Cerebellar Nicotinic Cholinergic Receptors are Intrinsic to the Cerebellum: Implications for Diverse Functional Roles

Although recent studies have delineated the specific nicotinic subtypes present in the mammalian cerebellum, very little is known about their location or function within the cerebellum. This is of increased interest since nicotinic receptors (nAChRs) in the cerebellum have recently been implicated in the pathology of autism spectrum disorders. To begin to better understand the roles of these heteromeric nAChRs in the cerebellar circuitry and their therapeutic potential as targets for drug development, we used various chemical and stereotaxic lesion models in conjunction with slice electrophysiology to examine how specific heteromeric nAChR subtypes may influence the surrounding cerebellar circuitry. Using subunit-specific immunoprecipitation of radiolabeled nAChRs in the cerebella following N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, p-chloroamphetamine, and pendunculotomy lesions, we show that most, if not all, cerebellar nicotinic receptors are present in cells within the cerebellum itself and not in extracerebellar afferents. Furthermore, we demonstrate that the β4-containing, but not the β2-containing, nAChRs intrinsic to the cerebellum can regulate inhibitory synaptic efficacy at two major classes of cerebellar neurons. These tandem findings suggest that nAChRs may present a potential drug target for disorders involving the cerebellum.     

Altered Hub Functioning and Compensatory Activations in the Connectome: A Meta-Analysis of Functional Neuroimaging Studies in Schizophrenia

Background:

Functional neuroimaging studies of schizophrenia have identified abnormal activations in many brain regions. In an effort to interpret these findings from a network perspective, we carried out a meta-analysis of this literature, mapping anatomical locations of under- and over-activation to the topology of a normative human functional connectome.

Methods:

We included 314 task-based functional neuroimaging studies including more than 5000 patients with schizophrenia and over 5000 controls. Coordinates of significant under- or over-activations in patients relative to controls were mapped to nodes of a normative connectome defined by a prior meta-analysis of 1641 functional neuroimaging studies of task-related activation in healthy volunteers.

Results:

Under-activations and over-activations were reported in a wide diversity of brain regions. Both under- and over-activations were significantly more likely to be located in hub nodes that constitute the “rich club” or core of the normative connectome. In a subset of 121 studies that reported both under- and over-activations in the same patients, we found that, in network terms, these abnormalities were located in close topological proximity to each other. Under-activation in a peripheral node was more frequently associated specifically with over-activation of core nodes than with over-activation of another peripheral node.

Conclusions:

Although schizophrenia is associated with altered brain functional activation in a wide variety of regions, abnormal responses are concentrated in hubs of the normative connectome. Task-specific under-activation in schizophrenia is accompanied by over-activation of topologically central, less functionally specialized network nodes, which may represent a compensatory response.Key words: schizophrenia, connectome, fMRI, graph analysis, hubs     

Differential Excitability of PV and SST Neurons Results in Distinct Functional Roles in Inhibition Stabilization of Up States

Up states are the best studied example of an emergent neural dynamic regime. Computational models based on a single class of inhibitory neurons indicate that Up states reflect bistable dynamic systems in which positive feedback is stabilized by strong inhibition and predict a paradoxical effect in which increased drive to inhibitory neurons results in decreased inhibitory activity. To date, however, computational models have not incorporated empirically defined properties of parvalbumin (PV) and somatostatin (SST) neurons. Here we first experimentally characterized the frequency–current (F–I) curves of pyramidal (Pyr), PV, and SST neurons from mice of either sex, and confirmed a sharp difference between the threshold and slopes of PV and SST neurons. The empirically defined F–I curves were incorporated into a three-population computational model that simulated the empirically derived firing rates of pyramidal, PV, and SST neurons. Simulations revealed that the intrinsic properties were sufficient to predict that PV neurons are primarily responsible for generating the nontrivial fixed points representing Up states. Simulations and analytical methods demonstrated that while the paradoxical effect is not obligatory in a model with two classes of inhibitory neurons, it is present in most regimes. Finally, experimental tests validated predictions of the model that the Pyr ↔ PV inhibitory loop is stronger than the Pyr ↔ SST loop.SIGNIFICANCE STATEMENT Many cortical computations, such as working memory, rely on the local recurrent excitatory connections that define cortical circuit motifs. Up states are among the best studied examples of neural dynamic regimes that rely on recurrent excitatory excitation. However, this positive feedback must be held in check by inhibition. To address the relative contribution of PV and SST neurons, we characterized the intrinsic input–output differences between these classes of inhibitory neurons and, using experimental and theoretical methods, show that the higher threshold and gain of PV leads to a dominant role in network stabilization.     

Electrical Stimulation in Lower Limb During Exercise to Improve Gait Speed and Functional Motor Ability 6 Months Poststroke. A Review with Meta-Analysis

IntroductionStroke is the third most common cause of disability in adults over 65 years of age and there are 30.7 million survivors after stroke worldwide. Stroke survivors have the highest odds of reporting severe disability and the greatest variety of individual domains of disability compared to a range of other conditions. Electrical stimulation of peripheral sensory-motor systems increases voluntary movement and muscle strength and thereby raises the activities of daily living (ADL). Little is known about electrical stimulation during physical activity in rehabilitation; the objective of this review is therefore to investigate whether external electrical stimulation combined with activity improves functional motor ability and gait speed in patients who have experienced a stroke within the last 6 months.MethodsA review and random effects meta-analysis of randomized controlled clinical trials on gait speed and functional motor ability measured with Barthel Index (BI) and Bergs Balance Scale (BBS).ResultsEight trials were included (n = 191). Explorative meta-analysis was performed on gait speed (5 trials, n = 120), BI (3 trials, n = 74), and BBS (3 trial n = 79). A small, significant difference on gait speed 0.15 (95% confidence interval [CI]: 0.08-0.21) m/s, but no difference in BI 2.88 (95 % CI: −3.3 to 9.07) and BBS 1.73 (95% CI: −2.8 to 6.27).ConclusionsSparse, low-quality evidence indicates that electrical stimulation combined with activity is a relevant intervention to improve ADL within 6 months poststroke.     

Meta-Analysis of Caregiver-Directed Psychosocial Interventions for Schizophrenia

With the recent movement toward a personal-recovery paradigm to treat schizophrenia, the locus of mental health care delivery has shifted toward community-based care. Family caregivers comprise a substantial component of that community, and are often providing care for longer periods, but often have no formal training or support. Caregiver-directed psychosocial interventions (CDPI) have been developed to train and assist caregivers in their efforts to maximize the odds of treatment success for those in their care. This meta-analysis compared CDPI versus treatment as usual (TAU) on outcomes such as hospitalization, relapse, non-compliance, and “other outcomes” (emergency services utilization, suicide attempt, and death). A systematic literature search (2005–2015) was conducted to identify randomized controlled trials of outpatient administered CDPI versus TAU to treat adult patients recovering from schizophrenia. Relative risks (RR) with 95% confidence intervals derived via random effects meta-analysis were calculated to compare CDPI versus TAU on the aforementioned outcomes. Eighteen of the 693 citations were retained for analysis. Overall RR for CDPI versus TAU suggested improved outcomes associated with CDPI: hospitalization [0.62 (0.46, 0.84) p?<?0.00001], relapse [0.58 (0.47, 0.73) p?<?0.00001] and other outcomes [0.70 (0.19, 2.57) p?=?0.59]. CDPI was associated with significantly better compliance with medication and clinical activities combined [0.38 (0.19, 0.74) p?=?0.005]. Medication compliance alone favored CDPI but was non-significant. Compliance with clinical activities alone favored CDPI significantly [0.22 (0.11, 0.47) p?<?0.00001]. CDPI is associated with reductions in hospitalization, relapse, and treatment non-compliance.     

Meta-Analysis in Neuropsychology: An Introduction

ABSTRACT

This special issue is an introduction to meta-analytic approaches, methods, and findings in neuropsychology. The six articles that comprise this issue include a review article, one article examining the statistical power of a specific research literature, and four new meta-analyses on neuropsychological topics. Together these articles provide a user-friendly introduction to meta-analysis in neuropsychology and are designed to assist the clinician in using and applying findings from these studies to their own research and/or clinical work.     

Meta-Analysis of the Association of Urbanicity With Schizophrenia

The association between urbanicity and risk of schizophrenia is well established. The incidence of schizophrenia has been observed to increase in line with rising levels of urbanicity, as measured in terms of population size or density. This association is expressed as Incidence Rate Ratio (IRR), and the results are usually presented by comparing the most urban with the most rural environment. In this study, we undertook to express the effect of urbanicity on the risk of schizophrenia in a linear form and to perform a meta-analysis of all available evidence. We first employed a simple regression analysis of log (IRR) as given in each study on the urbanicity category, assuming a uniform distribution and a linear association. In order to obtain more accurate estimates, we developed a more sophisticated method that generates individual data points with simulation from the summary data presented in the original studies, and then fits a logistic regression model. The estimates from each study were combined with meta-analysis. Despite the challenges that arise from differences between studies as regards to the number and relative size of urbanicity levels, a linear association was observed between the logarithm of the odds of risk for schizophrenia and urbanicity. The risk for schizophrenia at the most urban environment was estimated to be 2.37 times higher than in the most rural environment. The same effect was found when studies measuring the risk for nonaffective psychosis were included.Key words: schizophrenia, psychosis, review, urban environment     

Hemorrhagic Complications of Ventriculostomy Placement: A Meta-Analysis

Introduction  The reported intracerebral hemorrhage rate due to ventriculostomy placement varies widely. As studies emerge regarding alternative techniques of ventriculostomy placement, and placement by non-neurosurgeons, further definition of the true intracerebral hemorrhage rate associated with ventriculostomy is warranted. We performed a meta-analysis of the existing literature to further elucidate the incidence of intracerebral hemorrhage due to ventriculostomy. Methods  We performed an extensive literature search using Ovid MEDLINE and PubMed for relevant studies published after 1970. Only studies with more than 25 ventriculostomy procedures were included. Data were extracted regarding number of hemorrhages, clinically significant hemorrhages, and the use of routine post-ventriculostomy CT scanning. We performed subgroup analyses based on the use of routine post-ventriculostomy CT scanning. Chi-squared test was used to determine statistical significance. Results  Overall, 102 hemorrhagic complications from 1,790 ventriculostomies were reported, a hemorrhage rate of 5.7%. Of the 102 hemorrhages, 11 were clinically significant (clinically significant hemorrhage rate = 0.61%). In studies that used routine post-placement CT scans, the hemorrhage rate was 10.06%, compared to a hemorrhage rate of 1.53% in studies in which routine CT scans were not performed (P < 0.001). Eight clinically significant hemorrhages (0.91%) were identified in the studies utilizing routine post-procedural CT scanning, compared to three clinically significant hemorrhages (0.33%) in studies without routine CT scans (P = 0.113). Conclusion  The overall hemorrhage risk associated with ventriculostomy placement based on the existing literature is 5.7%. Clinically significant hemorrhage due to ventriculostomy is less than 1%. Modifications of technique that might reduce hemorrhage risk, and the utility of routine post-procedural CT scanning, merit further investigation.