized into a dorsolateral motor, a central associative, and a ventromedial limbic territories and clinical effects of STN DBS seem to depend on the position of the active electrode contact within the STN in a manner that reflects the functional organization and connectivity of the STN. Objectives Considering the functional organization of the STN, we aimed to analyze the relationship between changes in subjective emotional experience to pictures presenting fearful stimuli and the active electrode contact position within the STN. Patients and methods Twenty off-medicated PD patients (all men, aged 58.4 ± (SD)6 years, disease duration 15 ± 4 years, 2.3 ± 1 years after implantation) viewed series of 84 pictures depicting primary rewarding, aversive fearful or neutral stimuli and performed ratings according to emotional valence (from 1 to 9, ranging from unpleasant to pleasant) and arousal (from 1 to 9, ranging from calm to excited) in DBS switched ON- and OFF-conditions. To localize the active electrode contact position, both the preoperative 3T T2-weighted MR (T2W) images visualizing the STN and the postoperative 1.5T T1W images displaying the susceptibility artifact of the permanent DBS electrode were automatically co-registered with the frame-based preoperative 1.5T T1W images into one stereotactic space using software for neurosurgical planning. The active electrode contact position in the STN was reconstructed based on the location of the susceptibility artifact of the permanent DBS electrode. Furthermore, each STN was manually delineated and fitted onto the STN reference model by Morel. The relationship between the affective ratings to aversive stimuli including the ON vs. OFF differences to the active contact positions in was assessed using linear models. Results In the DBS ON-condition, patients attributed lower valence scores compared with the OFF-condition (P Conclusions Our results confirm previous observations STN DBS affects emotional processing related to aversive stimuli. They further suggest emotional valence and arousal are processed separately at this subcortical level and their representations are organized along the anterior–posterior axis in the STN. Supported by Grant GACR 16-13323S and PRVOUK P26/LF1/4.

EP 33. Prolonged pauses in verbal fluency tasks under active VIM-DBS – Does it delay automatic lexical co-activation?

Background Deep Brain Stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) is a common therapeutic option for patients with essential tremor (ET). Despite a generally low risk of side effects, declines in verbal fluency performance have previously been reported. Objectives This study aimed at specifying effects of VIM-DBS on the two main subcomponents of verbal fluency output, i.e., lexical clustering and switching. This approach was chosen in order to discriminate between DBS effects on automatic activation within lexical fields (during clusters) and on attention demanding processes (switches). Patients & methods Thirteen ET patients with VIM-DBS performed verbal fluency tasks in their VIM-DBS ON and OFF conditions. Analysis of clusters and switches were accomplished on the basis of curve fittings using an improved mathematical function for the description of word output dynamics. All results were compared to those of fifteen healthy control subjects, and significant OFF-ON-change scores were correlated to stimulation parameters. Results In addition to a reduction in the number of words produced, the intervals between words within clusters were significantly prolonged in the DBS ON vs. OFF condition. This effect correlated with a more anterior electrode position. Switches were not affected by DBS but took longer in patients than in controls. Conclusion VIM-DBS seems to impair verbal fluency primarily on the level of automatic lexical co-activation. This finding is discussed in the context of the hypothesized role of the thalamus in lexical processing. More posterior electrode positions appear safer in this regard.

Effect of subthalamic deep brain stimulation on turning kinematics and related saccadic eye movements in Parkinson disease

BackgroundPersons with Parkinson disease (PD) experience turning difficulty, often leading to freezing of gait and falls. Visual information plays a significant role in locomotion and turning, and while the effects of deep brain stimulation (DBS) on oculomotor function have been well documented, the effects of DBS on oculomotor function during turning and on turning itself have yet to be fully elucidated. ObjectiveTo determine the effects of STN DBS on turning performance and related oculomotor performance in PD. MethodsEleven subjects with PD and DBS of the subthalamic nucleus performed a seated voluntary saccade task and standing 180° turns in DBS OFF and DBS ON conditions. Oculomotor data were captured using an infrared eye tracking system while segment rotations were measured using 3-D motion capture. ResultsDuring the seated saccade task, DBS did not improve saccade amplitude or latency. DBS also did not improve gait velocity and stride length during forward walking. During turning, DBS improved turn performance (turn duration), reduced the number of saccades performed during the turns, and increased the amplitude and velocity of the saccade initiating the turn. DBS decreased the intersegmental latencies (eye–head, eye–foot, and head–trunk) but this effect was lost for eye–head and eye–foot after controlling for the duration of the first gait cycle. ConclusionsDBS significantly improves turn performance and related oculomotor performance. These findings add to the growing list of therapeutic benefits offered by DBS.

Subthalamic nucleus stimulation affects incentive salience attribution in Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinson's disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age ± SD, 58.3 ± 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty-four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS-related sensitivity to food reward stimuli cues might drive DBS-treated patients to higher food intake and subsequent weight gain.

Gait and balance in essential tremor: Variable effects of bilateral thalamic stimulation

Essential tremor (ET) is a multi-faceted condition best known for postural and action tremor but also may include disordered gait and postural instability. Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus provides substantial tremor reduction yet some patients with bilateral VIM DBS have gait and balance impairment. This study examines gait and balance performance in 13 participants with ET who have bilateral VIM DBS compared with a matched control group. Participants with ET were tested with their stimulators off (DBS OFF) and on (DBS ON). For both standard and tandem walking, participants with ET walked significantly more slowly than controls, with significantly lower cadence, spending a lower percentage of the gait cycle in single limb support and a higher percentage in double support compared with controls. Participants with ET also had significantly lower tandem and one leg stance times, Berg balance scores, balance confidence, and required significantly greater time to perform the Timed Up-and-Go relative to controls. There were no significant differences in any gait or balance measures in the DBS OFF versus DBS ON conditions, but the effects of DBS on gait and balance were highly variable among individuals. Future studies are needed to determine why some individuals experience gait and balance difficulties after bilateral thalamic DBS and others do not. A better understanding of the mechanisms underlying gait and balance impairments in those with bilateral DBS is critical to reduce falls and fractures in this group.

Subthalamic nucleus deep brain stimulation improves deglutition in Parkinson's disease

Relatively little is known about the role of the basal ganglia in human deglutition. Deep brain stimulation (DBS) affords us a model for examining deglutition in humans with known impairment of the basal ganglia. The purpose of this study was to examine the effects of subthalamic nuclei (STN) DBS on the oral and pharyngeal stages of deglutition in individuals with Parkinson's Disease (PD). It was hypothesized that DBS would be associated with improved deglutition. Within participant, comparisons were made between DBS in the ON and OFF conditions using the dependent variables: pharyngeal transit time, maximal hyoid bone excursion, oral total composite score, and pharyngeal total composite score. Significant improvement occurred for the pharyngeal composite score and pharyngeal transit time in the DBS ON condition compared with DBS OFF. Stimulation of the STN may excite thalamocortical or brainstem targets to sufficiently overcome the bradykinesia/hypokinesia associated with PD and return some pharyngeal stage motor patterns to performance levels approximating those of "normal" deglutition. However, the degree of hyoid bone excursion and oral stage measures did not improve, suggesting that these motor acts may be under the control of different sensorimotor pathways within the basal ganglia.

Effect of Vim thalamic DBS in Parkinson’s disease on F wave duration

F waves were recorded from abductor hallucis muscle in eight Parkinsonian patients with deep brain stimulation (DBS) electrodes surgically implanted in their Vim thalamic nucleus in two conditions of DBS ON and OFF. Patients with relatively anteriorly located electrodes exhibited a significant reduction in F wave duration and also in the UPDRS rigidity score of the corresponding foot when the DBS was ON. In contrast, patients with relatively posteriorly located electrodes exhibited no significant difference in F wave duration in the two DBS ON and OFF conditions. The rigidity UPDRS score in the corresponding foot diminished very little in the latter group. Both groups had great improvement in their tremor at rest UPDRS score in that foot when the DBS was ON. Vim surgery is generally accepted to affect tremor mechanisms. However, surgical intervention in anterior parts of Vim has been reported to affect rigidity mechanisms. This correspondence of these two symptoms of rigidity and tremor with the two locations of anterior and relatively posterior Vim may indicate the contribution of mechanisms of rigidity, but not tremor, in enhancement of F wave duration and hyper excitability of spinal motoneuron.