Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive. METHODS: In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies. FINDINGS: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na+ conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation. INTERPRETATION: These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD. FUNDING: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.

The role of the neurometer CPT/C in sacral neuromodulation.

OBJECTIVE: The aim of the current research project was to study the role of the Neurometer® as a tool to predict responders to sacral neuromodulation therapy (SNM). MATERIAL AND METHODS: This was a prospective, open study in male and female patients, aged 18 and over with voiding dysfunction [non-obstructive retention and/or frequency/ urgency syndrome]. The first group underwent a screening test to evaluate percutaneous nerve functions (PNE) and to determine whether they are candidates for SNM with the InterStim®. Prior to PNE testing, all patients were evaluated with the pain tolerance test (PTT) using the electro-diagnostic Neurometer® CPT/C device. An InterStim® implant was placed in patients who were responders to PNE testing underwent. On the other hand, non-responders underwent a staged implant placement. The second group consisted of patients who already had InterStim® implanted for voiding dysfunction. During the routine office follow-up, the patients implanted with Interstim® underwent a PTT using the Neurometer® CPT/C device. All the testing using the Neurometer CPT/C was performed on the day of the PNE for the first group, and the day of the routine follow-up visit for the second group. All of the results for the Neurometer® testing were kept blinded from the PNE results, and those of the outcome of the follow-up visit. The study received approval by the Research Ethics Board of the University Health Network (No. 14-8196). RESULTS: We recruited a total of 123 patients. The results presented here include 110 patients who completed the study, 48 of whom were in the first group, and 62 in the second group. The statistical analysis used was as follows: Group 1: Simple linear regression analysis and the linear discriminate analysis were preformed. It was found that for patients without the InterStim® implant with a combined CPT/CPD of 800 and above, the Neurometer® could predict the test screening results with an accuracy of 71%. Group 2: Same analysis and tests were conducted for patients with the InterStim® implant, and the results showed that if the patient had a combined CPT/CPD of 600 and above, the Neurometer® could predict the patients satisfaction or dissatisfaction with an accuracy of 72%. CONCLUSION: Neurometer® may play a role in predicting test trial positive responders and patient satisfaction after the placement of InterStim® implant.