scholarly journals Spectral Signatures of L-DOPA-Induced Dyskinesia Depend on L-DOPA Dose and are Suppressed by Ketamine

2020 ◽  
Author(s):  
Tony Ye ◽  
Mitchell J. Bartlett ◽  
Scott J. Sherman ◽  
Torsten Falk ◽  
Stephen L. Cowen
Keyword(s):  
Replacement Therapy ◽  
Low Dose ◽  
Field Potential ◽  
Gamma Activity ◽  
High Dose ◽  
Therapeutic Effects ◽  
Neural Synchrony ◽  
Spectral Signatures ◽  
Dopamine Replacement Therapy ◽  
High Gamma

AbstractL-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson’s disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub - anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks - long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 hours. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine’s therapeutic effects are region specific. Our findings also have clinical implications as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

scholarly journals Home treatment with intravenous enzyme replacement therapy for Gaucher disease: an international collaborative study of 33 patients

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1107-1109 ◽  
Author(s):  
A Zimran ◽  
CE Hollak ◽  
A Abrahamov ◽  
MH van Oers ◽  
M Kelly ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
High Frequency ◽  
Gaucher Disease ◽  
Low Dose ◽  
Collaborative Study ◽  
Stable Condition ◽  
Home Treatment ◽  
High Dose ◽  
Enzyme Replacement

Intravenous enzyme replacement therapy (Alglucerase; Ceredase; Genzyme Corp, Boston, MA) is an effective and safe treatment for patients with type 1 Gaucher disease. In an attempt to reduce its high cost, a “low- dose high-frequency” protocol (30 U/kg/mo, 3 times a week) was introduced and found to be as effective as the original high-dose protocol (60 U/kg every 2 weeks). Because receiving frequent infusions creates a burden for many patients, we have implemented a program of home treatment for our patients. We now report the safety and feasibility of low-dose/high-frequency home intravenous enzyme- replacement therapy in 33 patients with Gaucher disease. The chronic nature of the treatment, its safety, lack of adverse effects, the stable condition of most patients, and the need to reduce the high cost make enzyme replacement for Gaucher disease a good candidate for intravenous home therapy.

scholarly journals Differentiation of speech-induced artifacts from physiological high gamma activity in intracranial recordings

2021 ◽  
Author(s):  
Alan Bush ◽  
Anna Chrabaszcz ◽  
Victoria Peterson ◽  
Varun Saravanan ◽  
Christina Dastolfo-Hromack ◽  
...  
Keyword(s):  
Speech Production ◽  
Field Potential ◽  
Vibration Sensor ◽  
Gamma Activity ◽  
Time Frequency ◽  
Related Data ◽  
Syllable Repetition ◽  
Stereotactic Frame ◽  
High Gamma ◽  
Intracranial Recordings

AbstractThere is great interest in identifying the neurophysiological underpinnings of speech production. Deep brain stimulation (DBS) surgery is unique in that it allows intracranial recordings from both cortical and subcortical regions in patients who are awake and speaking. The quality of these recordings, however, may be affected to various degrees by mechanical forces resulting from speech itself. Here we describe the presence of speech-induced artifacts in local-field potential (LFP) recordings obtained from mapping electrodes, DBS leads, and cortical electrodes. In addition to expected physiological increases in high gamma (60-200 Hz) activity during speech production, time-frequency analysis in many channels revealed a narrowband gamma component that exhibited a pattern similar to that observed in the speech audio spectrogram. This component was present to different degrees in multiple types of neural recordings. We show that this component tracks the fundamental frequency of the participant’s voice, correlates with the power spectrum of speech and has coherence with the produced speech audio. A vibration sensor attached to the stereotactic frame recorded speech-induced vibrations with the same pattern observed in the LFPs. No corresponding component was identified in any neural channel during the listening epoch of a syllable repetition task. These observations demonstrate how speech-induced vibrations can create artifacts in the primary frequency band of interest. Identifying and accounting for these artifacts is crucial for establishing the validity and reproducibility of speech-related data obtained from intracranial recordings during DBS surgery.

scholarly journals Subthalamic nucleus and sensorimotor cortex activity during speech production

2018 ◽  
Author(s):  
A Chrabaszcz ◽  
WJ Neumann ◽  
O Stretcu ◽  
WJ Lipski ◽  
A Bush ◽  
...  
Keyword(s):  
Deep Brain Stimulation ◽  
Speech Production ◽  
Subthalamic Nucleus ◽  
Sensorimotor Cortex ◽  
Vocal Tract ◽  
Field Potential ◽  
Gamma Activity ◽  
High Gamma ◽  
Gamma Power ◽  
Deep Brain

ABSTRACTThe sensorimotor cortex is somatotopically organized to represent the vocal tract articulators, such as lips, tongue, larynx, and jaw. How speech and articulatory features are encoded at the subcortical level, however, remains largely unknown. We analyzed local field potential (LFP) recordings from the subthalamic nucleus (STN) and simultaneous electrocorticography recordings from the sensorimotor cortex of 11 patients (1 female) with Parkinson’s disease during implantation of deep brain stimulation (DBS) electrodes, while patients read aloud three-phoneme words. The initial phonemes involved either articulation primarily with the tongue (coronal consonants) or the lips (labial consonants). We observed significant increases in high gamma (60–150 Hz) power in both the STN and the sensorimotor cortex that began before speech onset and persisted for the duration of speech articulation. As expected from previous reports, in the sensorimotor cortex, the primary articulator involved in the production of the initial consonant was topographically represented by high gamma activity. We found that STN high gamma activity also demonstrated specificity for the primary articulator, although no clear topography was observed. In general, subthalamic high gamma activity varied along the ventral-dorsal trajectory of the electrodes, with greater high gamma power recorded in the more dorsal locations of the STN. These results demonstrate that articulator-specific speech information is contained within high gamma activity of the STN, with similar temporal but less specific topographical organization, compared to similar information encoded in the sensorimotor cortex.SIGNIFICANCE STATEMENTClinical and electrophysiological evidence suggests that the subthalamic nucleus is involved in speech, however, this important basal ganglia node is ignored in current models of speech production. We previously showed that subthalamic nucleus neurons differentially encode early and late aspects of speech production, but no previous studies have examined subthalamic functional organization for speech articulators. Using simultaneous local field potential recordings from the sensorimotor cortex and the subthalamic nucleus in patients with Parkinson’s disease undergoing deep brain stimulation surgery, we discovered that subthalamic nucleus high gamma activity tracks speech production at the level of vocal tract articulators, with high gamma power beginning to increase prior to the onset of vocalization, similar to cortical articulatory encoding.

scholarly journals Afferent inputs to cortical fast-spiking interneurons organize pyramidal cell network oscillations at high-gamma frequencies (60–200 Hz)

2014 ◽  
Vol 112 (11) ◽  
pp. 3001-3011 ◽  
Author(s):  
Piotr Suffczynski ◽  
Nathan E. Crone ◽  
Piotr J. Franaszczuk
Keyword(s):  
Local Field ◽  
Local Field Potential ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Gamma Oscillations ◽  
Cortical Activation ◽  
Gamma Activity ◽  
High Gamma ◽  
Fast Spiking ◽  
Gamma Frequencies

High-gamma activity, ranging in frequency between ∼60 Hz and 200 Hz, has been observed in local field potential, electrocorticography, EEG and magnetoencephalography signals during cortical activation, in a variety of functional brain systems. The origin of these signals is yet unknown. Using computational modeling, we show that a cortical network model receiving thalamic input generates high-gamma responses comparable to those observed in local field potential recorded in monkey somatosensory cortex during vibrotactile stimulation. These high-gamma oscillations appear to be mediated mostly by an excited population of inhibitory fast-spiking interneurons firing at high-gamma frequencies and pacing excitatory regular-spiking pyramidal cells, which fire at lower rates but in phase with the population rhythm. The physiological correlates of high-gamma activity, in this model of local cortical circuits, appear to be similar to those proposed for hippocampal ripples generated by subsets of interneurons that regulate the discharge of principal cells.

scholarly journals 578 CD8-targeted IL-2 drives potent anti-tumor efficacy and promotes action of tumor specific vaccines

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A607-A607
Author(s):  
Hussein Sultan ◽  
Kelly Moynihan ◽  
Yuang Song ◽  
Samuel Ameh ◽  
Ton Schumacher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Low Dose ◽  
Body Weight Loss ◽  
Tumor Rejection ◽  
High Dose ◽  
Therapeutic Effects ◽  
Toxicity Profile ◽  
Tumor Bearing

BackgroundIL-2 and currently available engineered variants are of interest for solid tumor treatment, but their efficacy and toxicity profiles remain suboptimal. These results reflect the pleiotropic signaling via IL-2 receptors on different cell types that may simultaneously drive desired and undesired responses. We hypothesized that restricting IL-2’s activity to CD8+ T cells would improve efficacy while also lowering its toxicity profile.MethodsWe developed a cis-targeted IL-2 that selectively acts on CD8+ T cells (CD8-IL2) and assessed its activity using the T3 progressor MCA sarcoma model, which was selected because (a) it is sensitive to anti-PD-1 therapy when tumors are small but develops insensitivity as tumor size increase, (b) rejection requires both CD4+ and CD8+ T cells and (c) rejection is dependent on tumor expression of two neoantigens: mItgb1 (MHC-II) and mLama4 (MHC-I).ResultsWhereas mice bearing 8-day T3 tumors had become insensitive to anti-PD-1 mediated tumor rejection, 90% of mice treated with single dose CD8-IL2 monotherapy rejected their tumors, while high dose IL-2 produced minimal efficacy. Efficacy occurred without body weight loss. These results suggest that CD8-IL2 can induce therapeutic effects at a time when tumors became insensitive to anti-PD-1. To assess this possibility in a more controlled manner, we used a tumor neoantigen vaccine model that depends on CD4+ T cell help for development of functional CD8+ T cells at both the priming stage in the lymph node as well as the effector stage at the tumor site. Mice bearing T3 tumors were vaccinated with a synthetic long peptide (SLP) containing the mLama4 neoepitope and either a high or low dose of an SLP containing the mItgb1 neoepitope. Whereas 85% of tumor bearing mice that received the vaccine containing mLama4 plus low dose mItgb1 SLP rejected their tumors, surprisingly none of the mice receiving high dose mItgb1 underwent tumor rejection. This high dose inhibition was reversed when CD8-IL2 was administered after high dose vaccination and at concentrations that had only modest activity in tumor bearing, non-vaccinated mice. With CD8-IL2 treatment, antigen specific T cells were expanded and displayed increased expression of activation-associated markers and reduced expression of exhaustion-associated markers.ConclusionsCD8-IL2 outperformed other forms of engineered IL-2 in anti-tumor efficacy, showed a significantly improved toxicity profile, and rescued deficient CD8 T cell responses resulting from poor CD4 help. In sum, we demonstrate high level antitumor efficacy and tolerability with a new form of targeted IL-2.Ethics ApprovalMice used in this study were between 8 and 12 weeks of age and were maintained in accordance with procedures approved by the Association for Assessment and Accreditation of Laboratory Animal Care and Accredited Animal Studies Committee of Washington University in St. Louis

scholarly journals “γδT Cell-IL17A-Neutrophil” Axis Drives Immunosuppression and Confers Breast Cancer Resistance to High-Dose Anti-VEGFR2 Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhigang Zhang ◽  
Chenghui Yang ◽  
Lili Li ◽  
Ying Zhu ◽  
Ke Su ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Low Dose ◽  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Γδ T Cells ◽  
High Dose ◽  
Therapeutic Effects ◽  
Cancer Resistance ◽  
Breast Cancer Patients

Angiogenesis is an essential physiological process and hallmark of cancer. Currently, antiangiogenic therapy, mostly targeting the vascular endothelial growth factor (VEGF)/VEGFR2 signaling axis, is commonly used in the clinic for solid tumors. However, antiangiogenic therapies for breast cancer patients have produced limited survival benefits since cancer cells rapidly resistant to anti-VEGFR2 therapy. We applied the low-dose and high-dose VEGFR2 mAb or VEGFR2-tyrosine kinase inhibitor (TKI) agents in multiple breast cancer mouse models and found that low-dose VEGFR2 mAb or VEGFR2-TKI achieved good effects in controlling cancer progression, while high-dose treatment was not effective. To further investigate the mechanism involved in regulating the drug resistance, we found that high-dose anti-VEGFR2 treatment elicited IL17A expression in γδ T cells via VEGFR1-PI3K-AKT pathway activation and then promoted N2-like neutrophil polarization, thus inducing CD8+ T cell exhaustion to shape an immunosuppressive microenvironment. Combining anti-VEGFR2 therapy with immunotherapy such as IL17A, PD-1 or Ly-6G mAb therapy, which targeting the immunomodulatory axis of “γδT17 cells-N2 neutrophils” in vivo, showed promising therapeutic effects in breast cancer treatment. This study illustrates the potential mechanism of antiangiogenic therapy resistance in breast cancer and provides synergy treatment for cancer.

scholarly journals Protective Effects of Ophiocordyceps lanpingensis on Glycerol-Induced Acute Renal Failure in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Yanyan Zhang ◽  
Yaxi Du ◽  
Hong Yu ◽  
Yongchun Zhou ◽  
Feng Ge
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Low Dose ◽  
Treated Group ◽  
High Dose ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Immune Organ

Objective. Oxidative stress and immune response are associated with acute renal failure (ARF). Ophiocordyceps lanpingensis (OL) might be an antioxidant and immunopotentiator. In this study, we explored the protective effects of OL on glycerol-induced ARF. Methods. Male mice were randomly divided into four groups, specifically, glycerol-induced ARF model group, low-dose OL-treated group (1.0 g/kg/d), high-dose OL-treated group (2.0 g/kg/d), and control group. Renal conditions were evaluated using kidney index, serum creatinine (Cr), blood urea nitrogen (BUN), and histological analysis. Rhabdomyolysis was monitored using creatine kinase (CK) level. Oxidative stress was determined using kidney tissue glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. Immune status was evaluated using immune organ indices and immunoglobulin G (IgG) level. Results. OL could relieve renal pathological injury and decrease the abnormal levels of kidney index, serum Cr, CK, BUN, and MDA, as well as increase the immune organ indices and the levels of IgG, GSH, and SOD. Treatment with a high dose of OL had more positive therapeutic effects on ARF than using a low dose of OL. Conclusion. OL could ameliorate renal dysfunction in glycerol-induced ARF in mice by inhibiting oxidative stress and enhancing immune response.

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