BackgroundThe debilitating nature of migraine and challenges associated with treatment-refractory migraine have a profound impact on patients. With the need for alternatives to pharmacologic agents, vagus nerve stimulation has demonstrated efficacy in treatment-refractory primary headache disorders. We investigated the use of cervical non-invasive vagus nerve stimulation (nVNS) for the acute treatment and prevention of migraine attacks in treatment-refractory episodic and chronic migraine (EM and CM) and evaluated the impact of nVNS on migraine-associated sleep disturbance, disability, and depressive symptoms.MethodsTwenty patients with treatment-refractory migraine were enrolled in this 3-month, open-label, prospective observational study. Patients administered nVNS prophylactically twice daily at prespecified times and acutely as adjunctive therapy for migraine attacks. The following parameters were evaluated: pain intensity (visual analogue scale [VAS]); number of headache days per month and number of migraine attacks per month; number of acutely treated attacks; sleep quality (Pittsburgh Sleep Quality Index [PSQI]); migraine disability assessment (MIDAS); depressive symptoms (Beck Depression Inventory® [BDI]); and adverse events (AEs).ResultsOf the 20 enrolled patients, 10 patients each had been diagnosed with EM and CM. Prophylaxis with nVNS was associated with significant overall reductions in patient-perceived pain intensity; median (interquartile range) VAS scores at baseline versus 3 months were 8.0 (7.5, 8.0) versus 4.0 (3.5, 5.0) points (p < 0.001). Baseline versus 3-month values (mean ± standard error of the mean) were 14.7 ± 0.9 versus 8.9 ± 0.8 (p < 0.001) for the number of headache days per month and 7.3 ± 0.9 versus 4.5 ± 0.6 (p < 0.001) for the number of attacks per month. Significant improvements were also noted in MIDAS (p < 0.001), BDI (p < 0.001), and PSQI global (p < 0.001) scores. No severe or serious AEs occurred.ConclusionIn this study, treatment with nVNS was safe and provided clinically meaningful decreases in the frequency and intensity of migraine attacks in patients with treatment-refractory migraine. Improvements in migraine-associated disability, depression, and sleep quality were also noted.

L-DOPA is still the most effective pharmacological therapy for the treatment of motor symptoms in Parkinson's disease (PD) almost four decades after it was first used. Deep brain stimulation (DBS) is a safe and highly effective treatment option in patients with PD. Even though a clear understanding of the mechanisms of both treatment methods is yet to be obtained, the combination of both treatments is the most effective standard evidenced-based therapy to date. Recent studies have demonstrated that DBS is a therapy option even in the early course of the disease, when first complications arise despite a rigorous adjustment of the pharmacological treatment. The unique feature of this therapeutic approach is the ability to preferentially modulate specific brain networks through the choice of stimulation site. The clinical effects have been unequivocally confirmed in recent studies; however, the impact of DBS and the supplementary effect of L-DOPA on the neuronal network are not yet fully understood. In this review, we present emerging data on the presumable mechanisms of DBS in patients with PD and discuss the pathophysiological similarities and differences in the effects of DBS in comparison to dopaminergic medication. Targeted, selective modulation of brain networks by DBS and pharmacodynamic effects of L-DOPA therapy on the central nervous system are presented. Moreover, we outline the perioperative algorithms for PD patients before and directly after the implantation of DBS electrodes and strategies for the reduction of side effects and optimization of motor and non-motor symptoms.

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The disruption of pathologically enhanced beta oscillations is considered one of the key mechanisms mediating the clinical effects of deep brain stimulation on motor symptoms in Parkinson’s disease. However, a specific modulation of other distinct physiological or pathological oscillatory activities could also play an important role in symptom control and motor function recovery during deep brain stimulation. Finely tuned gamma oscillations have been suggested to be prokinetic in nature, facilitating the preferential processing of physiological neural activity. In this study, we postulate that clinically effective high-frequency stimulation of the subthalamic nucleus imposes cross-frequency interactions with gamma oscillations in a cortico-subcortical network of interconnected regions and normalizes the balance between beta and gamma oscillations. To this end we acquired resting state high-density (256 channels) EEG from 31 patients with Parkinson’s disease who underwent deep brain stimulation to compare spectral power and power-to-power cross-frequency coupling using a beamformer algorithm for coherent sources. To show that modulations exclusively relate to stimulation frequencies that alleviate motor symptoms, two clinically ineffective frequencies were tested as control conditions. We observed a robust reduction of beta and increase of gamma power, attested in the regions of a cortical (motor cortex, supplementary motor area, premotor cortex) and subcortical network (subthalamic nucleus and cerebellum). Additionally, we found a clear cross-frequency coupling of narrowband gamma frequencies to the stimulation frequency in all of these nodes, which negatively correlated with motor impairment. No such dynamics were revealed within the control posterior parietal cortex region. Furthermore, deep brain stimulation at clinically ineffective frequencies did not alter the source power spectra or cross-frequency coupling in any region. These findings demonstrate that clinically effective deep brain stimulation of the subthalamic nucleus differentially modifies different oscillatory activities in a widespread network of cortical and subcortical regions. Particularly the cross-frequency interactions between finely tuned gamma oscillations and the stimulation frequency may suggest an entrainment mechanism that could promote dynamic neural processing underlying motor symptom alleviation.

2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1187-1199.

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Parkinson’s disease (PD) is a neurodegenerative disease, neuropathologically characterized by progressive loss of neurons in distinct brain areas. We hypothesize that quantifiable network alterations are caused by neurodegeneration. The primary motivation of this study was to assess the specific network alterations in PD patients that are distinct but appear in conjunction with physiological aging. 178 subjects (130 females) stratified into PD patients, young, middle-aged and elderly healthy controls (age- and sex-matched with PD patients), were analyzed using 3D-T1 magnetization-prepared rapid gradient-echo (MPRAGE) and diffusion weighted images acquired in 3T MRI scanner. Diffusion modeling and probabilistic tractography analysis were applied for generating voxel-based connectivity index maps from each seed voxel. The obtained connectivity matrices were analyzed using graph theoretical tools for characterization of involved network. By network-based statistic (NBS) the interregional connectivity differences between the groups were assessed. Measures evaluating local diffusion properties for anisotropy and diffusivity were computed for characterization of white matter microstructural integrity. The graph theoretical analysis showed a significant decrease in distance measures – eccentricity and characteristic path length – in PD patients in comparison to healthy subjects. Both measures as well were lower in PD patients when compared to young and middle-aged healthy controls. NBS analysis demonstrated lowered structural connectivity in PD patients in comparison to young and middle-aged healthy subject groups, mainly in frontal, cingulate, olfactory, insula, thalamus, and parietal regions. These specific network differences were distinct for PD and were not observed between the healthy subject groups. Microstructural analysis revealed diffusivity alterations within the white matter tracts in PD patients, predominantly in the body, splenium and tapetum of corpus callosum, corticospinal tract, and corona radiata, which were absent in normal aging. The identified alterations of network connectivity presumably caused by neurodegeneration indicate the disruption in global network integration in PD patients. The microstructural changes identified within the white matter could endorse network reconfiguration. This study provides a clear distinction between the network changes occurring during aging and PD. This will facilitate a better understanding of PD pathophysiology and the direct link between white matter changes and their role in the restructured network topology.