The most frequently used animal models for Parkinson's disease (PD) utilize unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB), which results in total denervation of the dopaminergic nigrostriatal pathway. However, neuroprotective interventions in PD require models resembling earlier stages of PD, where some dopaminergic cells and fibres remain. The aim of the present study was therefore to establish a MFB partial lesion model in mice. We tested four different 6-OHDA doses, and our results show a dose-dependent loss of nigral dopaminergic cells and striatal fibres that correlated with behavioural impairment in several behavioural tests. Specifically, doses of 0.7 μg and 1 μg of 6-OHDA induced a partial denervation of the nigrostriatal pathway, associated with a mild but quantifiable behavioural impairment. We identified the amphetamine-induced rotation, stepping, corridor and cylinder test to be sensitive enough to select partial lesion animals. Based on our data, we proposed a range of cut-off values for these different behavioural tests to select partial lesion mice. Using a statistical prediction model we identified two behavioural tests (the stepping test and amphetamine-induced rotation test) that with a high sensitivity and specificity predict the extent of nigral dopaminergic cell loss and select mice with a partial nigrostriatal lesion prior to further interventions. This model can serve as an important tool to study neuroprotective therapies for PD in mouse models, especially when the treatment targets the substantia nigra and/or the striatum.

Striatal C-PE2I appears to show greater sensitivity for detecting differences in motor severity than F-dopa. Furthermore, dopamine transporter decline is closely associated with motor progression over time, whereas no such relationship was found with aromatic l-amino acid decarboxylase. C-PE2I may be more effective for evaluating the efficacy of neuroprotective treatments in PD. © 2017 International Parkinson and Movement Disorder Society.

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IntroductionDopaminergic neuron loss in substantia nigra (SN) in patients with PD is associated with deposits of iron. Susceptibility weighted imaging (SWI) is a high-resolution MR-based imaging technique for quantifying iron depositions in vivo. SWI may be a robust biomarker for clinical characterization of PD.MethodsForty-two patients with PD were studied with SWI imaging. Average phase shift (radians) and percentage iron deposition of the SN were analysed using SPIN software. SWI data were also compared between PD patients with early (4.0±0.5 PD duration) vs. established PD (7.7±1.9), and according to low (21.2±4.5) vs. high (41.3±8.7) UPDRS-III-assessed motor symptoms severity. Data were interrogated using analysis of covariance (age), relative to healthy controls, and using post hoc univariate tests.ResultsPD patients had higher phase shift values (p<0.01) and iron deposition percentage (p<0.001) in the SN bilaterally, compared to healthy controls. Phase shift values were significantly higher in patients with established PD compared to those with early PD (p<0.05) and higher UPDRS-III motor scores (p<0.05).ConclusionsPD patients show higher levels of deposits of iron in SN compared to healthy controls, and increased iron levels in SN are associated with prolonged disease and increased motor disability

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Background Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone‐anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo‐controlled, double‐blind, 6‐month main study followed by an active‐treatment 6‐month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE‐PE2I. Results Drug‐related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: The core intrinsic connectivity networks (ICNs), encompassing the default-mode network (DMN), salience network (SN) and central executive network (CEN), have been shown to be dysfunctional in individual’s with internalizing disorders (IDs; e.g. major depressive disorder, MDD; generalized anxiety disorder, GAD; social anxiety disorder, SOC). As such, source-localised electroencephalogram neurofeedback (EEG-NFB) therapy targeting key cortical nodes within these networks has the potential to reduce symptoms associated with IDs and restore normal core ICN function. We intend to conduct a transdiagnostic, randomized, double-blind, sham-controlled, dose-response, parallel-group trial of standardized low-resolution electromagnetic tomography electrophysiological infraslow (<0.1 Hz) fluctuation neurofeedback (sLORETA eISF-NFB) 3 times per week over 4 weeks in participants (n=60) with IDs. Our primary aim will be to assess the clinical efficacy of sLORETA eISF-NFB via relevant patient-reported outcomes (PROs). Methods: We will randomly assign participants with a current diagnosis of MDD, GAD, and/or SOC to one of four groups: 1) 12 sessions of posterior cingulate cortex (PCC) up-training (n=15), 2) 6 sessions of yoked-sham training followed by 6 sessions of PCC up-training (n=15), 3) 12 sessions of concurrent mid-cingulate (MCC) down-training and PCC up-training (n=15), or 4) 6 sessions of yoked-sham training followed by 6 sessions of concurrent MCC down-training and PCC up-training. Transdiagnostic PROs, as well as resting-state neuro-physiological measures (EEG; electrocardiography, ECG; electrodermal activity, EDA), will be collected from all subjects at baseline, mid-training, 1 week post-training, and 1 month post-training. We will further compare baseline PROs and neuro-physiological measures to age- and sex-matched non-ID (i.e. no ID diagnosis) controls. Discussion: This protocol will outline the rationale and research methodology for a clinical trial of sLORETA eISF-NFB targeting key nodes within the core ICNs in a population with IDs with the primary aim being to assess its specific (e.g. non-placebo induced) efficacy via PROs. Trial Registration: Our study was prospectively registered with the Australia New Zealand Clinical Trials Registry (ANZCTR; Trial Id: ACTRN12619001428156)

Background: Mental illnesses are increasing worldwide with the internalizing disorders (IDs; e.g., anxiety disorders, depressive disorders) being the most prevalent. Current first-line therapies (e.g., pharmacotherapy) offer high failure rates and substantial side effects. Electroencephalographic neurofeedback (EEG-NFB) has been shown to be an effective and safe treatment for these conditions; however, there remains much doubt regarding the existence of specificity (i.e., clinical effects specific to the modulation of the EEG variables of interest). This is a protocol for a quantitative review that will attempt to determine if there is evidence for EEG-NFB specificity in the treatment of IDs. Methods: We will consider all published and unpublished randomized, double-blind (i.e., trainees and raters), sham/placebo-controlled (i.e., feedback contingent on a random signal, the activity from a different person's brain, or an unrelated signal from the trainee's own brain) trials involving humans with at least one ID diagnosis without exclusion by language, locality, ethnicity, age, or sex. Effect sizes will be calculated for individual studies and combined in a meta-analysis. Discussion: This protocol outlines the research methodology for a quantitative review undertaken to assess for evidence of EEG-NFB specificity in the treatment of IDs. Registration: This review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42020159702).