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CNS Neuroscience & Therapeutics Mar 2024Acupuncture has shown promise in treating neck pain. Clinical trials have shown mixed results, possibly due to heterogeneous methodologies and the lack of knowledge... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Acupuncture has shown promise in treating neck pain. Clinical trials have shown mixed results, possibly due to heterogeneous methodologies and the lack of knowledge regarding underlying brain circuit mechanism of action. In this study, we investigated the specific contribution of the serotonergic system in treating neck pain, and the specific brain circuits involved.
METHODS
A total of 99 patients with chronic neck pain (CNP) were randomized to receive true acupuncture (TA) or sham acupuncture (SA) 3 times weekly for 4 weeks. Patients with CNP in each group were assessed for primary outcomes by measuring the Visual Analog Scale (VAS) and the duration of each attack; secondary outcomes were measured using the Neck Disability Index (NDI), Northwick Park Neck Pain Questionnaire (NPQ), McGill Pain Questionnaire (MPQ), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS) and the 12-item Short Form Quality Life Scale (SF-12); levels of functional circuits connectivity were assessed using resting-state functional magnetic resonance imaging in the dorsal (DR) and median (MR) raphe nucleus, before and after undergoing acupuncture.
RESULTS
Patients receiving TA showed more extensive symptom improvement compared with SA. Regarding the primary outcomes, changes observed in the TA group were as follows: VAS = 16.9 mm (p < 0.001) and the duration of each attack = 4.30 h (p < 0.001); changes in the SA group: VAS = 5.41 mm (p = 0.138) and the duration of each attack = 2.06 h (p = 0.058). Regarding the secondary outcomes, changes in the TA group: NDI = 7.99 (p < 0.001), NPQ = 10.82 (p < 0.001), MPQ = 4.23 (p < 0.001), SAS = 5.82 (p < 0.001), SDS = 3.67 (p = 0.003), and SF-12 = 3.04 (p < 0.001); changes in the SA group: NDI = 2.97 (p = 0.138), NPQ = 5.24 (p = 0.035) and MPQ = 2.90 (p = 0.039), SAS = 1.48 (p = 0.433), SDS = 2.39 (p = 0.244), and SF-12 = 2.19 (p = 0.038). The modulatory effect of TA exhibited increased functional connectivity (FC) between the DR and thalamus, between the MR and parahippocampal gyrus, amygdala, and insula, with decreased FC between the DR and lingual gyrus and middle frontal gyrus, between the MR and middle frontal gyrus. Furthermore, changes in the DR-related circuit were specifically associated with the intensity and duration of pain, and the MR-related circuit was correlated with the quality of life with CNP.
CONCLUSION
These results demonstrated the effectiveness of TA in treating neck pain and suggested that it regulates CNP by reconfiguring the function of the raphe nucleus-related serotonergic system.
Topics: Humans; Neck Pain; Quality of Life; Acupuncture Therapy; Amygdala; Neuroimaging; Raphe Nuclei
PubMed: 37408438
DOI: 10.1111/cns.14335 -
Neurology International Dec 2023Various MRI markers-including midbrain and pons areas (M, P) and volumes (M, P), ratios (M/P, M/P), and composite markers (magnetic resonance imaging Parkinsonism... (Review)
Review
Planimetric and Volumetric Brainstem MRI Markers in Progressive Supranuclear Palsy, Multiple System Atrophy, and Corticobasal Syndrome. A Systematic Review and Meta-Analysis.
BACKGROUND
Various MRI markers-including midbrain and pons areas (M, P) and volumes (M, P), ratios (M/P, M/P), and composite markers (magnetic resonance imaging Parkinsonism Indices 1,2; MRPI 1,2)-have been proposed as imaging markers of Richardson's syndrome (RS) and multiple system atrophy-Parkinsonism (MSA-P). A systematic review/meta-analysis of relevant studies aiming to compare the diagnostic accuracy of these imaging markers is lacking.
METHODS
Pubmed and Scopus were searched for studies with >10 patients (RS, MSA-P or CBS) and >10 controls with data on M, P, M, P, M/P, M/P, MRPI 1, and MRPI 2. Cohen's , as a measure of effect size, was calculated for all markers in RS, MSA-P, and CBS.
RESULTS
Twenty-five studies on RS, five studies on MSA-P, and four studies on CBS were included. Midbrain area provided the greatest effect size for differentiating RS from controls (Cohen's = -3.10; < 0.001), followed by M/P and MRPI 1. MSA-P had decreased midbrain and pontine areas. Included studies exhibited high heterogeneity, whereas publication bias was low.
CONCLUSIONS
Midbrain area is the optimal MRI marker for RS, and pons area is optimal for MSA-P. M/P and MRPIs produce smaller effect sizes for differentiating RS from controls.
PubMed: 38392951
DOI: 10.3390/neurolint16010001 -
Biological Psychiatry. Cognitive... Feb 2024Sensory prediction allows the brain to anticipate and parse incoming self-generated sensory information from externally generated signals. Sensory prediction breakdowns...
BACKGROUND
Sensory prediction allows the brain to anticipate and parse incoming self-generated sensory information from externally generated signals. Sensory prediction breakdowns may contribute to perceptual and agency abnormalities in psychosis (hallucinations, delusions). The pons, a central node in a cortico-ponto-cerebellar-thalamo-cortical circuit, is thought to support sensory prediction. Examination of pons connectivity in schizophrenia and its role in sensory prediction abnormalities is lacking.
METHODS
We examined these relationships using resting-state functional magnetic resonance imaging and the electroencephalography-based auditory N1 event-related potential in 143 participants with psychotic spectrum disorders (PSPs) (with schizophrenia, schizoaffective disorder, or bipolar disorder); 63 first-degree relatives of individuals with psychosis; 45 people at clinical high risk for psychosis; and 124 unaffected comparison participants. This unique sample allowed examination across the psychosis spectrum and illness trajectory. Seeding from the pons, we extracted average connectivity values from thalamic and cerebellar clusters showing differences between PSPs and unaffected comparison participants. We predicted N1 amplitude attenuation during a vocalization task from pons connectivity and group membership. We correlated participant-level connectivity in PSPs and people at clinical high risk for psychosis with hallucination and delusion severity.
RESULTS
Compared to unaffected comparison participants, PSPs showed pons hypoconnectivity to 2 cerebellar clusters, and first-degree relatives of individuals with psychosis showed hypoconnectivity to 1 of these clusters. Pons-to-cerebellum connectivity was positively correlated with N1 attenuation; only PSPs with heightened pons-to-postcentral gyrus connectivity showed this pattern, suggesting a possible compensatory mechanism. Pons-to-cerebellum hypoconnectivity was correlated with greater hallucination severity specifically among PSPs with schizophrenia.
CONCLUSIONS
Deficient pons-to-cerebellum connectivity linked sensory prediction network breakdowns with perceptual abnormalities in schizophrenia. Findings highlight shared features and clinical heterogeneity across the psychosis spectrum.
PubMed: 38311290
DOI: 10.1016/j.bpsc.2024.01.010 -
Science Advances Nov 2023A substantial proportion of raphe neurons are glutamatergic. However, little is known about how these glutamatergic neurons modulate the forebrain. We investigated how...
A substantial proportion of raphe neurons are glutamatergic. However, little is known about how these glutamatergic neurons modulate the forebrain. We investigated how glutamatergic median raphe nucleus (MRN) input modulates the medial prefrontal cortex (mPFC), a critical component of fear circuitry. We show that vesicular glutamate transporter 3 (VGLUT3)-expressing MRN neurons activate VGLUT3- and somatostatin-expressing neurons in the mPFC. Consistent with this modulation of mPFC GABAergic neurons, activation of MRN (VGLUT3) neurons enhances GABAergic transmission in mPFC pyramidal neurons and attenuates fear memory in female but not male mice. Serotonin plays a key role in MRN (VGLUT3) neuron-mediated GABAergic plasticity in the mPFC. In agreement with these female-specific effects, we observed sex differences in glutamatergic transmission onto MRN (VGLUT3) neurons and in mPFC (VGLUT3) neuron-mediated dual release of glutamate and GABA. Our results demonstrate a cell type-specific modulation of the mPFC by MRN (VGLUT3) neurons and reveal a sex-specific role of this neuromodulation in mPFC synaptic plasticity.
Topics: Female; Mice; Animals; Male; Vesicular Glutamate Transport Proteins; Raphe Nuclei; Pyramidal Cells; GABAergic Neurons; Prefrontal Cortex
PubMed: 37948526
DOI: 10.1126/sciadv.adg4800 -
BioRxiv : the Preprint Server For... Feb 2024There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone...
There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone marrow--these nerves consist of noradrenergic fibers that immunostain for tyrosine hydroxylase, dopamine beta hydroxylase, or neuropeptide Y. Nonetheless, the brain sites that send efferent SNS outflow to bone have not yet been characterized. Using pseudorabies (PRV) viral transneuronal tracing, we report, for the first time, the identification of central SNS outflow sites that innervate bone. We find that the central SNS outflow to bone originates from 87 brain nuclei, sub-nuclei and regions of six brain divisions, namely the midbrain and pons, hypothalamus, hindbrain medulla, forebrain, cerebral cortex, and thalamus. We also find that certain sites, such as the raphe magnus (RMg) of the medulla and periaqueductal gray (PAG) of the midbrain, display greater degrees of PRV152 infection, suggesting that there is considerable site-specific variation in the levels of central SNS outflow to bone. This comprehensive compendium illustrating the central coding and control of SNS efferent signals to bone should allow for a greater understanding of the neural regulation of bone metabolism, and importantly and of clinical relevance, mechanisms for central bone pain.
PubMed: 38370676
DOI: 10.1101/2024.02.07.579382 -
Advanced Science (Weinheim,... Mar 2024Locus coeruleus (LC) dysfunction is involved in the pathophysiology of depression; however, the neural circuits and specific molecular mechanisms responsible for this...
Locus coeruleus (LC) dysfunction is involved in the pathophysiology of depression; however, the neural circuits and specific molecular mechanisms responsible for this dysfunction remain unclear. Here, it is shown that activation of tyrosine hydroxylase (TH) neurons in the LC alleviates depression-like behaviors in susceptible mice. The dorsolateral septum (dLS) is the most physiologically relevant output from the LC under stress. Stimulation of the LC -dLS innervation with optogenetic and chemogenetic tools bidirectionally can regulate depression-like behaviors in both male and female mice. Mechanistically, it is found that brain-derived neurotrophic factor (BDNF), but not norepinephrine, is required for the circuit to produce antidepressant-like effects. Genetic overexpression of BDNF in the circuit or supplementation with BDNF protein in the dLS is sufficient to produce antidepressant-like effects. Furthermore, viral knockdown of BDNF in this circuit abolishes the antidepressant-like effect of ketamine, but not fluoxetine. Collectively, these findings underscore the notable antidepressant-like role of the LC -dLS pathway in depression via BDNF-TrkB signaling.
Topics: Mice; Animals; Male; Female; Depression; Locus Coeruleus; Norepinephrine; Brain-Derived Neurotrophic Factor; Antidepressive Agents
PubMed: 38155473
DOI: 10.1002/advs.202303503 -
Science Advances Sep 2023Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used...
Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat obesity require complete characterization of the central mechanisms that mediate both the food intake-suppressive and illness-like effects of GLP-1R signaling. Our studies, in the rat, demonstrate that GLP-1Rs in the locus coeruleus (LC) are pharmacologically and physiologically relevant for food intake control. Furthermore, agonism of LC GLP-1Rs induces illness-like behaviors, and antagonism of LC GLP-1Rs can attenuate GLP-1R-mediated nausea. Electrophysiological and behavioral pharmacology data support a role for LC GLP-1Rs expressed on presynaptic glutamatergic terminals in the control of feeding and malaise. Collectively, our work establishes the LC as a site of action for GLP-1 signaling and extends our understanding of the GLP-1 signaling mechanism necessary for the development of improved obesity pharmacotherapies.
Topics: United States; Animals; Rats; Appetite Depressants; Locus Coeruleus; Obesity; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Nausea
PubMed: 37729419
DOI: 10.1126/sciadv.adh0980 -
JCI Insight Nov 2023Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To...
Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level-dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.
Topics: Adult; Humans; Child; Apnea; Sudden Unexpected Death in Epilepsy; Carbon Dioxide; Hunger; Electroencephalography; Seizures; Amygdala
PubMed: 37788112
DOI: 10.1172/jci.insight.172423 -
The American Journal of Case Reports Aug 2023BACKGROUND A first psychotic episode requires the exclusion of toxic-metabolic, inflammatory, infective, and neoplastic causes. Wilson disease is a rare, autosomal...
BACKGROUND A first psychotic episode requires the exclusion of toxic-metabolic, inflammatory, infective, and neoplastic causes. Wilson disease is a rare, autosomal recessive disorder of copper metabolism and can present with neuropsychiatric symptoms secondary to copper accumulation in the brain. CASE REPORT We describe the case of a 48-year-old man with parkinsonism on a background of longstanding schizophrenia and psychotic depression in the setting of previously undiagnosed Wilson disease. The common history of neuropsychiatric disturbance and neuroleptic use complicated the assessment of parkinsonism. However, close attention to the temporal appearance of symptoms and signs differentiated his case from drug-induced parkinsonism, which commonly develops hours to weeks after commencement or uptitration of antipsychotic medication. The early features of sialorrhea and dysarthria were also atypical for idiopathic Parkinson disease. The diagnosis was confirmed by serum copper testing and supported by Kayser-Fleischer rings on bedside ophthalmological examination. Magnetic resonance imaging (MRI) of the brain demonstrated copper accumulation in the basal ganglia and pons, contributing to the characteristic neurological manifestations of an akinetic-rigid syndrome with dysarthria. CONCLUSIONS Serum copper testing is easily obtained and should be considered as part of the first-line investigations for new neuropsychiatric disturbances. Although rare, Wilson disease, if diagnosed early, is a potentially treatable and reversible cause of psychosis. With advanced disease, extrapyramidal findings on examination correlate with MRI brain changes, aiding the clinical assessment in differentiating the disease from drug-induced parkinsonism.
Topics: Male; Humans; Middle Aged; Hepatolenticular Degeneration; Copper; Dysarthria; Psychotic Disorders; Parkinsonian Disorders
PubMed: 37583127
DOI: 10.12659/AJCR.940561 -
Clinical Neurophysiology : Official... Oct 2023Cortico-cortical paired associative stimulation (ccPAS) is a form of dual-site transcranial magnetic stimulation (TMS) entailing a series of single-TMS pulses paired at...
OBJECTIVE
Cortico-cortical paired associative stimulation (ccPAS) is a form of dual-site transcranial magnetic stimulation (TMS) entailing a series of single-TMS pulses paired at specific interstimulus intervals (ISI) delivered to distant cortical areas. The goal of this article is to systematically review its efficacy in inducing plasticity in humans focusing on stimulation parameters and hypotheses of underlying neurophysiology.
METHODS
A systematic review of the literature from 2009-2023 was undertaken to identify all articles utilizing ccPAS to study brain plasticity and connectivity. Six electronic databases were searched and included.
RESULTS
32 studies were identified. The studies targeted connections within the same hemisphere or between hemispheres. 28 ccPAS studies were in healthy participants, 1 study in schizophrenia, and 1 in Alzheimer's disease (AD) patients. 2 additional studies used cortico-cortical repetitive paired associative stimulation (cc-rPAS) in generalized anxiety disorder (GAD) patients. Outcome measures include electromyography (EMG), behavioral measures, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). ccPAS seems to be able to modulate brain connectivity depending on the ISI.
CONCLUSIONS
ccPAS can be used to modulate corticospinal excitability, brain activity, and behavior. Although the stimulation parameters used across studies reviewed in this paper are varied, ccPAS is a promising approach for basic research and potential clinical applications.
SIGNIFICANCE
Recent advances in neuroscience have caused a shift of interest from the study of single areas to a more complex approach focusing on networks of areas that orchestrate brain activity. Consequently, the TMS community is also witnessing a change, with a growing interest in targeting multiple brain areas rather than a single locus, as evidenced by an increasing number of papers using ccPAS. In light of this new enthusiasm for brain connectivity, this review summarizes existing literature and stimulation parameters that have proven effective in changing electrophysiological, behavioral, or neuroimaging-derived measures.
Topics: Humans; Motor Cortex; Evoked Potentials, Motor; Transcranial Magnetic Stimulation; Brain; Neuronal Plasticity
PubMed: 37634335
DOI: 10.1016/j.clinph.2023.06.016