Deep brain stimulation for essential tremor versus essential tremor plus: should we target the same spot in the thalamus?

BackgroundAlthough ET is a phenomenologically heterogeneous condition, thalamic DBS appears to be equally effective across subtypes. We hypothesized stimulation sites optimized for individuals with essential tremor (ET) would differ from individuals with essential tremor plus syndrome (ET-plus). We examined group differences in optimal stimulation sites within the ventral thalamus and their overlap of with relevant white matter tracts. By capturing these differences, we sought to determine whether ET subtypes are associated with anatomically distinct neural pathways.MethodsA retrospective chart review was conducted on ET patients undergoing VIM DBS at MUSC between 01/2012 and 02/2022. Clinical, demographic, neuroimaging, and DBS stimulation parameter data were collected. Clinical characteristics and pre-DBS videos were reviewed to classify ET and ET-plus cohorts. Patients in ET-plus cohorts were further divided into ET with dystonia, ET with ataxia, and ET with others. DBS leads were reconstructed using Lead-DBS1 and the volume of tissue activated (VTA) overlap was performed using normative connectomes. Tremor improvement was measured by reduction in a subscore of tremor rating scale (TRS) post-DBS lateralized to the more affected limb.ResultsSixty-eight ET patients were enrolled after initial screening, of these 10 ET and 24 ET-plus patients were included in the final analyses. ET group had an earlier age at onset (p = 0.185) and underwent surgery at a younger age (p = 0.096). Both groups achieved effective tremor control. No significant differences were found in lead placement or VTA overlap within ventral thalamus. The VTA center of gravity (COG) in the ET-plus cohort was located dorsal to that of the ET cohort. No significant differences were found in VTA overlap with the dentato-rubral-thalamic (DRTT) tracts or the ansa lenticularis. Dystonia was more prevalent than ataxia in the ET-plus subgroups (n = 18 and n = 5, respectively). ET-plus with dystonia subgroup had a more medial COG compared to ET-plus with ataxia.ConclusionVIM DBS therapy is efficacious in patients with ET and ET-plus. There were no significant differences in optimal stimulation site or VTA overlap with white-matter tracts between ET, ET-plus and ET-plus subgroups

Bilateral deep transcranial magnetic stimulation of motor and prefrontal cortices in Parkinson’s disease: a comprehensive review

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by both motor and non-motor symptoms, many of which are resistant to currently available treatments. Since the discovery that non-invasive transcranial magnetic stimulation (TMS) can cause dopamine release in PD patients, there has been growing interest in the use of TMS to fill existing gaps in the treatment continuum for PD. This review evaluates the safety and efficacy of a unique multifocal, bilateral Deep TMS protocol, which has been evaluated as a tool to address motor and non-motor symptoms of PD. Six published clinical trials have delivered a two-stage TMS protocol with an H-Coil targeting both the prefrontal cortex (PFC) and motor cortex (M1) bilaterally (220 PD patients in total; 108 from two randomized, sham-controlled studies; 112 from open label or registry studies). In all studies TMS was delivered to M1 bilaterally (Stage 1) and then to the PFC bilaterally (Stage 2) with approximately 900 pulses per stage. For Stage 1 (M1), two studies delivered 10 Hz at 90% motor threshold (MT) while four studies delivered 1 Hz at 110% MT. For Stage 2 (PFC), all studies delivered 10 Hz at 100% MT. The results suggest that this two-stage Deep TMS protocol is a safe, moderately effective treatment for motor symptoms of PD, and that severely impaired patients have the highest benefits. Deep TMS also improves mood symptoms and cognitive function in these patients. Further research is needed to establish optimal dosing and the long-term durability of treatment effects

Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors

Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined how expression of a mutant GluN1 subunit (F639A) that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl) significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; IP) increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg) reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg). In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg) as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol. © 2013 den Hartog et al

Data_Sheet_1_Bilateral deep transcranial magnetic stimulation of motor and prefrontal cortices in Parkinson’s disease: a comprehensive review.DOCX

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by both motor and non-motor symptoms, many of which are resistant to currently available treatments. Since the discovery that non-invasive transcranial magnetic stimulation (TMS) can cause dopamine release in PD patients, there has been growing interest in the use of TMS to fill existing gaps in the treatment continuum for PD. This review evaluates the safety and efficacy of a unique multifocal, bilateral Deep TMS protocol, which has been evaluated as a tool to address motor and non-motor symptoms of PD. Six published clinical trials have delivered a two-stage TMS protocol with an H-Coil targeting both the prefrontal cortex (PFC) and motor cortex (M1) bilaterally (220 PD patients in total; 108 from two randomized, sham-controlled studies; 112 from open label or registry studies). In all studies TMS was delivered to M1 bilaterally (Stage 1) and then to the PFC bilaterally (Stage 2) with approximately 900 pulses per stage. For Stage 1 (M1), two studies delivered 10 Hz at 90% motor threshold (MT) while four studies delivered 1 Hz at 110% MT. For Stage 2 (PFC), all studies delivered 10 Hz at 100% MT. The results suggest that this two-stage Deep TMS protocol is a safe, moderately effective treatment for motor symptoms of PD, and that severely impaired patients have the highest benefits. Deep TMS also improves mood symptoms and cognitive function in these patients. Further research is needed to establish optimal dosing and the long-term durability of treatment effects.</p

Individualized anodal transcranial direct current stimulation increases corticospinal excitability in children with hemiparesis due to early stroke: transcranial magnetic stimulation assessment data

**This dataset contains 19 individuals (N01-N21, excl N10 and N18) with stroke and hemiparesis, age 7-22. Data are stored in Matlab data structures, which contain a table and two sub-structures: 1. BasicInfo (table): demographics, group assignment 2. LesionedHemisphere (sub-structure): MEP data for lesioned hemisphere single-pulse TMS 3. NonlesionedHemispehre (sub-structure): MEP data for non-lesioned hemisphere single-pulse TMS The data in the two sub-structures contain Matlab 6 tables, one for each time point: 1. Pre (i.e. Baseline) 2. Post0 (0 minutes after tDCS) 3. Post15 (15 minutes after tDCS) 4. Post30 (30 minutes after tDCS) 5. Post45 (45 minutes after tDCS) 6. Post60 (60 minutes after tDCS) These tables contain a 20x24 array. Each row is an individual trial, each column is defined as follows: Left hand muscle (Channel 1) Column 1: Valid trial 1=yes, 0=no Column 2: MEP amplitude (uV) Column 3: MEP latency (ms) Column 4: MEP AUC Column 5: MEP number of peaks Column 6: MEP duration (ms) Columns 7-12: same as 1-6 for Right Hand muscle (Channel 2) Columns 12-18: same as 1-6 for Left Wrist muscle (Channel 3) Columns 19-24: same as 1-6 for Right Wrist muscle (Channel 4) **For all data in Matlab tables, use the command table2array to convert the table to a numeric matrix.National Center for Neuromodulation for Rehabilitation (NC NM4R) and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (P2CHD086844 andHD078484-01A1), the University of Minnesota Foundation and University of Minnesota Medical School, the University of Minnesota Center for Magnetic Resonance Research (P41 EB027061, P30 NS076408, 1S10OD017974-01

Image_1_Multi-session transcutaneous auricular vagus nerve stimulation for Parkinson's disease: evaluating feasibility, safety, and preliminary efficacy.JPEG

BackgroundIn pre-clinical animal models of Parkinson's disease (PD), vagus nerve stimulation (VNS) can rescue motor deficits and protect susceptible neuronal populations. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive alternative to traditional invasive cervical VNS. This is the first report summarizing the safety, feasibility, and preliminary efficacy of repeated sessions of taVNS in participants with PD.ObjectivesTo evaluate the feasibility, safety, and possible efficacy of taVNS for motor and non-motor symptoms in mild to moderate PD.MethodsThis is a double-blind, sham controlled RCT (NCT04157621) of taVNS in 30 subjects with mild to moderate PD without cognitive impairment. Participants received 10, 1-h taVNS sessions (25 Hz, 200% of sensory threshold, 500 μs pulse width, 60 s on and 30 s off) over a 2-week period. Primary outcome measures were feasibility and safety of the intervention; secondary outcomes included the MDS-UPDRS, cognitive function and self-reported symptom improvement.ResultstaVNS treatment was feasible, however, daily in-office visits were reported as being burdensome for participants. While five participants in the taVNS group and three in the sham group self-reported one or more minor adverse events, no major adverse events occurred. There were no group differences on blood pressure and heart rate throughout the intervention. There were no group differences in MDS-UPDRS scores or self-reported measures. Although global cognitive scores remained stable across groups, there was a reduction in verbal fluency within the taVNS group.ConclusionstaVNS was safe, and well-tolerated in PD participants. Future studies of taVNS for PD should explore at-home stimulation devices and optimize stimulation parameters to reduce variability and maximize engagement of neural targets.</p

Targeted point mutation (F639A) in the GluN1 subunit decreases ethanol sensitivity of NMDA receptors.

<p>(<i>A</i>), Top: Schematic of GluN1 protein with transmembrane domains (<i>solid bars</i>) and corresponding exons. Bottom: Gene construct used to generate the F639A mice. F(A) is site of mutation within exon 16. NEO cassette flanked by <i>loxp</i> sites is between exons 18 and 19. (<i>B</i>), Percent of wild-type (F/F), heterozygous (F/A), and homozygous (A/A) F639A mice alive at embryonic day 18 or post-natal day 21. Symbol: (<b>*</b>) no surviving mice. (<i>C</i>), Top panel: Sample traces from 14-day old primary hippocampal cultures during (<i>black bar</i>) application of 50 µM NMDA/10 µM glycine. Scale bars: y-axis, 2000 pA; x-axis, 2.5 ms. Bottom panel: Mean amplitude of NMDA evoked currents in cultures from wild-type (F/F, n = 14), heterozygous (F/A, n = 21) and homozygous (A/A, n = 12) F639A mice. (<i>D</i>), Ethanol inhibition from 14-day old primary hippocampal cultures. Percent inhibition of steady state current by 100 mM ethanol from wild-type (F/F, n = 10), heterozygous (F/A, n = 12) and homozygous (A/A, n = 7) F639A mice. Symbol (<b>*</b>): value significantly different from wild-type (<b>*</b><i>p</i><0.05; one-way ANOVA, Dunnett's <i>post hoc</i> test). (<i>E</i>), Ethanol inhibition of recombinant wild-type and mutant NMDA receptors expressed in HEK293 cells. Data represent percent inhibition by 100 mM ethanol in cells expressing GluN1 or GluN1(F639A) with either GluN2A (F/F, n = 5; F/A, n = 14; A/A, n = 10) or GluN2B subunits (F/F, n = 6; F/A, n = 8; A/A, n = 9). Symbols: (<b>*</b>) significantly different from wild-type (<b><i>*</i></b><i> p</i><0.05, <b><i>**</i></b><i> p</i><0.01, <b><i>***</i></b><i> p</i><0.001; one-way ANOVA, Bonferroni's <i>post hoc</i> test); (<b>#</b>) significantly different from F639A Het (<b>##</b><i>p</i><0.01, <b>###</b><i>p</i><0.001; one-way ANOVA, Bonferroni's <i>post hoc</i> test).</p