Evaluation of microglia activation related markers following a clinical course of TBS: A non-human primate study.

While the applicability and popularity of theta burst stimulation (TBS) paradigms remain, current knowledge of their neurobiological effects is still limited, especially with respect to their impact on glial cells and neuroinflammatory processes. We used a multimodal imaging approach to assess the effects of a clinical course of TBS on markers for microglia activation and tissue injury as an indirect assessment of neuroinflammatory processes. Healthy non-human primates received continuous TBS (cTBS), intermittent TBS (iTBS), or sham stimulation over the motor cortex at 90% of resting motor threshold.

Combined In Vivo Microdialysis and PET Studies to Validate [C]Yohimbine Binding as a Marker of Noradrenaline Release.

The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore if [C]yohimbine, a selective antagonist radioligand of the α2 adrenoceptors, may be used to assess in vivo changes in synaptic noradrenaline during acute pharmacological challenges. Anesthetised Göttingen minipigs were positioned in a head holder in a PET/CT device.

Continuous but not intermittent theta burst stimulation decreases striatal dopamine release and cortical excitability.

Dopamine modulation is thought to underpin some of the therapeutic effects associated with repetitive transcranial magnetic stimulation (rTMS). However, patient studies have failed to demonstrate consistent changes in the dopamine system in vivo after a therapeutic course of rTMS. Here, we evaluated acute and chronic changes in striatal dopamine release elicited by a clinically relevant course of theta burst (TBS) or sham stimulation using [C]raclopride in healthy non-human primates (n = 11).

Insight Into the Effects of Clinical Repetitive Transcranial Magnetic Stimulation on the Brain From Positron Emission Tomography and Magnetic Resonance Imaging Studies: A Narrative Review.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a therapeutic tool to alleviate symptoms for neurological and psychiatric diseases such as chronic pain, stroke, Parkinson's disease, major depressive disorder, and others. Although the therapeutic potential of rTMS has been widely explored, the neurological basis of its effects is still not fully understood. Fortunately, the continuous development of imaging techniques has advanced our understanding of rTMS neurobiological underpinnings on the healthy and diseased brain.

Comparison of Invasive and Non-invasive Estimation of [C]PBR28 Binding in Non-human Primates.

Purpose: To identify a reliable alternative to the full blood [C]PBR28 quantification method that would be easily replicated in multiple research and clinical settings.

Procedures: Ten [C]PBR28 scans were acquired from 7 healthy non-human primates (NHP). Arterial input functions (AIFs) were averaged to create a population template input function (TIF).

On the learning of addictive behavior: Sensation-seeking propensity predicts dopamine turnover in dorsal striatum.

We asked if sensation-seeking is linked to premorbid personality characteristics in patients with addictive disorders, or the characteristics follow the sensation-seeking activity. We interpreted the former as a state associated with normal rates of dopamine synthesis, and the latter as a trait of individuals with abnormally high rates of synthesis. We previously determined dopaminergic receptor density in striatum, and we now tested the hypothesis that an elevated dopaminergic condition with increased extracellular dopamine and receptor density follows increased dopamine synthesis capacity in highly sensation-seeking individuals, as measured by positron emission tomography of 18 men with tracer fluorodopa (FDOPA).

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data.

Type of Anaesthetic Influences [C]MDL100,907 Binding to 5HT Receptors in Porcine Brain.

Purpose: Anaesthesia routinely is used in animal neuroimaging in order to reduce head motion artefacts and minimize the influence of stress. However, anaesthetics can modify radioligand binding profiles at receptor targets studied by positron emission tomography (PET). Here, we determined the effects of two routine anaesthetics on the binding of a tracer of the serotonin 5HT receptors.

fMRI in Non-human Primate: A Review on Factors That Can Affect Interpretation and Dynamic Causal Modeling Application.

Dynamic causal modeling (DCM)-a framework for inferring hidden neuronal states from brain activity measurements (e. g., fMRI) and their context-dependent modulation-was developed for human neuroimaging, and has not been optimized for non-human primate (NHP) studies, which are usually done under anesthesia.

Electroconvulsive stimulation differentially affects [C]MDL100,907 binding to cortical and subcortical 5HT receptors in porcine brain.

Background: Electroconvulsive therapy is an effective therapy of depression. We hypothesized that the beneficial effects are mediated partly by decreased serotonin receptor availability in the cortex.

Aims: We used positron emission tomography with the serotonin 5HT receptor radioligand [C]MDL100,907 to determine serotonin receptor availability in response to electroconvulsive stimulation (ECS).

Cortical and striatal serotonin transporter binding in a genetic rat model of depression and in response to electroconvulsive stimuli.

Depression is a debilitating mental illness and two thirds of patients respond insufficiently to conventional antidepressants. Electroconvulsive therapy (ECT) remains the most effective treatment to alleviate drug-refractory depression, however the neurobiological mechanisms are mostly unknown. The serotonergic system plays an important role in depression and alterations in the serotonin transporter (SERT) are seen both in depression and response to antidepressant pharmacotherapies.

Single Inflammatory Trigger Leads to Neuroinflammation in LRRK2 Rodent Model without Degeneration of Dopaminergic Neurons.

Background: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson's disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system.

Objective: To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design.

Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs.

Impairment of the ubiquitin proteasome system has been implicated in Parkinson's disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Göttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port.

In vivo quantification of glial activation in minipigs overexpressing human α-synuclein.

Parkinson's disease is characterized by a progressive loss of substantia nigra (SN) dopaminergic neurons and the formation of Lewy bodies containing accumulated alpha-synuclein (α-syn). The pathology of Parkinson's disease is associated with neuroinflammatory microglial activation, which may contribute to the ongoing neurodegeneration. This study investigates the in vivo microglial and dopaminergic response to overexpression of α-syn.

Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs.

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Göttingen minipig by administering lactacystin into the medial forebrain bundle (MFB).

Elevated dopamine D1 receptor availability in striatum of Göttingen minipigs after electroconvulsive therapy.

Electroconvulsive therapy (ECT), a direct form of brain stimulation, is an effective antidepressant. We hypothesized that the beneficial effects of ECT are mediated by increased dopaminergic neurotransmission, in which the baseline activity of D1 receptors may predict the response to ECT. We established a novel model of brain stimulation in Göttingen minipigs based on the protocol of ECT applied in humans.

Differential behavioral outcomes following neonatal versus fetal human retinal pigment epithelial cell striatal implants in parkinsonian rats.

Following the failure of a Phase II clinical study evaluating human retinal pigment epithelial (hRPE) cell implants as a potential treatment option for Parkinson's disease, speculation has centered on implant function and survival as possible contributors to the therapeutic outcomes. We recently reported that neonatal hRPE cells, similar to hRPE cells used in the Phase II clinical study, produced short-lived in vitro and limited in vivo trophic factors, which supports that assumption. We hypothesize that the switch from fetal to neonatal hRPE cells, between the Phase I and the Phase II clinical trial may be partly responsible for the later negative outcomes.

Continuous MPTP intoxication in the Göttingen minipig results in chronic parkinsonian deficits.

Parkinson's disease (PD) is a common neurodegenerative disorder, resulting from progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Neuroprotective therapies in PD are still not available, perhaps because animal models do not imitate the chronic and progressive nature of the clinical state of PD. To address this, we performed a feasibility study aimed at establishing a chronic non-primate large animal PD model in Göttingen minipigs based on continuous infusion of the neurotoxin 1-methyl-4-phenyl‑1,2,3,6-tetrahydropyridine (MPTP).

Modulation of Abnormal Metabolic Brain Networks by Experimental Therapies in a Nonhuman Primate Model of Parkinson Disease: An Application to Human Retinal Pigment Epithelial Cell Implantation.

Unlabelled: Abnormal covariance pattern of regional metabolism associated with Parkinson disease (PD) is modulated by dopaminergic pharmacotherapy. Using high-resolution F-FDG PET and network analysis, we previously derived and validated a parkinsonism-related metabolic pattern (PRP) in nonhuman primate models of PD. It is currently not known whether this network is modulated by experimental therapeutics.

Interpreting DTBZ binding data in rodent: Inherent variability and compensation.

[11C]-dihydrotetrabenazine (DTBZ) Positron Emission Tomography was used to evaluate the vesicular monoamine transporter type 2 as an index of dopaminergic function in the striatum of adult Sprague-Dawley rats obtained from two different animal sources (Charles River Laboratories [CR] or UBC's Animal Care Centre [ACC]) and later submitted to two different unilateral lesions of the nigro-striatal pathway. The results showed a significant difference in the striatal binding potential (BP(ND)) at baseline (before lesioning) between the CR and ACC groups providing evidence that the origin of the animals, possibly due to differences in early environmental factors or breeding conditions associated with different animal vendors plays a role in the development of the adult dopaminergic system. Further, in both animal models, an increase in DTBZ BP(ND) was observed, after unilateral intervention, in the striatum contralateral to the lesion, likely reflecting compensatory effects.

Neonatal human retinal pigment epithelial cells secrete limited trophic factors in vitro and in vivo following striatal implantation in parkinsonian rats.

Human retinal pigment epithelial (hRPE) cell implants into the striatum have been investigated as a potential cell-based treatment for Parkinson's disease in a Phase II clinical trial that recently failed. We hypothesize that the trophic factor potential of the hRPE cells could potentially influence the function and/or survival of the implants and may be involved in an alternative mechanism of action. However, it is unclear if hRPE cells secreted trophic factors when handled in the manner used in the clinical Phase II trial.

How Relevant Are Imaging Findings in Animal Models of Movement Disorders to Human Disease?

The combination of novel imaging techniques with the use of small animal models of disease is often used in attempt to understand disease mechanisms, design potential clinical biomarkers and therapeutic interventions, and develop novel methods with translatability to human clinical conditions. However, it is clear that most animal models are deficient when compared to the complexity of human diseases: they cannot sufficiently replicate all the features of multisystem disorders. Furthermore, some practical differences may affect the use or interpretation of animal imaging to model human conditions such as the use of anesthesia, various species differences, and limitations of methodological tools.

α2-adrenoceptor binding in Flinders-sensitive line compared with Flinders-resistant line and Sprague-Dawley rats.

Objectives: Disturbances in the noradrenergic system, including alterations in the densities of α2-adrenoceptors, are posited to be involved in the pathophysiology of depression. In this study, we investigate the binding of α2-adrenoceptors in regions relevant to depression in an animal model of depression.

Methods: Using in vitro autoradiography techniques and the selective α2-ligand, [3H]RX 821002, we investigated the density of α2-adrenoceptors in female Flinders-sensitive line (FSL) rats, a validated model of depression, and in two traditional control groups - female Flinders-resistant line (FRL) and Sprague-Dawley (SD) rats.

Acute Vagal Nerve Stimulation Lowers α2 Adrenoceptor Availability: Possible Mechanism of Therapeutic Action.

Background: Vagal nerve stimulation (VNS) emerged as an anti-epileptic therapy, and more recently as a potential antidepressant intervention.

Objective/hypothesis: We hypothesized that salutary effects of VNS are mediated, at least in part, by augmentation of the inhibitory effects of cortical monoaminergic neurotransmission at appropriate receptors, specifically adrenoceptors. Our objective was to measure the effect of acute VNS on α2 adrenoceptor binding.