Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug‐resistant epilepsy (DRE). The primary goal of this systematic review and meta‐analysis is to describe recent ...advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty‐four articles were included in the meta‐analysis (23 for anterior thalamic nucleus ANT, 8 for centromedian thalamic nucleus CMT, and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta‐analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.
Summary Since the N-methyl-D-aspartate receptor (NMDAR) subunits were cloned less than two decades ago, a substantial amount of research has been invested into understanding their physiological ...function in the healthy CNS. Research has also been directed at their pathological roles in various neurological diseases, including disorders resulting from acute excitotoxic insults (eg, ischaemic stroke, traumatic brain injury), diseases due to chronic neurodegeneration (eg, Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis), disorders arising from sensitisation of neurons (eg, epilepsy, neuropathic pain), and neurodevelopmental disorders associated with NMDAR hypofunction (eg, schizophrenia). Selective NMDAR antagonists have not produced positive results in clinical trials. However, there are other NMDAR-targeted therapies used in current practice that are effective for treating some neurological disorders. In this Review, we describe the evidence for the use of these therapies and provide an overview of drugs being investigated in clinical trials. We also discuss new NMDAR-targeted strategies in clinical neurology.
There is an emerging need for noninvasive neuromodulation techniques to improve patient outcomes while minimizing adverse events and morbidity. Low-intensity focused ultrasound (LIFUS) is gaining ...traction as a non-surgical experimental approach of modulating brain activity. Several LIFUS sonication parameters have been found to potentiate neural firing, suppress cortical and epileptic discharges, and alter behavior when delivered to cortical and subcortical mammalian brain regions.
This review introduces the elements of an effective sonication protocol and summarizes key preclinical studies on LIFUS as a neuromodulation modality. The state of the art in human ultrasound neuromodulation is then comprehensively summarized, and current hypotheses regarding the underlying mechanism of action on neural activity are presented.
Peer-reviewed literature on human ultrasound neuromodulation was obtained by searching several electronic databases. The abstracts of all reports were read and publications which examined low-intensity transcranial ultrasound applied to human subjects were selected for review.
LIFUS can noninvasively influence human brain activity by suppressing cortical evoked potentials, influencing cortical oscillatory dynamics, and altering outcomes of sensory/motor tasks compared to sham sonication. Proposed mechanisms include cavitation, direct effects on neural ion channels, and plasma membrane deformation.
Though optimal sonication paradigms and transcranial delivery methods are still being established, future applications may include non-invasive human brain mapping experiments, and nonsurgical treatments for functional neurological disorders.
•Low-intensity ultrasound can noninvasively modulate mammalian brain activity.•Pulsing parameters and intensity determine excitatory or inhibitory neural effects.•Human US neuromodulation has been achieved in cortical and deep structures.•Ultrasound holds promise as a precise, nonsurgical and safe brain stimulation tool.
Outcomes from stereotactic surgery for essential tremor Dallapiazza, Robert Francis; Lee, Darrin J; De Vloo, Philippe ...
Journal of neurology, neurosurgery and psychiatry,
04/2019, Letnik:
90, Številka:
4
Journal Article
Recenzirano
Odprti dostop
There are several different surgical procedures that are used to treat essential tremor (ET), including deep brain stimulation (DBS) and thalamotomy procedures with radiofrequency (RF), radiosurgery ...(RS) and most recently, focused ultrasound (FUS). Choosing a surgical treatment requires a careful presentation and discussion of the benefits and drawbacks of each. We conducted a literature review to compare the attributes and make an appraisal of these various procedures. DBS was the most commonly reported treatment for ET. One-year tremor reductions ranged from 53% to 63% with unilateral Vim DBS. Similar improvements were demonstrated with RF (range, 74%-90%), RS (range, 48%-63%) and FUS thalamotomy (range, 35%-75%). Overall, bilateral Vim DBS demonstrated more improvement in tremor reduction since both upper extremities were treated (range, 66%-78%). Several studies show continued beneficial effects from DBS up to five years. Long-term follow-up data also support RF and gamma knife radiosurgical thalamotomy treatments. Quality of life measures were similarly improved among patients who received all treatments. Paraesthesias, dysarthria and ataxia were commonly reported adverse effects in all treatment modalities and were more common with bilateral DBS surgery. Many of the neurological complications were transient and resolved after surgery. DBS surgery had the added benefit of programming adjustments to minimise stimulation-related complications. Permanent neurological complications were most commonly reported for RF thalamotomy. Thalamic DBS is an effective, safe treatment with a long history. For patients who are medically unfit or reluctant to undergo DBS, several thalamic lesioning methods have parallel benefits to unilateral DBS surgery. Each of these surgical modalities has its own nuance for treatment and patient selection. These factors should be carefully considered by both neurosurgeons and patients when selecting an appropriate treatment for ET.
Abstract
Commonly used for Parkinson’s disease (PD), deep brain stimulation (DBS) produces marked clinical benefits when optimized. However, assessing the large number of possible stimulation ...settings (i.e., programming) requires numerous clinic visits. Here, we examine whether functional magnetic resonance imaging (fMRI) can be used to predict optimal stimulation settings for individual patients. We analyze 3 T fMRI data prospectively acquired as part of an observational trial in 67 PD patients using optimal and non-optimal stimulation settings. Clinically optimal stimulation produces a characteristic fMRI brain response pattern marked by preferential engagement of the motor circuit. Then, we build a machine learning model predicting optimal vs. non-optimal settings using the fMRI patterns of 39 PD patients with a priori clinically optimized DBS (88% accuracy). The model predicts optimal stimulation settings in unseen datasets: a priori clinically optimized and stimulation-naïve PD patients. We propose that fMRI brain responses to DBS stimulation in PD patients could represent an objective biomarker of clinical response. Upon further validation with additional studies, these findings may open the door to functional imaging-assisted DBS programming.
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by prominent degeneration of dopaminergic neurons in the substantia nigra and aggregation of the protein ...alpha-synuclein within intraneuronal inclusions known as Lewy bodies. Ninety percent of PD cases are idiopathic while the remaining 10% are associated with gene mutations that affect cellular functions ranging from kinase activity to mitochondrial quality control, hinting at a multifactorial disease process. Mutations in LRRK2 and SNCA (the gene coding for alpha-synuclein) cause monogenic forms of autosomal dominant PD, and polymorphisms in either gene are also associated with increased risk of idiopathic PD. Although Lewy bodies are a defining neuropathological feature of PD, an appreciable subset of patients with LRRK2 mutations present with a clinical phenotype indistinguishable from idiopathic PD but lack Lewy pathology at autopsy, suggesting that LRRK2-mediated PD may occur independently of alpha-synuclein aggregation. Here, we examine whether LRRK2 and alpha-synuclein, as mediators of neurodegeneration in PD, exist in common or distinct pathways. Specifically, we review evidence from preclinical models and human neuropathological studies examining interactions between the two proteins. Elucidating the degree of interplay between LRRK2 and alpha-synuclein will be necessary for treatment stratification once effective targeted disease-modifying therapies are developed.
Ventral intermediate thalamic stimulation is effective in treating essential tremor and tremor-dominant Parkinson's disease, but its precise mechanism of action is unclear. Milosevic et al. show that ...thalamic inhibition of neuronal firing is necessary for tremor reduction, suggesting that the thalamus acts as a filter for uncoupling central and peripheral tremor networks.
Abstract
Ventral intermediate thalamic deep brain stimulation is a standard therapy for the treatment of medically refractory essential tremor and tremor-dominant Parkinson's disease. Despite the therapeutic benefits, the mechanisms of action are varied and complex, and the pathophysiology and genesis of tremor remain unsubstantiated. This intraoperative study investigated the effects of high frequency microstimulation on both neuronal firing and tremor suppression simultaneously. In each of nine essential tremor and two Parkinson's disease patients who underwent stereotactic neurosurgery, two closely spaced (600 µm) microelectrodes were advanced into the ventral intermediate nucleus. One microelectrode recorded action potential firing while the adjacent electrode delivered stimulation trains at 100 Hz and 200 Hz (2-5 s, 100 µA, 150 µs). A triaxial accelerometer was used to measure postural tremor of the contralateral hand. At 200 Hz, stimulation led to 68 ± 8% (P < 0.001) inhibition of neuronal firing and a 53 ± 5% (P < 0.001) reduction in tremor, while 100 Hz reduced firing by 26 ± 12% (not significant) with a 17 ± 6% (P < 0.05) tremor reduction. The degree of cell inhibition and tremor suppression were significantly correlated (P < 0.001). We also found that the most ventroposterior stimulation sites, closest to the border of the ventral caudal nucleus, had the best effect on tremor. Finally, prior to the inhibition of neuronal firing, microstimulation caused a transient driving of neuronal activity at stimulus onset (61% of sites), which gave rise to a tremor phase reset (73% of these sites). This was likely due to activation of the excitatory glutamatergic cortical and cerebellar afferents to the ventral intermediate nucleus. Temporal characteristics of the driving responses (duration, number of spikes, and onset latency) significantly differed between 100 Hz and 200 Hz stimulation trains. The subsequent inhibition of neuronal activity was likely due to synaptic fatigue. Thalamic neuronal inhibition seems necessary for tremor reduction and may function in effect as a thalamic filter to uncouple thalamo-cortical from cortico-spinal reflex loops. Additionally, our findings shed light on the gating properties of the ventral intermediate nucleus within the cerebello-thalamo-cortical tremor network, provide insight for the optimization of deep brain stimulation technologies, and may inform controlled clinical studies for assessing optimal target locations for the treatment of tremor.
The role of protein aggregates, such as Lewy body inclusions, in the molecular pathogenesis of Parkinson's disease has remained controversial and elusive. The protein α-synuclein is a major component ...of these inclusions but it can exist in many alternate conformations. Here we review advances in our understanding of the roles of Lewy pathology and α-synuclein in Parkinson's disease.
Recent work has demonstrated that certain α-synuclein conformations are directly toxic to neurons and may also propagate Lewy pathology within the nervous system. Investigation into clinicopathological correlates in rare genetic forms of Parkinson's disease has revealed that Lewy pathology is associated with nonmotor features but may not contribute to motor symptoms in Parkinson's disease.
These recent findings open up new avenues of investigation into the molecular pathogenesis of Parkinson's disease. Future work will need to identify the most toxic conformations of α-synuclein and define their relationship to Lewy pathology. This work will be necessary to be able to develop novel therapeutic strategies that target specific pathogenic forms of α-synuclein for disease modification in Parkinson's disease.
Deep Brain Stimulation (DBS) is an effective treatment extended broadly to many neurological and psychiatric disorders. Nevertheless, complications may arise during DBS procedures or following ...implantation due to implanted hardware. This may result in both minor and major adverse events that may necessitate hardware removal and/or compromise maximal therapeutic benefit for the patient.
To identify relevant literature on hardware-related complications from DBS procedures by performing a systematic review, and propose how to identify at-risk group and possible preventive approaches.
Of 4592 abstract screened, 96 articles fulfilled the selection criteria and were reviewed. Overall, the most common hardware-related complications were infections (5.12% of patients), followed by lead migration (1.60%), fracture or failure of the lead or other parts of the implant (1.46% and 0.73%, respectively), IPG malfunctions (1.06% of patients), and skin erosions without infections (0.48% of patients). New indications for DBS, including Tourette's syndrome, cluster headache, and refractory partial epilepsy, were found to bear a higher incidence of hardware-related infections than established indications such as Parkinson's disease. The highest rate of lead fracture or failure was found in dystonia patients (4.22%). Ultimately, the highest rate of pain at the implantation sites was found in refractory partial epilepsy patients (16.55%).
Our analysis identified a variety of potential hardware-related complications among patients who underwent DBS procedures. Patients who were at risk of complications, such as patients with dystonia and off-label indications (e.g. Tourette's syndrome) should be informed prior to surgery and closely followed thereafter.
•This review identified the potential hardware-related complications from DBS procedures.•New indications for DBS were found a higher incidence of infections than established indications.•Patients who are at risk of complications should be informed prior and closely followed thereafter.
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