ABSTRACT

The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.

Background Balance problems contribute to reduced quality of life in Parkinson’s disease (PD) and available treatments are often insufficient for treating axial and postural motor symptoms. Objective To investigate the safety of use and possible effects of stochastic vestibular stimulation (SVS) alone and combined with LDOPA in patients with PD. Methods SVS or sham stimulation was administered to 10 PD patients in a double-blind placebo controlled cross-over pilot study. Motor symptoms and balance were evaluated in a defined off-medication state and after a 200 mg test dose of LDOPA, using UPDRS-III, Posturo- Locomotor-Manual (PLM) movement times (MT), static posturography and force plate measurements of the correcting response to a balance perturbation. Results Patients did not detect when SVS was active, but SVS increased nausea after LDOPA in two patients. Mixed model analysis demonstrated that SVS improved balance corrections after a backward perturbation and shortened the postural response time. In static posturography there was significant interaction between effects of SVS, medication and proprioceptive input (standing on foam vs. on hard support) and SVS decreased the total sway-path with eyes closed and off medication. As expected, LDOPA improved the UPDRS-III scores and MT. There was an interaction between the effect of SVS and LDOPA on UPDRS-III partly because of reduced UPDRS-III scores with SVS in the off-medication state. Conclusions Short term use of SVS is safe, improves corrective postural responses and may have a small positive effect on motor symptoms in PD patients off treatment.

Patients need to feel well informed and find an added value in using wearables. Wearables need to be user-friendly, have an attractive design, and show clinical efficacy in improving disease management. Variations in perceptions regarding integrity, benefits, and effectiveness of monitoring indicate possible conflicts of expectations among participants. The engagement of end users, patients, and health professionals, in the design and implementation process, is crucial for the development of wearable devices that enhance and facilitate neurological rehabilitation practice.

Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression.

We investigated the role of the vestibular commissural inhibitory system in vestibular compensation (VC, the behavioural recovery that follows unilateral vestibular loss), using in vivo microdialysis to measure GABA levels in the bilateral medial vestibular nucleus (MVN) at various times after unilateral labyrinthectomy (UL). Immediately after UL, in close correlation with the appearance of the characteristic oculomotor and postural symptoms, there is a marked increase in GABA release in the ipsi-lesional MVN. This is not prevented by bilateral flocculectomy, indicating that it is due to hyperactivity of vestibular commissural inhibitory neurones. Over the following 96 h, as VC occurs and the behavioural symptoms ameliorate, the ipsi-lesional GABA levels return to near-normal. Contra-lesional GABA levels do not change significantly in the initial stages of VC, but decrease at late stages so that when static symptoms have abated there remains a significant difference between the MVNs of the two sides. We also investigated the role of the commissural inhibition in Bechterew's phenomenon, by reversibly inactivating the intact contra-lesional labyrinth in compensating animals through superfusion of local anaesthetic on the round window. Transient inactivation of the intact labyrinth elicited the lateralized behaviour described by Bechterew, but did not alter the GABA levels in either MVN, suggesting the involvement of distinct cellular mechanisms. These findings indicate that an imbalanced commissural inhibitory system is a root cause of the severe oculomotor and postural symptoms of unilateral vestibular loss, and that re-balancing of commissural inhibition occurs in parallel with the subsequent behavioural recovery during VC.

Motor aspects of Parkinson’s disease, such as fluctuations and dyskinesia, can be reliably evaluated using a variety of “wearable” technologies, but practical guidance on objective measurement (OM) and the optimum use of these devices is lacking. Therefore, as a first step, a panel of movement disorder specialists met to provide guidance on how OM could be assessed and incorporated into clinical guidelines. A key aspect of the incorporation of OM into the management of Parkinson’s disease (PD) is defining cutoff values that separate “controlled” from “uncontrolled” symptoms that can be modified by therapy and that relate to an outcome that is relevant to the person with PD (such as quality of life). Defining cutoffs by consensus, which can be subsequently tested and refined, is the first step to optimizing OM in the management of PD. OM should be used by all clinicians that treat people with PD but the least experienced may find the most value, but this requires guidance from experts to allow non-experts to apply guidelines. While evidence is gained for devices that produce OM, expert opinion is needed to supplement the evidence base.

IntroductionEstablishing the presence and severity of fluctuations is important in managing Parkinson’s Disease yet there is no reliable, objective means of doing this. In this study we have evaluated a Fluctuation Score derived from variations in dyskinesia and bradykinesia scores produced by an accelerometry based system.MethodsThe Fluctuation Score was produced by summing the interquartile range of bradykinesia scores and dyskinesia scores produced every 2 minutes between 0900-1800 for at least 6 days by the accelerometry based system and expressing it as an algorithm.ResultsThis Score could distinguish between fluctuating and non-fluctuating patients with high sensitivity and selectivity and was significant lower following activation of deep brain stimulators. The scores following deep brain stimulation lay in a band just above the score separating fluctuators from non-fluctuators, suggesting a range representing adequate motor control. When compared with control subjects the score of newly diagnosed patients show a loss of fluctuation with onset of PD. The score was calculated in subjects whose duration of disease was known and this showed that newly diagnosed patients soon develop higher scores which either fall under or within the range representing adequate motor control or instead go on to develop more severe fluctuations.ConclusionThe Fluctuation Score described here promises to be a useful tool for identifying patients whose fluctuations are progressing and may require therapeutic changes. It also shows promise as a useful research tool. Further studies are required to more accurately identify therapeutic targets and ranges.