tremor

Magnetic resonance true temperature imaging with high spatial and temporal resolution

ABSTRACT The knowledge of temperature and temperature distribution within the brain can be critical to understanding the healthy and diseased brain, its response to acute injury, and in monitoring critically important thermal interventions. There are several temperature sensitive properties such relaxation rates and the proton resonance frequency shift (PRFS) that can be measured with magnetic resonance imaging (MRI) methods but these methods can only measure temperature change. The PRFS method, which provides the most accurate measurement of temperature change can only measure true tissue temperature if the starting true temperature distribution is known. Fortunately, MR spectroscopy (MRS) methods have been developed that show great promise in the measurement of true temperature. These methods rely on the detection of a temperature independent spectral peak of protons bound to carbon atoms in high concentration metabolites, such as N- acetylaspartate (NAA), creatine (Cr) and choline (Cho) which can be used as a reference for the temperature dependent spectral peak of water protons. Both single voxel spectroscopy (SVS) methods and MRS imaging (MRSI) methods have been described but are slow because of the long readout time needed to achieve adequate spectral resolution and the need to perform multiple averages due to the low signal being measured. Echo-planar spectroscopic imaging (EPSI) speeds up MRSI by interleaving an oscillating imaging gradient to spatially encode one of the imaging dimensions simultaneously with spectral readout. Unfortunately, SVS, MRSI, and even EPSI are unsuitable for clinical applications because of the low spatial resolution (voxel size 1 cm3) and temporal resolution (multiple minutes). The goal of this project is to develop an MRI technique that can measure true temperature in the whole brain at spatial and temporal resolutions that enable clinical utility for acutely assessing and longitudinally monitoring healthy and diseased brain tissue, and real time monitoring of thermal interventional therapies. This innovative true temperature measurement technique combines EPSI, for low resolution background field measurements, with PRFS for high spatial and temporal resolution water proton measurements. While conventional EPSI methods interleave volumetric acquisitions with and without water suppression, we propose an innovative modification to take advantage of the very strong water signal to obtain a very high resolution, dynamic method for true temperature measurements. The MRI pulse sequence will be refined, validated (Aim 1), applied to healthy subjects and post-surgery patients at risk for infections (Aim 2), and applied to essential tremor (ET) patients during the required delay between repeated focused ultrasound sonications (Aim 3). Successful completion of the aims of this study will result in a clinically practical method to obtain true temperature measurements in the brain with a spatial and temporal resolution sufficiently high to meet the needs of monitoring focal thermal therapy treatments as well as to provide true temperature measurements over the entire brain for assessment of the state of the brain with disease, infection, and injury.

Targeting thalamic circuits rescues motor and mood deficits in PD mice

Although bradykinesia, tremor, and rigidity are hallmark motor defects in Parkinson’s disease (PD) patients, they also experience motor learning impairments and non-motor symptoms such as depression. The neural basis for these different PD symptoms are not well understood. While current treatments are effective for locomotion deficits in PD, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking. We found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN), and nucleus accumbens (NAc). While PF-->CPu and PF-->STN circuits are critical for locomotion and motor learning respectively, inhibition of the PF-->NAc circuit induced a depression-like state. While chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation at PF-->STN synapses restored motor learning behavior in PD model mice. Furthermore, activation of NAc-projecting PF neurons rescued depression-like PD phenotypes. Importantly, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

Elucidating the mechanism underlying Stress and Caffeine-induced motor dysfunction using a mouse model of Episodic Ataxia Type 2

Episodic Ataxia type 2 (EA2), caused by mutations in the CACNA1A gene, results in a loss-of-function of the P/Q type calcium channel, which leads to baseline ataxia, and attacks of dyskinesia, that can last a few hours to a few days. Attacks are brought on by consumption of caffeine, alcohol, and physical or emotional stress. Interestingly, caffeine and stress are common triggers among other episodic channelopathies, as well as causing tremor or shaking in otherwise healthy adults. The mechanism underlying stress and caffeine induced motor impairment remains poorly understood. Utilizing behavior, and in vivo and in vitro electrophysiology in the tottering mouse, a well characterized mouse model of EA2, or WT mice, we first sought to elucidate the mechanism underlying stress-induced motor impairment. We found stress induces attacks in EA2 though the activation of cerebellar alpha 1 adrenergic receptors by norepinephrine (NE) through casein kinase 2 (CK2) dependent phosphorylation. This decreases SK2 channel activity, causing increased Purkinje cell irregularity and motor impairment. Knocking down or blocking CK2 with an FDA approved drug CX-4945 prevented PC irregularity and stress-induced attacks. We next hypothesized caffeine, which has been shown to increase NE levels, could induce attacks through the same alpha 1 adrenergic mechanism in EA2. We found caffeine increases PC irregularity and induces attacks through the same CK2 pathway. Block of alpha 1 adrenergic receptors, however, failed to prevent caffeine-induced attacks. Caffeine instead induces attacks through the block of cerebellar A1 adenosine receptors. This increases the release of glutamate, which interacts with mGluR1 receptors on PC, resulting in erratic firing and motor attacks. Finally, we show a novel direct interaction between mGluR1 and CK2, and inhibition of mGluR1 prior to initiation of attack, prevents the caffeine-induced increase in phosphorylation. These data elucidate the mechanism underlying stress and caffeine-induced motor impairment. Furthermore, given the success of CX-4945 to prevent stress and caffeine induced attacks, it establishes ground-work for the development of therapeutics for the treatment of caffeine and stress induced attacks in EA2 patients and possibly other episodic channelopathies.

Translational upregulation of STXBP1 by non-coding RNAs as an innovative treatment for STXBP1 encephalopathy

Developmental and epileptic encephalopathies (DEEs) are a broad spectrum of genetic epilepsies associated with impaired neurological development as a direct consequence of a genetic mutation, in addition to the effect of the frequent epileptic activity on brain. Compelling genetic studies indicate that heterozygous de novo mutations represent the most common underlying genetic mechanism, in accordance with the sporadic presentation of DEE. De novo mutations may exert a loss-of-function (LOF) on the protein by decrementing expression level and/or activity, leading to functional haploinsufficiency. These diseases share several features: severe and frequent refractory seizures, diffusely abnormal background activity on EEG, intellectual disability often profound, and severe consequences on global development. One of major causes of early onset DEE are de novo heterozygous mutations in syntaxin-binding-protein-1 gene STXBP1, which encodes a membrane trafficking protein playing critical role in vesicular docking and fusion. LOF STXBP1 mutations lead to a failure of neurotransmitter secretion from synaptic vesicles. Core clinical features of STXBP1 encephalopathy include early-onset epilepsy with hypsarrhythmic EEG, or burst-suppression pattern, or multifocal epileptiform activity. Seizures are often resistant to standard treatments and patients typically show intellectual disability, mostly severe to profound. Additional neurologic features may include autistic traits, movement disorders (dyskinesia, dystonia, tremor), axial hypotonia, and ataxia, indicating a broader neurologic impairment. Patients with severe neuro-cognitive features but without epilepsy have been reported. Recently, a new class of natural and synthetic non-coding RNAs have been identified, enabling upregulation of protein translation in a gene-specific way (SINEUPs), without any increase in mRNA of the target gene. SINEUPs are translational activators composed by a Binding Domain (BD) that overlaps, in antisense orientation, to the sense protein-coding mRNA, and determines target selection; and an Effector Domain (ED), that is essential for protein synthesis up regulation. SINEUPs have been shown to restore the physiological expression of a protein in case of haploinsufficiency, without driving excessive overexpression out of the physiological range. This technology brings many advantages, as it mainly acts on endogenous target mRNAs produced in situ by the wild-type allele; this action is limited to mRNA under physiological regulation, therefore no off-site effects can be expected in cells and tissues that do not express the target transcript; by acting only on a posttranscriptional level, SINEUPs do not trigger hereditable genome editing. After bioinformatic analysis of the promoter region of interest, we designed SINEUPs with 3 different BD for STXBP1. Human neurons from iPSCs were treated and STXBP1 levels showed a 1.5-fold increase compared to the Negative control. RNA levels of STXBP1 after the administration of SINEUPs remained stable as expected. These preliminary results proved the SINEUPs potential to specifically increase the protein levels without impacting on the genome. This is an extremely flexible approach to target many developmental and epileptic encephalopathies caused by haploinsufficiency, and therefore to address these diseases in a more tailored and radical way.

Neurotoxicity is a major health problem in Africa: focus on Parkinson's / Parkinsonism

Parkinson's disease (PD) is the second most present neurodegenerative disease in the world after Alzheimer's. It is due to the progressive and irreversible loss of dopaminergic neurons of the substantia nigra Pars Compacta. Alpha synuclein deposits and the appearance of Lewi bodies are systematically associated with it. PD is characterized by four cardinal motor symptoms: bradykinesia / akinesia, rigidity, postural instability and tremors at rest. These symptoms appear when 80% of the dopaminergic endings disappear in the striatum. According to Braak's theory, non-motor symptoms appear much earlier and this is particularly the case with anxiety, depression, anhedonia, and sleep disturbances. In 90 to 95% of cases, the causes of the appearance of the disease remain unknown, but polluting toxic molecules are incriminated more and more. In Africa, neurodegenerative diseases of the Parkinson's type are increasingly present and a parallel seems to exist between the increase in cases and the presence of toxic and polluting products such as metals. My Web conference will focus on this aspect, i.e. present experimental arguments which reinforce the hypothesis of the incrimination of these pollutants in the incidence of Parkinson's disease and / or Parkinsonism. Among the lines of research that we have developed in my laboratory in Rabat, Morocco, I have chosen this one knowing that many of our PhD students and IBRO Alumni are working or trying to develop scientific research on neurotoxicity in correlation with pathologies of the brain.

Visual perception and fixational eye movements: microsaccades, drift and tremor

Objective and easily performed assessment of fine motor skills to support the differential diagnosis of Parkinson’s disease (PD) and other movement disorders with tremor

The Prevalence of Dystonic Tremor and Tremor Associated with Dystonia in Patients with Cervical Dystonia

Stimulation of GABA-Aα2/3, but not α1, receptors inhibits essential and parkinsonian-like tremors in rats

Comparing stimulation and lesioning in a network model of essential tremor: Mechanisms and treatment

FENS Forum 2024

Neuroprotective and antioxidant effects of oxotremorine‑M, a non‑selective muscarinic acetylcholine receptors agonist, in a cellular model of Alzheimer disease

FENS Forum 2024

Postmortem cerebellar volume is not reduced in essential tremor: A comparison with multiple system atrophy and controls

FENS Forum 2024

Targeting cerebellar, alpha6-containing GABA-A receptors with novel compounds based on computational pharmacophore screening as potential therapy for essential tremor

FENS Forum 2024