EEG and MEG primers for tracking DBS network effects.

Deep brain stimulation (DBS) is an effective treatment method for a range of neurological and psychiatric disorders. It involves implantation of stimulating electrodes in a precisely guided fashion into subcortical structures and, at a later stage, chronic stimulation of these structures with an implantable pulse generator. While the DBS surgery makes it possible to both record brain activity and stimulate parts of the brain that are difficult to reach with non-invasive techniques, electroencephalography (EEG) and magnetoencephalography (MEG) provide complementary information from other brain areas, which can be used to characterize brain networks targeted through DBS. This requires, however, the careful consideration of different types of artifacts in the data acquisition and the subsequent analyses. Here, we review both the technical issues associated with EEG/MEG recordings in DBS patients and the experimental findings to date. One major line of research is simultaneous recording of local field potentials (LFPs) from DBS targets and EEG/MEG. These studies revealed a set of cortico-subcortical coherent networks functioning at distinguishable physiological frequencies. Specific network responses were linked to clinical state, task or stimulation parameters. Another experimental approach is mapping of DBS-targeted networks in chronically implanted patients by recording EEG/MEG responses during stimulation. One can track responses evoked by single stimulation pulses or bursts as well as brain state shifts caused by DBS. These studies have the potential to provide biomarkers for network responses that can be adapted to guide stereotactic implantation or optimization of stimulation parameters. This is especially important for diseases where the clinical effect of DBS is delayed or develops slowly over time. The same biomarkers could also potentially be utilized for the online control of DBS network effects in the new generation of closed-loop stimulators that are currently entering clinical use. Through future studies, the use of network biomarkers may facilitate the integration of circuit physiology into clinical decision making.

Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report.

We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved.

[Recommendation for treatment options in advanced Parkinson's disease]. / Ajánlás a Parkinson-kór elorehaladott stádiumának kezeléséhez.

The treatment of advanced Parkinson's disease is challenging for both physicians and caregivers. The device-aided therapies need expertise and dedicated hospital centers. In this summary we have concluded the available data and recommendation for the treatment options in advanced Parkinson's disease and adopt them to the daily care in Hungary.

p.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe.

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.

[Treatment possibilities in advanced Parkinson's disease]. / Kezelési lehetoségek a Parkinson-kór elorehaladott stádiumában.

In the course of Parkinson's disease, advanced and late stages can be distinguished. In the advanced stage, levodopa has good effect on motor symptoms, but patient care is often hindered by levodopa-induced complications such as motor fluctuation and dyskinesias. In the late stage levodopa response becomes poor, falls, dementia and psychotic symptoms appear and patients often need hospitalization. In the advanced stage, the quality of life may be improved better by device-aided therapy than by best oral medical treatment. The alternatives are apomorhin pump, levodopa carbidopa intestinal gel with pump and deep brain stimulation. The therapy plan should be based on the principle: "the right treatment, to the right patient, at the right time".

[Efficacy of deep brain stimulation in our patients with Parkinson's disease]. / A mély agyi stimuláció hatékonysaga Parkinson- kóros betegeink kezelésében.

BACKGROUND AND PURPOSES: In advanced Parkinson's disease, medically refractory motor fluctuation or medically resistant tremor considerably affects quality of life. However, these symptoms can be mostly successfully treated by deep brain stimulation. We analyzed the efficacy of bilateral subthalamic stimulation in our patients with Parkinson's disease. METHODS: We assessed the clinical data of ten patients who have been treated in the Department of Neurology, Semmelweis University and have been operated in the National Institute of Neurosciences between 2008 and 2011. The Hoehn-Yahr scale score, the Unified Parkinson's Disease Rating Scale score and the Parkinson's Disease Questionnaire 39, as well as the dose of antiparkinson medication were documented prior to and one year after surgery. RESULTS: Patient condition improved according to the Hoehn-Yahr scale, approximately by two stages. The dose of antiparkinson medication could be reduced by 63.4% (p = 0.005) post operation. Unified Parkinson's Disease Rating Scale scores decreased by 70.9% (p = 0.005). 12 hours after medication withdrawal, execution of daily activity improved by 57.1% (p < 0.01) and motor functions developed by 79.1% (p < 0.01). Duration of dyskinesias decreased by 62.5% (p = 0.018), duration of akinesia diminished by 87.5% (p = 0.005). Quality of life rose by 41.6% (p < 0.01). Neuropsychological tests detected improvement in verbal memory. CONCLUSION: With deep brain stimulation, the dosage of antiparkinson medication could be significantly reduced, with considerable improvements in motor function and quality of life. Although the number of patients is still low, good results have been established by careful patient selection, precise neurosurgical procedure and by appropriate programming and patient care.

Bilateral simultaneous thalamic hematomas - Unusual presentation of intracerebral hemorrhage: A case report.

Background: Bilateral symmetrical simultaneous thalamic hemorrhages are extremely rare. Case presentation: A 52-year-old female patient with a history of untreated hypertension, ischemic heart disease and type 2 diabetes mellitus was admitted with somnolence, disorientation, 3/5 right-sided hemiparesis and blood pressure of 200/110 mmHg. Cranial CT scan showed bilateral thalamic hemorrhages, with bilateral intraventricular propagation and subarachnoid component along the frontal, parietal and occipital lobes. CT angiography did not show any source of bleeding or cerebral vein or sinus thrombosis. Coagulation laboratory parameters were in normal range.The patient was treated with a combination of intravenous and oral antihypertensive medication; five days later she become normotensive with improving motor function but was still somnolent.Six weeks later she was fully alert, motor functions continued to improve, but had severe cognitive deficit. Repeated neuropsychological assessment showed a slow and moderate improvement of a major neurocognitive impairment. At discharge her Mini Mental State Examination score was 13/30 and Addenbrooke's Cognitive Examination III score was 42/100.Cranial MRI scan eight weeks later depicted subacute-chronic stages of the bilateral hemorrhages, regression of perifocal edema, cerebral microbleeds in the left external capsule and the pons.At discharge after 2 months, she was alert, had no focal neurological signs, but was unable to care for herself due to lack of motivation, spatial and temporal disorientation and severe cognitive deficit. Conclusion: Simultaneous bilateral thalamic hemorrhages are extremely rare, the most commonly observed symptom is cognitive impairment. Our case was caused by hypertensive crisis, but in the differential diagnosis, sinus thrombosis, hemorrhagic transformation of ischemic stroke and various hemophilias should be considered.

Factors affecting postural instability after more than one-year bilateral subthalamic stimulation in Parkinson's disease: A cross-sectional study.

BACKGROUND: Balance impairment in Parkinson's disease is multifactorial and its changes due to subthalamic stimulation vary in different studies. OBJECTIVE: We aimed to analyze the combination of predictive clinical factors of balance impairment in patients with Parkinson's disease treated with bilateral subthalamic stimulation for at least one year. METHODS: We recruited 24 patients with Parkinson's disease treated with bilateral subthalamic stimulation and 24 healthy controls. They wore an Opal monitor (APDM Inc.) consisting of three-dimensional gyroscopes and accelerometers in the lumbar region. We investigated four stimulation conditions (bilateral stimulation OFF, bilateral stimulation ON, and unilateral right- and left-sided stimulation ON) with four tests: stance on a plain ground with eyes open and closed, stance on a foam platform with eyes open and closed. Age, disease duration, the time elapsed after implantation, levodopa, and stimulation responsiveness were analyzed. The distance of stimulation location from the subthalamic motor center was calculated individually in each plane of the three dimensions. We analyzed the sway values in the four stimulation conditions in the patient group and compared them with the control values. We explored factor combinations (with age as confounder) in the patient group predictive for imbalance with cluster analysis and a machine-learning-based multiple regression method. RESULTS: Sway combined from the four tasks did not differ in the patients and controls on a group level. The combination of the disease duration, the preoperative levodopa responsiveness, and the stimulation responsiveness predicted individual stimulation-induced static imbalance. The more affected patients had more severe motor symptoms; primarily, the proprioceptive followed by visual sensory feedback loss provoked imbalance in them when switching on the stimulation. CONCLUSIONS: The duration of the disease, the severity of motor symptoms, the levodopa responsiveness, and additional sensory deficits should be carefully considered during preoperative evaluation to predict subthalamic stimulation-induced imbalance in Parkinson's disease.

Clinical parameters predict the effect of bilateral subthalamic stimulation on dynamic balance parameters during gait in Parkinson's disease.

We investigated the effect of deep brain stimulation on dynamic balance during gait in Parkinson's disease with motion sensor measurements and predicted their values from disease-related factors. We recruited twenty patients with Parkinson's disease treated with bilateral subthalamic stimulation for at least 12 months and 24 healthy controls. Six monitors with three-dimensional gyroscopes and accelerometers were placed on the chest, the lumbar region, the two wrists, and the shins. Patients performed the instrumented Timed Up and Go test in stimulation OFF, stimulation ON, and right- and left-sided stimulation ON conditions. Gait parameters and dynamic balance parameters such as double support, peak turn velocity, and the trunk's range of motion and velocity in three dimensions were analyzed. Age, disease duration, the time elapsed after implantation, the Hoehn-Yahr stage before and after the operation, the levodopa, and stimulation responsiveness were reported. We individually calculated the distance values of stimulation locations from the subthalamic motor center in three dimensions. Sway values of static balance were collected. We compared the gait parameters in the OFF and stimulation ON states and controls. With cluster analysis and a machine-learning-based multiple regression method, we explored the predictive clinical factors for each dynamic balance parameter (with age as a confounder). The arm movements improved the most among gait parameters due to stimulation and the horizontal and sagittal trunk movements. Double support did not change after switching on the stimulation on the group level and did not differ from control values. Individual changes in double support and horizontal range of trunk motion due to stimulation could be predicted from the most disease-related factors and the severity of the disease; the latter also from the stimulation-related changes in the static balance parameters. Physiotherapy should focus on double support and horizontal trunk movements when treating patients with subthalamic deep brain stimulation.

Frequency-specific network activity predicts bradykinesia severity in Parkinson's disease.

OBJECTIVE: Bradykinesia has been associated with beta and gamma band interactions in the basal ganglia-thalamo-cortical circuit in Parkinson's disease. In this present cross-sectional study, we aimed to search for neural networks with electroencephalography whose frequency-specific actions may predict bradykinesia. METHODS: Twenty Parkinsonian patients treated with bilateral subthalamic stimulation were first prescreened while we selected four levels of contralateral stimulation (0: OFF, 1-3: decreasing symptoms to ON state) individually, based on kinematics. In the screening period, we performed 64-channel electroencephalography measurements simultaneously with electromyography and motion detection during a resting state, finger tapping, hand grasping tasks, and pronation-supination of the arm, with the four levels of contralateral stimulation. We analyzed spectral power at the low (13-20 Hz) and high (21-30 Hz) beta frequency bands and low (31-60 Hz) and high (61-100 Hz) gamma frequency bands using the dynamic imaging of coherent sources. Structural equation modelling estimated causal relationships between the slope of changes in network beta and gamma activities and the slope of changes in bradykinesia measures. RESULTS: Activity in different subnetworks, including predominantly the primary motor and premotor cortex, the subthalamic nucleus predicted the slopes in amplitude and speed while switching between stimulation levels. These subnetwork dynamics on their preferred frequencies predicted distinct types and parameters of the movement only on the contralateral side. DISCUSSION: Concurrent subnetworks affected in bradykinesia and their activity changes in the different frequency bands are specific to the type and parameters of the movement; and the primary motor and premotor cortex are common nodes.

Lack of Accredited Clinical Training in Movement Disorders in Europe, Egypt, and Tunisia.

BACKGROUND: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. OBJECTIVE: To survey the accessible MD clinical training in these regions. METHODS: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. RESULTS: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. CONCLUSION: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.

Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson's Disease.

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.

Primary Sensorimotor Cortex Drives the Common Cortical Network for Gamma Synchronization in Voluntary Hand Movements.

Background: Gamma synchronization (GS) may promote the processing between functionally related cortico-subcortical neural populations. Our aim was to identify the sources of GS and to analyze the direction of information flow in cerebral networks at the beginning of phasic movements, and during medium-strength isometric contraction of the hand. Methods: We measured 64-channel electroencephalography in 11 healthy volunteers (age: 25 ± 8 years; four females); surface electromyography detected the movements of the dominant hand. In Task 1, subjects kept a constant medium-strength contraction of the first dorsal interosseus muscle, and performed a superimposed repetitive voluntary self-paced brisk squeeze of an object. In Task 2, brisk, and in Task 3, constant contractions were performed. Time-frequency analysis of the EEG signal was performed with the multitaper method. GS sources were identified in five frequency bands (30-49, 51-75, 76-99, 101-125, and 126-149 Hz) with beamformer inverse solution dynamic imaging of coherent sources. The direction of information flow was estimated by renormalized partial directed coherence for each frequency band. The data-driven surrogate test, and the time reversal technique were performed to identify significant connections. Results: In all tasks, we depicted the first three common sources for the studied frequency bands that were as follows: contralateral primary sensorimotor cortex (S1M1), dorsolateral prefrontal cortex (dPFC) and supplementary motor cortex (SMA). GS was detected in narrower low- (∼30-60 Hz) and high-frequency bands (>51-60 Hz) in the contralateral thalamus and ipsilateral cerebellum in all three tasks. The contralateral posterior parietal cortex was activated only in Task 1. In every task, S1M1 had efferent information flow to the SMA and the dPFC while dPFC had no detected afferent connections to the network in the gamma range. Cortical-subcortical information flow captured by the GS was dynamically variable in the narrower frequency bands for the studied movements. Conclusion: A distinct cortical network was identified for GS in voluntary hand movement tasks. Our study revealed that S1M1 modulated the activity of interconnected cortical areas through GS, while subcortical structures modulated the motor network dynamically, and specifically for the studied movement program.

Postoperative rehabilitation after deep brain stimulation surgery for movement disorders.

Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy for a set of neurological and psychiatric conditions and especially movement disorders such as Parkinson's disease, essential tremor and dystonia. Recent developments have improved the DBS technology. However, no unequivocal algorithms for an optimized postoperative care exist so far. The aim of this review is to provide a synopsis of the current clinical practice and to propose guidelines for postoperative and rehabilitative care of patients who undergo DBS. A standardized work-up in the DBS centers adapted to each patient's clinical state and needs is important, including a meticulous evaluation of clinical improvement and residual symptoms with a definition of goals for neurorehabilitation. Efficient and complete information transfer to subsequent caregivers is essential. A coordinated therapy within a multidisciplinary team (trained in movement disorders and DBS) is needed to achieve the long-range maximal efficiency. An optimized postoperative framework might ultimately lead to more effective results of DBS.

Delayed beta synchronization after movement of the more affected hand in essential tremor.

To investigate the pathomechanism of parkinsonian tremor (PT) and essential tremor (ET) by studying the correlation between tremor asymmetry and post-movement beta synchronization (PMBS) of the human EEG. We recorded the EEG of 10 patients with ET, 10 patients with Parkinson's disease and 10 controls. Subjects pressed an on-off switch in a self-paced manner with the thumb of their less (T+) and more (T++) tremulous hand. After digitalization of the EEG from the Cz, C3, C4 electrodes the movement reactive beta frequency, its maximum peak power value and its latency triggered to movement offset were determined. In ET tremor intensity did not influence the power of PMBS, however it was significantly delayed after the movement of the more tremulous hand. In Parkinson's disease after the movement of the more tremulous hand PMBS power was decreased, but it was not delayed. In controls the side of movement had no effect on the power and latency of the PMBS. The neuronal mechanisms underlying PMBS generation are differently affected in essential tremor and Parkinson's disease. The increase of PMBS latency after movement of the more affected hand in ET indicates possible cortical mechanisms in essential tremor generation.

Movement-related beta responses in essential tremor and Parkinson's disease.

OBJECTIVE: To investigate the pathomechanism of essential (ET) and parkinsonian tremor (PT) by studying the correlation between tremor severity and movement-related beta rhythm changes of the human electroencephalogram. PATIENTS AND METHODS: We recorded the electroencephalogram of 10 patients with essential tremor, 10 with Parkinsonian tremor and 10 controls. In a preliminary session we determined the side with lower and higher tremor intensity (T+, T++ respectively), using accelerometry. Subjects pressed an on-off switch in a self-paced manner with left and right thumb. After digitalization of the EEG from Cz, C3, C4 electrodes, the movement reactive beta frequency (MRBF), its minimum/maximum peak power values and their latencies triggered to movement offset were determined. RESULTS: The time course and amplitude of movement related beta desynchronization (ERD) were similar in each group regardless of tremor intensity. In ET tremor severity did not influence post-movement beta synchronization (PMBS) amplitude (PMBS(ET+) = 100.98 +/- 48.874%, PMBS(ET++) = 135.1 +/- 92.87%; p = 0.231), however it was significantly delayed after the movement of the more tremulous hand (latPMBS(ET+) = 1.26 +/- 0.566 s, latPMBS(ET++) = 1.57 +/- 0.565 s, p = 0.003). In the PT group on the side of pronounced tremor the amplitude of PMBS decreased but it was not delayed, compared to the less affected hand (PMBS(PT+) = 115.19 +/- 72.131%, PMBS(PT++) = 77.84 +/- 53.101%, p = 0.0028; latPMBS(PT+) = 1.4 +/- 0.74 s, latPMBS(PT++) = 1.25 +/- 0.797 s, p = 0.191). In controls the power and latency of PMBS was similar on both sides. CONCLUSIONS: The results suggest that neuronal mechanisms underlying PMBS generation are differently affected by ET and PT. Investigation of PMBS might be used for the differential diagnosis of essential tremor and Parkinson's disease.

Effect of subthalamic stimulation on distal and proximal upper limb movements in Parkinson's disease.

INTRODUCTION: A different innervation pattern of proximal and distal muscles from the contra- and ipsilateral motor circuits raises the question as to whether bilateral, contra- and ipsilateral subthalamic stimulation may have different effects on the distal and proximal movements of the upper limb. To answer this question, we performed kinematic analyzes in patients with Parkinson's disease. METHODS: Twenty-eight Parkinsonian patients treated by bilateral subthalamic stimulation were examined with an age-matched control group of 28 healthy subjects. They performed 14s of finger tapping, hand grasping and pronation-supination. The patient group performed these sessions in four conditions (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON) after withdrawal of dopaminergic medication for 12h and a fifth condition after taking medication (BOTH ON-MED ON). A motion sensor with a three-dimensional gyroscope was worn on the index finger. Speed, amplitude, rhythm and decrement of movements were calculated and compared across these conditions. RESULTS: Speed and amplitude of the more distal movements were improved similarly by contra- and bilateral stimulation. Bilateral stimulation was more effective than contralateral stimulation for the more proximal movements. Contra- and bilateral stimulation ameliorated the rhythm similarly in each movement task. Decrement of distal and proximal movements was not affected by the stimulation conditions. CONCLUSION: This is the first study to show that the outcome of bi- and unilateral subthalamic stimulation on proximal and distal upper limb movements should be evaluated separately postulating the different somatotopic organization of subloops in the cortico-basal ganglia motor circuits.