Optimizing Deep Brain Stimulation of the Nucleus Accumbens in a Reward Preference Rat Model.

OBJECTIVE/HYPOTHESIS: Deep brain stimulation (DBS) has become the preferred therapy for a growing number of treatment-resistant neuropsychiatric conditions, offering the benefit of being amenable to fine-tuning to enhance its efficacy. However, while some DBS parameters are routinely adjusted, the stimulation is almost always delivered in a continuous "tonic" pattern, which may be suboptimal at times. Our overall aim is to investigate the application of differing levels of rewarding DBS to the reconditioning of behavioral "trigger" and "non-trigger" stimuli in impulse-control disorders (including addiction). As a first step, we used a rat model of nucleus accumbens (NAc) DBS to rigorously compare the relative reward values of different stimulation paradigms. We hypothesized that delivering pulses in a more physiological pattern would prove more rewarding than delivering tonic stimulation. MATERIALS AND METHODS: We implanted microelectrodes in the left NAc shell and trained rats to initiate and terminate DBS to demonstrate their "preference" between different brain stimulation reward (BSR) paradigms. We tested a range of BSR paradigms, including tonic, intermittent tonic, and burst paradigms. Two paradigms were compared at a time, and paired t-tests were used to determine whether the rats significantly "preferred" one paradigm over another. RESULTS: The rats significantly preferred intermittent tonic BSR paradigms to continuous and burst paradigms, and generally preferred paradigms that delivered more pulses over the stimulation period. CONCLUSIONS: These findings highlight that the standard approach of delivering tonic DBS is not optimal under all circumstances. Further research should investigate which DBS paradigms are best for different brain disorders.

Modification to the Rice-Vannucci perinatal hypoxic-ischaemic encephalopathy model in the P7 rat improves the reliability of cerebral infarct development after 48hours.

BACKGROUND: The Rice-Vannucci model of hypoxic-ischaemic encephalopathy (HIE) has been associated with a high degree of variability with respect to the development of cerebral infarction and infarct lesion volume. For this reason, we examined the occurrence of communicational blood flow within the common carotid (CCA), internal (ICA), and external (ECA) carotid arteries following CCA occlusion as a source of variability in the model. NEW METHOD: We propose a novel modification to the Rice-Vannucci model, whereby both the CCA and ECA are permanently ligated; mitigating communicational blood flow. RESULTS: Using magnetic resonance angiography, phase-contrast velocity encoding, and pulsed arterial spin labelling, the modified Rice-Vannucci model (CCA/ECA occlusion) was demonstrated to mitigate communicational blood flow, whilst significantly reducing ipsilateral hemispherical cerebral blood flow (CBF). Comparatively, the original Rice-Vannucci model (CCA occlusion) demonstrated anterograde and retrograde blood flow within the ICA and CCA, respectively, with a non-significant reduction in ipsilateral CBF. Furthermore, CCA/ECA occlusion plus hypoxia (8% O2/92% N2; 2.5h) resulted in 100% of animals presenting with an infarct (vs 87%), significantly larger infarct volume at 48h (18.5% versus 10.0%; p<0.01), reduced standard deviation (±10% versus ±15%), and significantly worsened functional outcomes when compared to CCA occlusion plus hypoxia. COMPARISON WITH EXISTING METHOD: We compared a modified Rice-Vannucci model (CCA/ECA occlusion±hypoxia) to the commonly used Rice-Vannucci model (CCA occlusion±hypoxia). CONCLUSION: This study demonstrates that CCA/ECA occlusion in the Rice-Vannucci model of HIE reduces infarct volume variability by limiting communicational blood flow.

FAST-Mag protocol with or without mild hypothermia (35°C) does not improve outcome after permanent MCAO in rats.

The current study assessed the neuroprotective efficacy of magnesium using a FAST-Mag trial treatment protocol alone, and in combination with mild hypothermia, in Sprague Dawley rats subjected to permanent, middle cerebral artery occlusion (MCAO). Treatment with magnesium (MgSO4.7H2O) consisted of an intravenous loading dose (LD: 360 µmol/kg) and a 24 hour infusion (120 µmol/kg/h), while mild hypothermia at 35°C was maintained for 24 hours. Treatment groups consisted of animals receiving: i) saline; ii) magnesium LD/infusion at 1.5 h/2.5 h post-MCAO; iii) magnesium LD/infusion at 1.5 h/2.5 h post-MCAO and hypothermia commencing at 2.5 h post-MCAO; iv) magnesium LD and hypothermia at 1.5 h and magnesium infusion at 2.5 h post-MCAO; v) hypothermia commencing at 1.5 h post-MCAO and magnesium LD/infusion at 2.5 h post-MCAO; and vi/vii) hypothermia commencing at 1.5 h or 2.5 h post-MCAO. No treatment significantly reduced infarct volumes or improved adhesive tape removal time when measured 48 hours after MCAO. These findings indicate that FAST-Mag treatment alone or with mild hypothermia may not provide benefit after ischemic stroke, associated with permanent cerebral artery occlusion.

Short-term low intensity PMF does not improve functional or histological outcomes in a rat model of transient focal cerebral ischemia.

Stimulation with pulsed magnetic fields (PMF) is a non-invasive technique that can modulate neural activity and has the potential to facilitate functional recovery and tissue preservation/repair following brain injury. The effect of low intensity (8 mT) PMF on functional recovery and infarct tissue volume was assessed in a middle cerebral artery occlusion model of transient focal ischemia in Spontaneously Hypertensive rats. Rats received a combination of PMF protocols, including high and low frequencies and recovery was monitored over eight days. PMF treatment had no effect on functional recovery or infarct volume. Infarcted tissue accounted for ≈8% of total brain volume, encompassing both cortical and subcortical structures. The microglial and astrocytic response to PMF treatment was monitored and there was no change in glial scarring, however there was increased macrophage infiltration in animals that received chronic high (6-9 Hz) and low (1 Hz) stimulation. There was no effect of PMF on the degree of cell death observed within the ischemic core, with no TUNEL positive cells observed in the non-infarcted tissue. No detrimental side-effects of PMF were observed, indicating that low-intensity PMF may have limited safety concerns for future human and animal studies.