Dysfunction of motor cortices in Parkinson's disease.

The cerebral cortex has long been thought to be involved in the pathophysiology of motor symptoms of Parkinson's disease. The impaired cortical function is believed to be a direct and immediate effect of pathologically patterned basal ganglia output, mediated to the cerebral cortex by way of the ventral motor thalamus. However, recent studies in humans with Parkinson's disease and in animal models of the disease have provided strong evidence suggesting that the involvement of the cerebral cortex is much broader than merely serving as a passive conduit for subcortical disturbances. In the present review, we discuss Parkinson's disease-related changes in frontal cortical motor regions, focusing on neuropathology, plasticity, changes in neurotransmission, and altered network interactions. We will also examine recent studies exploring the cortical circuits as potential targets for neuromodulation to treat Parkinson's disease.

α-Synuclein aggregation decreases cortico-amygdala connectivity and impairs social behavior in mice.

Abnormal accumulation of insoluble α-synuclein (α-Syn) inclusions in neurons, neurites, and glial cells is the defining neuropathology of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Accumulation of α-Syn inclusions in the amygdala has been well-documented in post-mortem studies of PD and DLB brains, as well as preclinical animal models of these conditions. Though α-Syn pathology is closely associated with neurodegeneration, there is a poor correlation between neuronal loss in the amygdala and the clinical features of PD and DLB. Moreover, functional interaction between the cerebral cortex and the amygdala is critical to regulating emotion, motivation, and social behaviors. The cortico-amygdala functional interaction is likely to be disrupted by the development of α-Syn pathology in the brain. Thus, we hypothesize that neuronal α-Syn inclusions disrupt cortical modulation of the amygdala circuits and are sufficient to drive social behavioral deficits. In the present work, we designed a series of longitudinal studies to rigorously measure the time courses of neurodegeneration, functional impairment of cortico-amygdala connectivity, and development of amygdala-dependent social behavioral deficits to test this hypothesis. We injected α-Syn preformed fibrils (PFFs) into the dorsal striatum to induce α-Syn aggregation in the amygdala and the medial prefrontal cortex (mPFC) of C57BL6 mice of both sexes, followed by a detailed analysis of temporal development of α-Syn pathology, synaptic deficits, and neuronal loss in the amygdala, as well as behavioral deficits at 3-12 months post injections. Development of α-Syn inclusions caused losses of cortical axon terminals and cell death in the basolateral amygdala (BLA) at 6- and 12-months post injections, respectively. At a relatively early stage of 3 months post injections, the connection strength of the mPFC-BLA synapse was decreased in PFFs-injection mice compared to controls. Meanwhile, the PFFs-injected mice showed impaired social interaction behavior, which was rescued by chemogenetic stimulation of mPFC-BLA connections. Altogether, we presented a series of evidence to delineate circuit events in the amygdala associated with the accumulation of α-Syn inclusions in the mouse brain, highlighting that functional impairment of the amygdala is sufficient to cause social behavior deficits. The present work further suggests that early circuit modulation could be an effective approach to alleviate symptoms associated with α-Syn pathology, necessitating studies of functional consequences of α-Syn aggregation.

Can Virtual Reality-Assisted Therapy Offer Additional Benefits to Patients With Vestibular Disorders Compared With Conventional Vestibular Physical Therapy? A Meta-analysis.

OBJECTIVE: To determine whether virtual reality-assisted therapy (VRAT) significantly improves the treatment of peripheral or central vestibular disorders when compared with conventional vestibular physical therapy (CVPT) alone. Indicators of vestibular symptoms are used to determine this. DATA SOURCES: Two reviewers independently searched PubMed, EMBASE, ClinicalTrials.gov, Web of Science, and the Cochrane Collaboration database from January 2010 to January 2022 for studies reporting on VRAT in vestibular disorders. STUDY SELECTION: Randomized controlled trials (RCTs) were included that mainly focused on the following measures: the Dizziness Handicap Inventory (DHI), Simulator Sickness Questionnaire, visual analog scale, and balance measures such as the Activities-specific Balance Confidence Scale (ABC), timed Up and Go test, sensory organization test, and center of pressure. The primary outcome was assessment of symptomatic changes before and after VRAT. DATA EXTRACTION: Two authors independently conducted the literature search and selection. After screening, meta-analysis was performed on the RCTs using RevMan 5.3 software. DATA SYNTHESIS: The results showed that VRAT produced significantly greater improvement than CVPT alone in scores of DHI-Total (standardized mean difference [SMD]: -7.09, 95% confidence interval [CI]: [-12.17, -2.00], P=.006), DHI-Functional (SMD=-3.66, 95% CI: [-6.34, -0.98], P=.007), DHI-Physical (SMD=-3.14, 95% CI: [-5.46, -0.83], P=.008), and DHI-Emotional (SMD=-3.10, 95% CI: [-5.13, -1.08], P=.003). ABC scores did not show improvement (SMD: 0.58, 95% CI: [-3.69, 4.85], P=.79). Subgroup analysis showed that DHI-Total between-group differences were insignificant for central vestibular disorders (SMD=-1.47, 95% CI: [-8.71, -5.78], P=.69), although peripheral disorders showed significant improvements (SMD=-9.58, 95% CI: [-13.92, -5.25], P<.0001). However, the included studies showed high heterogeneity (I2>75%). CONCLUSIONS: VRAT may offer additional benefits for rehabilitation from vestibular diseases, especially peripheral disorders, when compared with CVPT alone. However, because of high heterogeneity and limited data, additional studies with a larger sample size and more sensitive and specific measurements are required to conclusively determine the evidence-based utility of virtual reality.

Cell Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism.

The hypokinetic motor symptoms of Parkinson's disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine (DA) alters the cellular properties of motor cortical neurons in PD remains undefined. We induced parkinsonism in adult C57BL/6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the primary motor cortical (M1) layer (L)5b was greatly decreased in parkinsonism; but the intratelencephalic neurons (ITNs) were not affected. The cell type-specific intrinsic adaptations were associated with a depolarized threshold and broadened width of action potentials (APs) in PTNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which could underlie their abnormal pattern of activity in the parkinsonian state. We also showed that the decreased excitability in parkinsonism was caused by an impaired function of both persistent sodium channels and the large conductance, Ca2+-activated K+ channels. Acute activation of dopaminergic receptors failed to rescue the impaired intrinsic excitability of M1 PTNs in parkinsonian mice. Altogether, our data demonstrated a cell type-specific decrease of the excitability of M1 pyramidal neurons in parkinsonism. Thus, intrinsic adaptations in the motor cortex provide novel insight in our understanding of the pathophysiology of motor deficits in PD.SIGNIFICANCE STATEMENT The degeneration of midbrain dopaminergic neurons in Parkinson's disease (PD) remodels the connectivity and function of cortico-basal ganglia-thalamocortical network. However, whether and how dopaminergic degeneration and the associated basal ganglia dysfunction alter motor cortical circuitry remain undefined. We found that pyramidal neurons in the layer (L)5b of the primary motor cortex (M1) exhibit distinct adaptations in response to the loss of midbrain dopaminergic neurons, depending on their long-range projections. Besides the decreased thalamocortical synaptic excitation as proposed by the classical model of Parkinson's pathophysiology, these results, for the first time, show novel cellular and molecular mechanisms underlying the abnormal motor cortical output in parkinsonism.

Synaptic and cellular plasticity in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease, which causes a tremendous socioeconomic burden. PD patients are suffering from debilitating motor and nonmotor symptoms. Cardinal motor symptoms of PD, including akinesia, bradykinesia, resting tremor, and rigidity, are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. In addition, decreased amounts of dopamine (DA) level in the basal ganglia induces numerous adaptive changes at the cellular and synaptic levels in the basal ganglia circuits. These cellular and synaptic adaptations are believed to underlie the emergence and propagation of correlated, rhythmic pattern of activity throughout the interconnected cortico-basal ganglia-thalamocortical network. The widespread pathological pattern of brain activity is closely linked to the devastating motor symptoms of PD. Accumulating evidence suggests that both dopaminergic degeneration and the associated abnormal cellular and circuit activity in the basal ganglia drive the motor symptoms of PD. In this short review I summarize the recent advances in our understanding of synaptic and cellular alterations in two basal ganglia nuclei (i.e. the striatum and the subthalamic nucleus) following a complete loss of DA, and in our conceptual understanding of the cellular and circuit bases for the pathological pattern of brain activity in parkinsonian state.

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study.

AIM: 3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation. METHODS: Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na(+) channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability. RESULTS: SKF83959 (50 µmol/L) shifted the inactivation curve of Na(+) current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 (examined with current injection at the soma) was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability (examined with current injection at the dendrite) was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency. CONCLUSION: SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug's anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.

Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation.

Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.

Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation.

Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.

Open-source platform for kinematic analysis of mouse forelimb movement.

Here we present an open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp task. We describe steps for assembling the box, training mice to perform the task, and processing the video with the custom software pipeline to analyze forepaw kinematics. The behavioral platform uses readily available and 3D-printed components and was designed to be affordable and universally reproducible. We provide the schematics, 3D models, code, and assembly instructions in the open GitHub repository.

Loss of Midbrain Dopamine Neurons Does Not Alter GABAergic Inhibition Mediated by Parvalbumin-Expressing Interneurons in Mouse Primary Motor Cortex.

The primary motor cortex (M1) integrates sensory and cognitive inputs to generate voluntary movement. Its functional impairments have been implicated in the pathophysiology of motor symptoms in Parkinson's disease (PD). Specifically, dopaminergic degeneration and basal ganglia dysfunction entrain M1 neurons into the abnormally synchronized bursting pattern of activity throughout the cortico-basal ganglia-thalamocortical network. However, how degeneration of the midbrain dopaminergic neurons affects the anatomy, microcircuit connectivity, and function of the M1 network remains poorly understood. The present study examined whether and how the loss of dopamine (DA) affects the morphology, cellular excitability, and synaptic physiology of Layer 5 parvalbumin-expressing (PV+) cells in the M1 of mice of both sexes. Here, we reported that loss of midbrain dopaminergic neurons does not alter the number, morphology, and physiology of Layer 5 PV+ cells in M1. Moreover, we demonstrated that the number of perisomatic PV+ puncta of M1 pyramidal neurons as well as their functional innervation of cortical pyramidal neurons were not altered following the loss of DA. Together, the present study documents an intact GABAergic inhibitory network formed by PV+ cells following the loss of midbrain dopaminergic neurons.

Open-Source Platform for Kinematic Analysis of Mouse Forelimb Movement.

We present an open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp task. The behavioral platform uses readily available and 3D-printed components and was designed to be affordable and universally reproducible. The protocol describes how to assemble the box, train mice to perform the task and process the video with the custom software pipeline to analyze forepaw kinematics. All the schematics, 3D models, code and assembly instructions are provided in the open GitHub repository.

Additional cognitive behavior therapy for persistent postural-perceptual dizziness: a meta-analysis.

OBJECTIVE: To investigate whether additional Cognitive Behavior Therapy (CBT) combined with conventional therapy improves outcomes for patients with Persistent Postural-Perceptual Dizziness (PPPD) compared with conventional therapy alone. METHODS: Two reviewers independently searched PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov for relevant Randomized Controlled Trials (RCTs) examining CBT for PPPD which were conducted and published in English from January 2002 to November 2022. RCTs reporting any indicators for assessing corresponding symptoms of PPPD were included, such as Dizziness Handicap Inventory (DHI), Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9). Two independent reviewers conducted extraction of relevant information and evaluation of risk of bias. The Cochrane Collaboration risk of bias tool version 1.0 was used to evaluate risks and assess the quality of the included studies, and Cochrane Review Manager 5.3 software (RevMan 5.3) was used to perform meta-analyses. RESULTS: The results of six RCTs indicated that combining additional CBT with conventional therapy significantly improved outcomes for PPPD patients compared with conventional therapy alone, especially in DHI-Total scores (Mean Difference [MD = -8.17], 95% Confidence Interval [95% CI: -10.26, -6.09], p < 0.00001), HAMA scores (MD = -2.76, 95% CI: [-3.57, -1.94], p < 0.00001), GAD-7 scores (MD = -2.50, 95% CI [-3.29, -1.70], p < 0.00001), and PHQ-9 scores (MD = -2.29, 95% CI [-3.04, -1.55], p < 0.00001). Subgroup analysis revealed a significant benefit of additional CBT compared with conventional therapies alone, including Vestibular Rehabilitation Therapy (VRT) (MD = -8.70, 95% CI: [-12.17, -5.22], p < 0.00001), Selective Serotonin Reuptake Inhibitor (SSRI) (with controlled SSRI: MD = -10.70, 95% CI: [-14.97, -6.43], p < 0.00001), and VRT combined with SSRI (MD = -6.08, 95% CI [-9.49, -2.67], p = 0.0005) in DHI-Total scores. CONCLUSION: Additional CBT combined with conventional therapy may provide additional improvement for patients with PPPD compared with conventional therapy alone. However, more RCTs are needed to support and guide the application of CBT in treating PPPD. LEVEL OF EVIDENCE: I; Systematic review of RCTs.

Epilepsy and psychiatric comorbidities: A bidirectional mendelian randomization study.

STUDY OBJECTIVES: Psychiatric comorbidities are relatively common among patients with epilepsy; however, the underlying mechanisms of this association remain largely unknown. The objective of this Mendelian randomization (MR) study was to analyze the genetic correlations and causality underlying these reciprocal associations. METHODS: Single-nucleotide polymorphisms associated with epilepsy (29,677 controls and 15,212 cases) and seven psychiatric comorbidities (485,436 controls and 269,495 cases) were identified from genome-wide association studies. Causal significance was estimated using inverse variance weighting. Sensitivity analyses included the weighted median, MR-Egger, and MR-PRESSO. The psychiatric comorbidities analyzed in this study included attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder (OCD), and anorexia nervosa. RESULTS: Both forward and reverse genetic associations were observed for the selected psychiatric disorders. Notably, ADHD was significantly associated with an increased risk of generalized epilepsy (odds ratio [OR], 1.09; 95 % confidence interval [CI], 1.01-1.18; p = 0.013). However, MR-PRESSO detected the existence of pleiotropy (p = 0.001). Additionally, focal epilepsy was significantly associated with a higher risk of OCD (OR, 1.44; 95 % CI, 1.08-1.92; p = 0.013), and all sensitivity tests yielded favorably nonsignificant results. There was no significant genetic association between epilepsy and other examined psychiatric disorders. However, due to the detection of pleiotropy by MR-Egger and considerations related to the threshold for genetic instruments, a cautious approach is warranted in interpreting some of the results. CONCLUSIONS: This study revealed significant genetic causality between focal epilepsy and OCD, as well as between ADHD and generalized epilepsy. However, no casual significance was observed with other psychiatric comorbidities examined. Considering the inherent limitations of MR studies, further research is warranted to definitively clarify these genetic causal associations.

Decreased cellular excitability of pyramidal tract neurons in primary motor cortex leads to paradoxically increased network activity in simulated parkinsonian motor cortex.

Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of parkinsonism. We hypothesized that decreased PT5B neuron excitability would substantially disrupt oscillatory and non-oscillatory firing patterns of neurons in layer 5 (L5) of primary motor cortex (M1). To test this hypothesis, we performed computer simulations using a previously validated computer model of mouse M1. Inclusion of the experimentally identified parkinsonism-associated decrease of PT5B excitability into our computational model produced a paradoxical increase in rest-state PT5B firing rate, as well as an increase in beta-band oscillatory power in local field potential (LFP). In the movement-state, PT5B population firing and LFP showed reduced beta and increased high-beta, low-gamma activity of 20-35 Hz in the parkinsonian, but not in control condition. The appearance of beta-band oscillations in parkinsonism would be expected to disrupt normal M1 motor output and contribute to motor activity deficits seen in patients with Parkinson's disease (PD).

Prognostic implications of T stage in different pathological types of colorectal cancer: an observational study using SEER population-based data.

OBJECTIVES: Colorectal cancer (CRC) encompasses a spectrum of pathological types, each exhibiting distinct biological behaviours that challenge the conventional T-staging system's predictive efficiency. Thus, this study aims to explore the prognostic significance of the T stage across various CRC pathological types, seeking to unravel insights that could enhance prognostic assessment in this complex disease. STUDY DESIGN: We performed a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database for primary CRC cases from 2010 to 2017. SETTING: The SEER database, comprising data from various US regional and state cancer registries, identified 39 321 patients with CRC. Our analysis focused on the three most common CRC pathological types: adenocarcinoma (AC), mucinous adenocarcinoma (MC) and signet ring cell carcinoma (SR). PRIMARY OUTCOME MEASURES: The study used Cox regression models to evaluate how different pathological characteristics impact mortality risk in patients with CRC. Time-dependent receiver operating characteristic curves were also applied to assess the prognostic accuracy of various tumour node metastasis (TNM)/non-mucinous (NM) stages. RESULTS: We observed significant associations between T stage and mortality risk for patients with AC and MC. Notably, in comparison to those at T1 stage, patients with AC in the T4 stage demonstrated a 2.01-fold increase in mortality risk (HR=2.01, 95% CI: 1.89 to 2.15), while patients with MC at T4 stage showed a 1.42-fold increase (HR=1.42, 95% CI: 1.03 to 1.97). However, within the SR group, T stages did not independently impact survival, showing no significant distinction (HR=1.07, 95% CI: 0.59 to 1.95). Intriguingly, the traditional TNM staging systems demonstrated limited discriminatory power in predicting prognosis for patients with SR when compared with the more innovative NM staging systems. CONCLUSIONS: This study uncovers important insights about the prognostic significance of the T stage in different types of CRC, highlighting the need for personalised assessments based on specific histological subtypes.

Target-specific suppression of GABA release from parvalbumin interneurons in the basolateral amygdala by dopamine.

Dopamine (DA) in the basolateral amygdala (BLA) promotes fear learning by disinhibiting principal neurons (PNs) and enabling synaptic plasticity in their sensory inputs. While BLA interneurons (INs) are heterogeneous, it is unclear which interneuron subtypes decrease GABAergic input to PNs in the presence of DA. Here, using cell type-selective photostimulation by channelrhodopsin 2 in BLA slices from mouse brain, we examined the role of parvalbumin-positive INs (PV-INs), the major interneuronal subpopulation in BLA, in the disinhibitory effect of DA. We found that DA selectively suppressed GABAergic transmission from PV-INs to PNs by acting on presynaptic D(2) receptors, and this effect was mimicked by Rp-cAMP, an inhibitor of cAMP-dependent signaling. In contrast, DA did not alter GABA release from PV-INs to INs. Furthermore, neither suppressing cAMP-dependent signaling by Rp-cAMP nor enhancing it by forskolin altered GABA release from PV-INs to BLA INs. Overall, DA disinhibits BLA, at least in part, by suppressing GABA release from PV-INs in the target cell-specific manner that results from differential control of this release by cAMP-dependent signaling.

Reduced thalamic excitation to motor cortical pyramidal tract neurons in parkinsonism.

Degeneration of midbrain dopaminergic (DA) neurons alters the connectivity and functionality of the basal ganglia-thalamocortical circuits in Parkinson's disease (PD). Particularly, the aberrant outputs of the primary motor cortex (M1) contribute to parkinsonian motor deficits. However, cortical adaptations at cellular and synaptic levels in parkinsonism remain poorly understood. Using multidisciplinary approaches, we found that DA degeneration induces cell subtype- and input-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. At molecular level, we identified that N-methyl-d-aspartate (NMDA) receptors play a key role in mediating the reduced thalamocortical excitation to PT neurons. At circuit level, we showed that the reduced thalamocortical transmission in parkinsonian mice can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that cell subtype- and synapse-specific adaptations in M1 contribute to altered cortical outputs in parkinsonism and are important aspects of PD pathophysiology.

Antiseizure medications for idiopathic generalized epilepsies: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy and safety of antiseizure medications (ASMs), both as monotherapies and adjunctive therapies, for idiopathic generalized epilepsies (IGEs) and related entities. METHODS: Two reviewers independently searched PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials from December 2022 to February 2023. Studies on the efficacy and safety of ASM monotherapies or adjunctive therapies for IGEs and related entities-including juvenile myoclonic epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, or generalized tonic-clonic seizures alone (GTCA)-were included. Efficacy outcomes were the proportions of patients remaining seizure free for 1, 3, 6, and 12 months; safety outcomes were the proportions of any treatment-emergent adverse event (TEAE) and TEAEs leading to discontinuation. Network meta-analyses were performed in a random-effects model to obtain odds ratios and 95% confidence intervals. Rankings of ASMs were based on the surface under the cumulative ranking curve (SUCRA). This study is registered with PROSPERO (No. CRD42022372358). RESULTS: Twenty-eight randomized controlled trials containing 4282 patients were included. As monotherapies, all ASMs were more effective than placebo, and valproate and ethosuximide were significantly better than lamotrigine. According to the SUCRA for efficacy, ethosuximide ranked first for CAE, whereas valproate ranked first for other types of IGEs. As adjunctive therapies, topiramate ranked best for GTCA as well as overall for IGEs, while levetiracetam ranked best for myoclonic seizures. For safety, perampanel ranked best (measured by any TEAE). CONCLUSIONS: All of the studied ASMs were more effective than placebo. Valproate monotherapy ranked best overall for IGEs, whereas ethosuximide ranked best for CAE. Adjunctive topiramate and levetiracetam were most effective for GTCA and myoclonic seizures, respectively. Furthermore, perampanel had the best tolerability.

Prophylactic treatments for vestibular migraine: a systematic review and network meta-analysis of randomized clinical trials.

Objectives: We compared and ranked the efficacy and tolerability of multiple prophylactic treatments for vestibular migraine (VM), including ß-blockers, calcium channel blockers, antiseizure medications, and antidepressants such as tricyclics and serotonin-noradrenaline reuptake inhibitors. Methods: PubMed, Web of Science, Embase, and Cochrane Center for Clinical Trials were systematically searched for relevant randomized clinical trials (RCTs) from March 2023 to May 2023. Studies on the efficacy and tolerability of prophylactic treatments for VM were included. Efficacy was measured using the average vertigo frequency per month and dizziness handicap inventory (DHI) improvement after 3-6 months of treatment. Tolerability was measured by the number of patients reporting at least one adverse event (AE). Network meta-analyses were performed according to a Bayesian framework and a random-effects model based on odds ratios or mean differences (MDs) and 95% confidence intervals (CIs). A sequence of ranking probability was calculated according to the surface under the cumulative ranking (SUCRA) curve. This network meta-analysis was previously registered with PROSPERO (CRD42023422258). Results: Five RCTs comprising 334 patients were analyzed by synthesizing the published evidence. Considering the examined prophylactic therapies, there is significant evidence that valproate acid (VPA) is superior to placebo or abortive treatment alone (MD = -4.12, 95% CI = -8.09, -0.15) in reducing the frequency of vertigo. Flunarizine (MD = 20.00, 95% CI = 10.90, 29.10), valproate acid (MD = 18.88, 95% CI = 10.42, 27.34), and venlafaxine (MD = 11.48, 95% CI = 9.84, 13.12) were significantly more effective than placebo or abortive treatment in reducing DHI. VPA most strongly reduced the frequency of vertigo according to SUCRA, but it ranked third-to-last in tolerability. Flunarizine ranked best in DHI improvement but worst in tolerability. Metoprolol ranked worst for efficacy but best for tolerability. Conclusion: VPA and flunarizine reduced the frequency of vertigo and improved DHI, but they had unfavorable tolerability. The effects of metoprolol on vertigo require further study. Given the low certainty and limited sample, additional head-to-head RCTs are warranted to further confirm efficacy. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/; Identifier CRD42023422258.