scholarly journals A Critical Review of Cranial Electrotherapy Stimulation for Neuromodulation in Clinical and Non-clinical Samples

2021 ◽  
Vol 15 ◽  
Author(s):  
Tad T. Brunyé ◽  
Joseph E. Patterson ◽  
Thomas Wooten ◽  
Erika K. Hussey
Keyword(s):  
Nervous System ◽  
Critical Review ◽  
Human Performance ◽  
Conflicts Of Interest ◽  
Electrical Current ◽  
Clinical Samples ◽  
Cognitive Responses ◽  
Occupational Training ◽  
Cranial Electrotherapy Stimulation ◽  
Reliability And Robustness

Cranial electrotherapy stimulation (CES) is a neuromodulation tool used for treating several clinical disorders, including insomnia, anxiety, and depression. More recently, a limited number of studies have examined CES for altering affect, physiology, and behavior in healthy, non-clinical samples. The physiological, neurochemical, and metabolic mechanisms underlying CES effects are currently unknown. Computational modeling suggests that electrical current administered with CES at the earlobes can reach cortical and subcortical regions at very low intensities associated with subthreshold neuromodulatory effects, and studies using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) show some effects on alpha band EEG activity, and modulation of the default mode network during CES administration. One theory suggests that CES modulates brain stem (e.g., medulla), limbic (e.g., thalamus, amygdala), and cortical (e.g., prefrontal cortex) regions and increases relative parasympathetic to sympathetic drive in the autonomic nervous system. There is no direct evidence supporting this theory, but one of its assumptions is that CES may induce its effects by stimulating afferent projections of the vagus nerve, which provides parasympathetic signals to the cardiorespiratory and digestive systems. In our critical review of studies using CES in clinical and non-clinical populations, we found severe methodological concerns, including potential conflicts of interest, risk of methodological and analytic biases, issues with sham credibility, lack of blinding, and a severe heterogeneity of CES parameters selected and employed across scientists, laboratories, institutions, and studies. These limitations make it difficult to derive consistent or compelling insights from the extant literature, tempering enthusiasm for CES and its potential to alter nervous system activity or behavior in meaningful or reliable ways. The lack of compelling evidence also motivates well-designed and relatively high-powered experiments to assess how CES might modulate the physiological, affective, and cognitive responses to stress. Establishing reliable empirical links between CES administration and human performance is critical for supporting its prospective use during occupational training, operations, or recovery, ensuring reliability and robustness of effects, characterizing if, when, and in whom such effects might arise, and ensuring that any benefits of CES outweigh the risks of adverse events.

Neurobiology of parasitic platyhelminths: possible solutions to the problems of correlating structure with function

Parasitology ◽  
1991 ◽  
Vol 102 (S1) ◽  
pp. S31-S39 ◽  
Author(s):  
R. A. Pax ◽  
J. L. Bennett
Keyword(s):  
Nervous System ◽  
Patch Clamp ◽  
Recent Work ◽  
Small Molecule ◽  
Critical Review ◽  
Patch Clamp Recording ◽  
Quantitative Fluorescence ◽  
Recording Techniques

This paper provides an overview of research on the nervous system of parasitic platyhelminths. We have emphasized studies concerned with the physiological, pharmacological and biochemical nature of the major small molecule neurotransmitters of these parasites. We have attempted to provide a critical review of the work by focusing on important unresolved issues. Finally, we have focused on some recent work in our laboratory, using patch-clamp recording techniques and quantitative fluorescence cytometry, as an example of newer methods that will hopefully resolve some of the unanswered questions concerning the nervous system of these parasites.

scholarly journals Contribution of Baroreceptor Function to Pain Perception and Perioperative Outcomes

2019 ◽  
Vol 130 (4) ◽  
pp. 634-650 ◽  
Author(s):  
Heberto Suarez-Roca ◽  
Rebecca Y. Klinger ◽  
Mihai V. Podgoreanu ◽  
Ru-Rong Ji ◽  
Martin I. Sigurdsson ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Pain Perception ◽  
Perioperative Outcomes ◽  
Cognitive Responses ◽  
Baroreceptor Function ◽  
Arterial Blood ◽  
Baroreceptor Reflexes ◽  
The Central Nervous System ◽  
Physiologic Responses

Abstract Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain homeostasis by coordinating physiologic responses to external and internal stimuli. While it is recognized that carotid and cardiopulmonary baroreceptor reflexes modulate autonomic output to mitigate excessive fluctuations in arterial blood pressure and to maintain intravascular volume, increasing evidence suggests that baroreflex pathways also project to key regions of the central nervous system that regulate somatosensory, somatomotor, and central nervous system arousal. In addition to maintaining autonomic homeostasis, baroreceptor activity modulates the perception of pain, as well as neuroimmune, neuroendocrine, and cognitive responses to physical and psychologic stressors. This review summarizes the role that baroreceptor pathways play in modulating acute and chronic pain perception. The contribution of baroreceptor function to postoperative outcomes is also presented. Finally, methods that enhance baroreceptor function, which hold promise in improving postoperative and pain management outcomes, are presented.

Platelet Delta Granule and Serotonin Concentrations Are Decreased in Patients with Postural Orthostatic Tachycardia Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2419-2419
Author(s):  
Lisa Rinker ◽  
Nicole Zadzilka ◽  
Mohammad K Kanjwal ◽  
Beverly Karabin ◽  
Kathryn Boehm ◽  
...  
Keyword(s):  
Nervous System ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Conflicts Of Interest ◽  
Orthostatic Intolerance ◽  
Postural Orthostatic Tachycardia Syndrome ◽  
Serotonin Level ◽  
Control Subjects ◽  
Storage Pool ◽  
Significant Difference ◽  
The Mean

Abstract Abstract 2419 Poster Board II-396 Syncope is generally defined as a state of temporary, partial or complete, loss of consciousness (fainting) with spontaneous recovery. The basis for the phenomenon is complex and includes a variety of orthostatic intolerance conditions including neurocardiogenic syncope (NCS), postural orthostatic tachycardia syndrome (POTS), and other disorders affecting the autonomic nervous system. NCS patients and POTS patients can be differentiated with an upright tilt test because either bradycardia or tachycardia will occur with hypotension, respectively. Both are induced by the inability to maintain adequate systemic blood pressure. Though the two primary types of syncope are different in origin, both conditions are treated similarly. Recent reports suggest that syncope is a low serotonin (5HT) disorder and selective serotonin reuptake inhibitors (SSRIs) are a commonly prescribed treatment for both NCS and POTS patients. The major storage pool of serotonin, independent of the central nervous system, is contained in platelet dense granules (DG). Peripheral serotonin aids in vasoconstriction and blood clotting. Individuals prone to syncope may be deficient in serotonin. Insufficient peripheral serotonin may create conditions that lead to hypotension and excessive bleeding in an individual. We previously reported that patients having episodes of syncope (Blood, 112(11):451, 2008) had statistically significant decreases of DG/PL, consistent with DG storage pool deficiency (δSPD), and PL 5HT concentrations when compared to control subjects. Our test subjects were screened by questionnaire to determine syncope and distinction between NCS and POTS was not considered. These patients had an average of 3.08 ± 0.52 DG/PL and a mean 5HT concentration of 248.40 ± 37.94 ng/109 PL (PL 5HT normal range = 215-850 ng/109 PL). Control subjects (n=24) had an average of 4.22 ± 0.12 DG/PL and a 5HT concentration of 666.54 ± 56.25; both values having a significant difference (p=.003 and p<.001) by a Mann-Whitney Rank Order test respectively. We now report the DG/PL and 5-HT values obtained exclusively from patients diagnosed with POTS by tilt-table assessment and compared with control subjects. Patients for this study were obtained from our cardiology clinic and all were positive for POTS; they were not currently taking or were recently prescribed a SSRI for therapeutic management of their condition. Control subjects did not have syncope or history of bleeding. Peripheral blood was collected and PLs obtained via centrifugation to determine the mean DG/PL by electron microscopy and the mean 5HT concentration extracted from PLs using an ELISA technique. POTS patients (n=14) had a mean serotonin level of 326.6 ± 76.7 ng/109 PL compared to 589.6 ± 56.3 ng/109PL (p<0.004) for control subjects (n=21). POTS patients exhibited a mean of 2.6 ± 0.31 DG/PL compared to the control subject value of 4.16 ± 0.09 DG/PL (p<0.001). To date there is no significant difference in the number of PL DG or 5HT levels POTS patients compared to our previous evaluation of undefined syncope patients. These results support the hypothesis that syncope (NCS and POTS) may be the result of low peripheral serotonin levels. Our preliminary data demonstrates that POTS patients have low serotonin levels and δSPD when compared to control subjects. This study is ongoing to increase the total number of POTS patients enrolled as well as to recruit subjects diagnosed with NCS to determine whether a difference in DG and/or 5HT exists to explain either bradycardia or tachycardia as an early symptom in the development of hypotension. Disclosures: No relevant conflicts of interest to declare.

Loss of PERK Signaling Results in Impaired Granulopoiesis in Transgenic Mice Expressing Mutant Ela2.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 551-551
Author(s):  
Suparna Nanua ◽  
Jun Xia ◽  
Mark Murakami ◽  
Jill Woloszynek ◽  
Daniel C. Link
Keyword(s):  
Er Stress ◽  
Protein Misfolding ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Clinical Samples ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Granulocytic Differentiation ◽  
Disease Pathogenesis ◽  
Chemical Inducers

Abstract Abstract 551 Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis characterized by chronic neutropenia, a block in granulocytic differentiation at the promyelocyte/myelocyte stage, and a marked propensity to develop acute myeloid leukemia. Approximately 50% of cases of SCN are associated with germline heterozygous mutations of ELA2, encoding neutrophil elastase (NE). To date, 59 different, mostly missense, mutations of ELA2 have been reported. A unifying mechanism by which all of the different ELA2 mutants disrupt granulopoiesis is lacking. We and others previously proposed a model in which the ELA2 mutations result in NE protein misfolding, induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and ultimately apoptosis of granulocytic precursors. Testing this (and other) models has been limited by the rarity of SCN and difficulty in obtaining clinical samples for testing. We previously reported preliminary findings of a novel transgenic mouse expressing a truncation mutation of Ela2 (G193X) reproducing a similar mutation found in some patients with SCN (2008 ASH abstract #314). We showed that the G193X Ela2 allele produced the expected truncated protein that was rapidly degraded. Surprisingly, basal and stress granulopoiesis were normal. We hypothesized that reduced expression of Ela2 in murine compared with human granulocytic precursors resulted in less delivery of misfolded mutant NE protein to the ER, attenuating UPR activation and preserving granulopoiesis in G193X Ela2 mice. Consistent with this hypothesis, only modest evidence of UPR activation was observed in G193X Ela2 granulocytic precursors, and these cells displayed increased sensitivity to chemical inducers of ER stress compared with wildtype granulocytic precursors. The UPR model of disease pathogenesis predicts that inhibition of the cellular pathways that handle misfolded proteins may sensitize G193X Ela2 cells to ER stress and result in impaired granulocytic differentiation. To test this prediction, we crossed G193X Ela2 mice with mice lacking protein kinase RNA (PKR)-like ER kinase (PERK); PERK is one of three major ER-resident proteins that sense ER stress and activate the UPR. Of note, homozygous loss-of-function mutations of PERK (EIF2AK3) are responsible for Wolcott-Rallison syndrome, which is characterized by infantile diabetes and neutropenia in approximately 50% of cases. Since PERK deficiency is embryonic lethal, we transplanted fetal liver cells from PERK-/-, PERK-/- × G193X Ela2, and wild type embryos into irradiated recipients. Complete donor engraftment was observed in all cohorts. Basal granulopoiesis was normal in mice reconstituted with PERK-/- cells. However, in the PERK-/- × G193X Ela2 chimeras, though blood neutrophil counts were normal, a significant reduction in bone marrow neutrophils was observed [6.01 × 106/femur ± 0.92 (PERK-/-) versus 3.14 × 106 ± 0.88 (PERK-/- × G193X Ela2); p < 0.001]. These data show that loss of PERK signaling combined with G193X Ela2 expression results in impaired granulopoiesis, providing new evidence in support of the UPR model of disease pathogenesis. Disclosures: No relevant conflicts of interest to declare.

CD34+/CD38- Leukemia Stem Cells Aberrantly Express CD82 Adhesion Molecule

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2168-2168
Author(s):  
Takayuki Ikezoe ◽  
Chie Nishioka ◽  
Jing Yang ◽  
Satoshi Serada ◽  
Tetsuji Naka ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Leukemia Stem Cells ◽  
Clinical Samples ◽  
Bone Marrow Niche ◽  
Absolute Quantitation ◽  
Aberrant Expression ◽  
Migration Capacity

Abstract Abstract 2168 To identify molecular targets in leukemia stem cells (LSCs), this study compared the protein expression profile of freshly isolated LSCs (CD34+/CD38- compartment) with that of non-LSC (CD34+/CD38+ compartment) counterparts from individuals with acute myelogenous leukemia (AML) using isobaric tags for relative and absolute quantitation (iTRAQ). A total of 98 proteins were overexpressed, while six proteins were underexpressed in LSCs compared with their non-LSC counterparts. Proteins overexpressed in LSCs included a number of proteins involved in DNA repair, cell cycle arrest, gland differentiation, anti-apoptosis, adhesion, and drug resistance. Aberrant expression of CD82, a family of adhesion molecules, in LSCs was noted in additional clinical samples (n=6) by flow cytometry. In addition, we found that imatinib-resistant chronic eosinophilic leukemi EOL-1R cells expressed a greater amount of CD82 and remained in a dormant state compared to the parental EOL-1 cells. Interestingly, down-regulation of CD82 in EOL-1R cells by a small interfering RNA stimulated their migration capacity, as assessed by the transwell assay. These observations suggested that the aberrant expression of CD82 probably played a role in adhesion of hematopoietic cells to bone marrow microenvironment. Targeting CD82 could detach LSCs from bone marrow niche and sensitized these cells to anti-leukemia agents. Disclosures: No relevant conflicts of interest to declare.

Dasatinib Cerebrospinal Fluid Concentration and Plasma Pharmacokinetics: Potential for Central Nervous System Prophylaxis In Philadelphia Chromosome-Positive Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1807-1807
Author(s):  
Naoto Takahashi ◽  
Masatomo Miura ◽  
Stuart Scott ◽  
Hirobumi Saitoh ◽  
Mutsuhito Motegi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
T Test ◽  
Lymphoid Leukemia ◽  
Csf Levels ◽  
Philadelphia Chromosome Positive

Abstract Abstract 1807 Dasatinib (DA) is approved for use in imatinib-resistant or intolerant chronic myeloid leukemia (CML)/Philadelphia-positive acute lymphoid leukemia (Ph+ALL) and may also be useful for central nervous system (CNS) leukemia accompanied with CML/Ph+ALL; however, little is known about the relationship between DA pharmacokinetics and its ability to penetrate the blood-brain barrier. Consequently, we measured DA plasma and cerebrospinal fluid (CSF) levels by high-performance liquid chromatography in 20 samples obtained from 11 DA-treated patients (seven Ph+ALL and four lymphoid crisis CML). DA was detected in 10 CSF samples from five patients who were treated with 100 mg QD of DA (CSF C4h of detectable group; 3.526±2.604 ng/mL, 1.11–7.95 ng/mL), which was above the IC50 level for wild type BCR-ABL positive leukemia cells in vitro (0.8 nM = 0.39 ng/mL). However, DA was not detected in 10 CSF samples from 7 patients (CSF C4h of non-detectable group; <1.0 ng/mL). The concentration ratio of CSF to plasma was 3.90% (0.42-12.23%), which approached previously reported ratios for imatinib. There were significant differences in the AUC0-4 and the plasma C4h between the CSF detectable (D) and non-detectable (ND) patients (AUC0-4: 268.29±92.452 vs. 90.83±76.45, P=0.00019 by Student t-test, Figure 1; plasma C4h: 126.15±62.58 vs. 47.41±50.935, P=0.00637 by Student t-test). Moreover, there were significant correlations between CSF C4h and AUC0-4 (P<0.01, Figure 2) and between CSF C4h and plasma C2h (P<0.001), together suggesting that penetration of DA into the CSF may depend on DA plasma concentration. To investigate any influence of pharmacogenetic variation on CSF penetration, single nucleotide polymorphisms in genes involved in DA pharmacokinetics and transport (ABCB1, ABCG2, SLC22A1, SLC22A3, and CYP3A4/5) were interrogated; however, no significant correlation between CSF levels and genotype were observed. DA has a 325 fold greater potency than imatinib for inhibiting BCR-ABL tyrosine kinase, which undoubtedly influences the efficacy of DA for Philadelphia-chromosome positive CNS leukemia; however, our data suggest that clinical DA blood level monitoring may help estimate the penetration of DA to the CSF. Disclosures: No relevant conflicts of interest to declare.

Treatment of Burkitt's Like Lymphoma: A Single Institution Case Series

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4962-4962
Author(s):  
Vishal Ranpura ◽  
Shilpan S. Shah
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Peripheral Blood ◽  
Chemotherapy Regimen ◽  
Conflicts Of Interest ◽  
Case Series ◽  
B Cell Lymphoma ◽  
Response To Treatment ◽  
Single Institution

Abstract Abstract 4962 Background: Burkits's like (BL) lymphoma is a new pathologic entity with features partially resembling to Burkitt's lymphoma and diffuse large B cell lymphoma. The incidence of BL lymphoma is infrequent and may present with lymph node enlargement, involvement of bone marrow and peripheral blood. The natural history of BL lymphoma and its treatment remains unclear. Here we present a single institution case series of five patients diagnosed with BL lymphoma and their treatment. Methods: We searched the pathology reports of all patients diagnosed with lymphoma over the last one year. No inclusion or exclusion criteria were used. Results: We identified a total of five patients with diagnosis of BL lymphoma. All patients presented with lymphadenopathy and with no involvement of bone marrow, central nervous system or peripheral blood. Table 1 summarizes characteristics of all patients, their chemotherapy regimen and subsequent response to treatment. Conclusion: BL lymphoma is a new pathologic entity with low incidence. Treatment with DA-EPOCH and R-HyperCVAD has very good response rate. The data is limited by single institution case series and limited follow up time. Further studies are recommended to evaluate optimal chemotherapy regimen. Table 1: Characteristics, presentation, treatment and response in patients with BL lymphoma No Age Sex LDH, Presentation Treatment Response Duration of response 1 68 F 386 Parotid and abdominal lymphadenopathy DA-R-EPOCH CR 16months 2^ 44 M 536 Neck, Axillary, media, abdomen pelvis and sacral mets R-HyperCVAD PR 3months 3* 66 F 310 Inguinal and pelvic lymphadenopathy R-HyperCVAD f/b Autologus BMT, CR 14months 4** 71 M 237 Parotid mass 3 cycles of DA-EPOCH f/b 3 cycles of R-CHOP CR 9months 5^ 52 M 186 Neck Lymphadenopathy R-HyperCVAD CR 3months DOX, DOXOL, and anthracenediones in soluble fractions of human myocardial strips after sequential DOX loading/clearance and anthracenedione treatment Notes: DA-REPOCH: Dose Adjusted Rituximab-Etoposide, Vincristine, Cyclophosphamide, Doxorubicine, Prednisone, R-HyperCVAD: Rituximab, hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone, CR: complete remission, BMT: bone marrow transplantation, R-CHOP: rituximab, doxorubicin, cyclophosphamide, vincristine and prednisone. CNS: central nervous system * patient underwent bone marrow transplant because of relapse at current presentation. ** patient was changed from DA EPOCH to R-CHOP as patient was not able to tolerate EPOCH ^ Epatients are halfway through their treatment cycles and are actively getting treatment Disclosures: No relevant conflicts of interest to declare.

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