Modulation of limbic resting-state networks by subthalamic nucleus deep brain stimulation.

Beyond the established effects of subthalamic nucleus deep brain stimulation (STN-DBS) in reducing motor symptoms in Parkinson's disease, recent evidence has highlighted the effect on non-motor symptoms. However, the impact of STN-DBS on disseminated networks remains unclear. This study aimed to perform a quantitative evaluation of network-specific modulation induced by STN-DBS using Leading Eigenvector Dynamics Analysis (LEiDA). We calculated the occupancy of resting-state networks (RSNs) in functional MRI data from 10 patients with Parkinson's disease implanted with STN-DBS and statistically compared between ON and OFF conditions. STN-DBS was found to specifically modulate the occupancy of networks overlapping with limbic RSNs. STN-DBS significantly increased the occupancy of an orbitofrontal limbic subsystem with respect to both DBS OFF (p = 0.0057) and 49 age-matched healthy controls (p = 0.0033). Occupancy of a diffuse limbic RSN was increased with STN-DBS OFF when compared with healthy controls (p = 0.021), but not when STN-DBS was ON, which indicates rebalancing of this network. These results highlight the modulatory effect of STN-DBS on components of the limbic system, particularly within the orbitofrontal cortex, a structure associated with reward processing. These results reinforce the value of quantitative biomarkers of RSN activity in evaluating the disseminated impact of brain stimulation techniques and the personalization of therapeutic strategies.

Safety of Endoscopic Transsphenoidal Pituitary Surgery during the COVID-19 Pandemic and Comparison to the Pre-Pandemic Era.

Objective The COVID-19 pandemic has caused significant disruption to the surgical care of patients with pituitary tumors. Guidance issued early during the pandemic suggested avoiding transnasal approaches to minimize risks of transmitting COVID-19 to health care professionals involved in these procedures. Methods This observational, single-center study compares results of endoscopic transsphenoidal approach (TSA) for pituitary tumors since the start of the pandemic to a pre-pandemic period. Anesthetic time, surgical time, and complication rates were compared. Newly acquired COVID-19 infections and transmission rates to patients and staff were reviewed. Data were analyzed by using the independent t -test, Mann-Whitney U test, and Pearson Chi-square test, significance set at p <0.05. Results Over a 12-month period, a total of 50 and 69 patients underwent endoscopic TSA for pituitary tumor during and before the pandemic, respectively. All patients tested negative for COVID-19 preoperatively. Median duration of anesthesia was 35 minutes (interquartile range [IQR]: 22) during the pandemic and 25 minutes (IQR: 8, p = 0.0002) pre-pandemic. Median duration of surgery was 70 minutes (IQR: 28) during the pandemic and 79 minutes (IQR: 33.75, p = 0.126) pre-pandemic. There were no statistically significant differences between intraoperative CSF leaks and complication rates. No staff members tested positive for COVID-19. Three patients tested positive for COVID-19 postdischarge, but the infections were community acquired. Conclusion In contrast to published guidelines, adequate preoperative testing, a multidisciplinary approach and the implementation of standardized protocols and vaccination against COVID-19 allow for endoscopic transsphenoidal surgery to be performed safely in patients with pituitary pathology during the pandemic.

Deep Brain Stimulation of the Nucleus Accumbens in Severe Enduring Anorexia Nervosa: A Pilot Study.

Introduction: Anorexia nervosa (AN) is one of the most debilitating psychiatric disorders, becoming severe and enduring in a third of cases; with few effective treatments. Deep brain stimulation is a reversible, adjustable neurosurgical procedure that has been gaining ground in psychiatry as a treatment for depression and obsessive-compulsive disorder, yet few studies have investigated AN. Abnormal eating behavior and the compulsive pursuit of thinness in AN is, in part, a consequence of dysfunction in reward circuitry and the nucleus accumbens (NAcc) is central to reward processing. Methods: Phase 1 prospective open-label pilot study of seven individuals with severe enduring AN. Electrodes were implanted bilaterally into the NAcc with stimulation at the anterior limb of the internal capsule using rechargeable implantable pulse generators. The protocol of 15 months included 12 months of deep brain stimulation incorporating two consecutive, randomized blind on-off fortnights 9 months after stimulation onset. The primary objectives were to investigate safety and feasibility, together with changes in eating disorder psychopathology. Results: Feasibility and safety was demonstrated with no serious adverse events due to deep brain stimulation. Three patients responded to treatment [defined as > 35% reduction in Eating Disorders Examination (EDE) score at 12 months] and four patients were non-responders. Responders had a statistically significant mean reduction in EDE scores (50.3% reduction; 95% CI 2.6-98.2%), Clinical Impairment Assessment (45.6% reduction; 95% CI 7.4-83.7%). Responders also had a statistically significant mean reduction in Hamilton Depression Scale, Hamilton Anxiety Scale and Snaith-Hamilton pleasure scale. There were no statistically significant changes in Body Mass Index, Yale-Brown-Cornell Eating Disorder Scale, Yale-Brown Obsessive-Compulsive Scale and World Health Organization Quality of Life Psychological subscale. Conclusion: This study provides some preliminary indication that deep brain stimulation to the NAcc. Might potentially improve some key features of enduring AN. In this small study, the three responders had comorbid obsessive-compulsive disorder which predated AN diagnosis. Future studies should aim to further elucidate predictors of outcome. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [Project ID 128658].

Early and ultra-early surgical decompression for acute spinal cord injury: bracing for the winds of change.

PURPOSE: Until recently, there has been no consensus on the optimal operative window for decompressive surgery in acute spinal cord injury (aSCI). However, recent evidence is now supporting a role for early intervention in improving outcomes in this type of patients. The purpose of this letter is to discuss the implications for clinical practice within the European community. METHODS: Critical appraisal and interpretation of these results for clinical implementation. RESULTS: Leveraging on the evidence that early (< 24 h), and possibly ultra-early (< 8 h), decompressive spinal surgery in aSCI affords better neurological outcomes, the next challenge for our community will be to ensure that spinal surgery services can accommodate this caseload. Here, we discuss the challenges that will be faced by spinal surgeons and draw parallels between the scaling of these services and the implementation of mechanical thrombectomy for acute ischaemic stroke. We outline key lessons that have been learnt from the rapid scaling of mechanical thrombectomy services and highlight the provisions in infrastructure, education, and staffing that will be required. CONCLUSION: This is a call for hospital systems to swiftly restructure spinal services in order to meet the need for early, and possibly ultra-early, spinal decompression in aSCI cases in the near future.

Pallido-putaminal connectivity predicts outcomes of deep brain stimulation for cervical dystonia.

Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables. We conclude that modulation of the primary motor putamen-posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting.

Effectiveness of upper limb functional electrical stimulation after stroke for the improvement of activities of daily living and motor function: a systematic review and meta-analysis.

BACKGROUND: Stroke can lead to significant impairment of upper limb function which affects performance of activities of daily living (ADL). Functional electrical stimulation (FES) involves electrical stimulation of motor neurons such that muscle groups contract and create or augment a moment about a joint. Whilst lower limb FES was established in post-stroke rehabilitation, there is a lack of clarity on the effectiveness of upper limb FES. This systematic review aims to evaluate the effectiveness of post-stroke upper limb FES on ADL and motor outcomes. METHODS: Systematic review of randomised controlled trials from MEDLINE, PsychINFO, EMBASE, CENTRAL, ISRCTN, ICTRP and ClinicalTrials.gov. Citation checking of included studies and systematic reviews. Eligibility criteria: participants > 18 years with haemorrhagic/ischaemic stroke, intervention group received upper limb FES plus standard care, control group received standard care. Outcomes were ADL (primary), functional motor ability (secondary) and other motor outcomes (tertiary). Quality assessment using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. RESULTS: Twenty studies were included. No significant benefit of FES was found for objective ADL measures reported in six studies (standardised mean difference (SMD) 0.64; 95% Confidence Interval (CI) [-0.02, 1.30]; total participants in FES group (n) = 67); combination of all ADL measures was not possible. Analysis of three studies where FES was initiated on average within 2 months post-stroke showed a significant benefit of FES on ADL (SMD 1.24; CI [0.46, 2.03]; n = 32). In three studies where FES was initiated more than 1 year after stroke, no significant ADL improvements were seen (SMD -0.10; CI [-0.59, 0.38], n = 35). Quality assessment using GRADE found very low quality evidence in all analyses due to heterogeneity, low participant numbers and lack of blinding. CONCLUSIONS: FES is a promising therapy which could play a part in future stroke rehabilitation. This review found a statistically significant benefit from FES applied within 2 months of stroke on the primary outcome of ADL. However, due to the very low (GRADE) quality evidence of these analyses, firm conclusions cannot be drawn about the effectiveness of FES or its optimum therapeutic window. Hence, there is a need for high quality large-scale randomised controlled trials of upper limb FES after stroke. TRIAL REGISTRATION: PROSPERO: CRD42015025162 , Date:11/08/2015.

High-resolution spatio-temporal bioactivity of a novel peptide revealed by optical imaging in rat orbitofrontal cortex in vitro: possible implications for neurodegenerative diseases.

Acetylcholinesterase (AChE) is now well known to have a secondary, non-enzymatic function independent of cholinergic transmission. In the last decade, the part of the molecule responsible for this action has been identified, i.e. a 14 amino acid peptide fragment ('T14'), deriving from the C-terminus of AChE: this peptide has been shown to be bioactive in a range of preparations and to act at an allosteric site on α7 nicotinic acetylcholine receptors (α7-nAChRs). Of particular significance is the finding that AChE-related peptides trigger calcium-induced neurotoxicity that may be pivotal in the process of neurodegenerative diseases, such as Alzheimer's. However to date all studies have been performed on isolated cell preparations. The aim of this study was therefore to characterise the bioactivity of T14 on meso-scale in vitro cortical networks ('neuronal assemblies') from rat brain slices containing orbitofrontal cortex. Local field potential (LFP) recordings showed that the T14 peptide has a selective, holistic action on cortical networks in a modulatory biphasic manner i.e. predisposing excitation at concentrations of up to 1 µM, after which the trend is reversed in favour of inhibition at higher doses (>1 µM). By contrast, a scrambled variant of the T14 peptide sequence (S14), showed no significant changes in neuronal activation. Optical imaging using voltage-sensitive dyes (VSDI) corroborated the electrophysiological findings and also provided further insight into the spatial dynamics of the effects of the peptide: T14 application had a facilitatory effect i.e. increased the time-course of activation at sub-micromolar concentrations only (700 nM) without significantly affecting the spread of evoked assemblies. Moreover: co-applying T14 with the α7-nAChR competitive antagonist methyllycaconitine (MLA) produced inhibition in activation synchrony not seen with either agent on their own, suggesting an additive inhibitory effect. In conclusion, the T14 peptide derived from AChE produced a dose-dependent biphasic modulation of cortical networks activity dependent on the α7-nAChR: these findings should thus provide a more comprehensive insight into the immediate actions of a novel bioactive agent of high potential relevance to neurodegenerative disorders such as Alzheimer's disease.