scholarly journals High-throughput microcircuit analysis of individual human brains through next-generation multineuron patch-clamp

2019 ◽  
Author(s):  
Yangfan Peng ◽  
Franz X. Mittermaier ◽  
Henrike Planert ◽  
Ulf C. Schneider ◽  
Henrik Alle ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Brain Regions ◽  
Small Sample ◽  
Synaptic Connections ◽  
Cortical Slice ◽  
Systematic Analysis ◽  
Small Sample Sizes ◽  
Human Brains ◽  
Individual Human

AbstractComparing neuronal microcircuits across different brain regions, species and individuals can reveal common and divergent principles of network computation. Simultaneous patch-clamp recordings from multiple neurons offer the highest temporal and subthreshold resolution to analyse local synaptic connectivity. However, its establishment is technically complex and the experimental performance is limited by high failure rates, long experimental times and small sample sizes. We introduce an in-vitro multipatch setup with an automated pipette pressure and cleaning system facilitating recordings of up to 10 neurons simultaneously and sequential patching of additional neurons. We present hardware and software solutions that increase the usability, speed and data throughput of multipatch experiments which allowed probing of 150 synaptic connections between 17 neurons in one human cortical slice and screening of over 600 connections in tissue from a single patient. This method will facilitate the systematic analysis of microcircuits and allow unprecedented comparisons at the level of individuals.

scholarly journals High-throughput microcircuit analysis of individual human brains through next-generation multineuron patch-clamp

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Yangfan Peng ◽  
Franz Xaver Mittermaier ◽  
Henrike Planert ◽  
Ulf Christoph Schneider ◽  
Henrik Alle ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Brain Regions ◽  
Individual Variability ◽  
Small Sample ◽  
Cortical Slice ◽  
Systematic Analysis ◽  
Small Sample Sizes ◽  
Human Brains ◽  
Individual Human

Comparing neuronal microcircuits across different brain regions, species and individuals can reveal common and divergent principles of network computation. Simultaneous patch-clamp recordings from multiple neurons offer the highest temporal and subthreshold resolution to analyse local synaptic connectivity. However, its establishment is technically complex and the experimental performance is limited by high failure rates, long experimental times and small sample sizes. We introduce an in vitro multipatch setup with an automated pipette pressure and cleaning system facilitating recordings of up to 10 neurons simultaneously and sequential patching of additional neurons. We present hardware and software solutions that increase the usability, speed and data throughput of multipatch experiments which allowed probing of 150 synaptic connections between 17 neurons in one human cortical slice and screening of over 600 connections in tissue from a single patient. This method will facilitate the systematic analysis of microcircuits and allow unprecedented assessment of inter-individual variability.

scholarly journals A Connectome-Wide Functional Signature of Trait Anger

2021 ◽  
pp. 216770262110302
Author(s):  
M. Justin Kim ◽  
Maxwell L. Elliott ◽  
Annchen R. Knodt ◽  
Ahmad R. Hariri
Keyword(s):  
Functional Connectivity ◽  
Visual Information ◽  
Past Research ◽  
Brain Regions ◽  
Small Sample ◽  
Trait Anger ◽  
Frontal Pole ◽  
Brain Correlates ◽  
Small Sample Sizes ◽  
The Right

Past research on the brain correlates of trait anger has been limited by small sample sizes, a focus on relatively few regions of interest, and poor test–retest reliability of functional brain measures. To address these limitations, we conducted a data-driven analysis of variability in connectome-wide functional connectivity in a sample of 1,048 young adult volunteers. Multidimensional matrix regression analysis showed that self-reported trait anger maps onto variability in the whole-brain functional connectivity patterns of three brain regions that serve action-related functions: bilateral supplementary motor areas and the right lateral frontal pole. We then demonstrate that trait anger modulates the functional connectivity of these regions with canonical brain networks supporting somatomotor, affective, self-referential, and visual information processes. Our findings offer novel neuroimaging evidence for interpreting trait anger as a greater propensity to provoked action, which supports ongoing efforts to understand its utility as a potential transdiagnostic marker for disordered states characterized by aggressive behavior.

A phase II study of combined methotrexate and teniposide infusions prior to reinduction therapy in relapsed childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study.

1991 ◽  
Vol 9 (1) ◽  
pp. 139-144 ◽  
Author(s):  
J Ochs ◽  
J Rodman ◽  
M Abromowitch ◽  
R Kavanagh ◽  
M Harris ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Index ◽  
Small Sample ◽  
Therapeutic Window ◽  
Infusion Schedule ◽  
Small Sample Sizes

Teniposide (VM-26) can increase intracellular methotrexate (MTX) and its polyglutamate derivatives in vitro and thus has the potential to improve the therapeutic index of regimens containing MTX. In this phase II study, children and adolescents with acute lymphoblastic leukemia (ALL) in first or second marrow relapse were randomly assigned to receive either simultaneous (n = 11) or sequential (n = 12) continuous infusions of MTX and VM-26 prior to reinduction. Infusions of VM-26 were begun 12 hours after completion of MTX infusion in the sequential group. Dosages were individually adjusted to maintain plasma concentration levels of 10 microns for MTX and 15 microns for VM-26; total infusion times were 24 and 72 hours, respectively. Significant toxicity in the first six patients who received the scheduled 72-hour VM-26 infusion (including one drug-related death) prompted a 50% reduction in infusion duration. The reduced dose was associated with similar but more manageable toxicity. Examination of bone marrow aspirates 10 days after therapy was begun showed one complete and two partial marrow remissions; a fourth patient who had an aplastic marrow on day 10 received no further chemotherapy and had a complete remission (CR) documented on day 31. There was no obvious clinical advantage associated with either infusion schedule, although small sample sizes preclude definitive conclusions. The 17% response rate to the MTX/VM-26 therapeutic window in patients with refractory disease suggests the need for further investigation to evaluate alternative schedules and concomitant therapy for this drug combination.

A-131 Treating Parkinson’s Disease with Mindfulness: A Systematic Review

2021 ◽  
Vol 36 (6) ◽  
pp. 1182-1182
Author(s):  
Jillian Lemke ◽  
Christopher Corbin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Sample ◽  
Survey Study ◽  
Motor Symptoms ◽  
Sample Sizes ◽  
Systematic Analysis ◽  
Small Sample Sizes ◽  
Non Motor Symptoms ◽  
Effective Adjunct

Abstract Objective Mindfulness has been recognized as an evidence-based treatment in a range of psychological and medical (i.e., chronic pain, dementia, diabetes) conditions. Despite several randomized and non-randomized control trials, there continues to be a lack of consensus regarding mindfulness as an effective treatment for individuals with Parkinson’s disease (PD). Methods PsychINFO, Medline, ProQuest, and Embase, were searched using a combination of terms such as “Parkinson’s” and “Mindfulness” or “Meditation.” Studies were included if they reported method, participants, interventions used, and outcomes. Results were extracted and assessed for quality and relevance. Data Synthesis The systematic analysis revealed that mindfulness was primarily effective in reducing non-motor symptoms of PD, except for one survey study of PD patients, which indicated that mindfulness was associated with improved motor symptoms. Otherwise, mindfulness resulted in decreased anxiety and distress while also improving social support. Of the two studies that included caregivers in treatment, mindfulness was associated with reduced caregiver burden. Conclusion The results supported the use of mindfulness as an effective adjunct to PD treatment, with the strongest effects on non-motor symptoms and caregiver distress. Notably, the studies included were limited by small sample sizes and patients with mild to moderate symptoms of PD. Further random controlled trials with larger sample sizes and differing degrees of PD severity are needed to conclusively determine the effects of mindfulness in treating PD.

scholarly journals Current Understanding of Religion, Spirituality, and Their Neurobiological Correlates

2020 ◽  
Author(s):  
James I. Rim ◽  
Jesse Caleb Ojeda ◽  
Connie Svob ◽  
Jürgen Kayser ◽  
Elisa Drews ◽  
...  
Keyword(s):  
Functional Neuroimaging ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Clinical Applications ◽  
Small Sample ◽  
Control Group ◽  
Religion And Spirituality ◽  
Wide Range ◽  
Small Sample Sizes ◽  
And Behavior

Religion and spirituality (R/S) have been prominent aspects of most human cultures through the ages; however, scientific inquiry into this phenomenon has been limited. We conducted a systematic literature review of research on the neurobiological correlates of R/S, which resulted in 25 reports studying primarily R/S with electroencephalography, structural neuroimaging (MRI), and functional neuroimaging (fMRI, PET). These studies investigated a wide range of religions (e.g., Christianity, Buddhism, Islam) and R/S states and behaviors (e.g., resting state, prayer, judgments) and employed a wide range of methodologies, some of which (e.g., no control group, varying measures of religiosity, small sample sizes) raise concerns about the validity of the results. Despite these limitations, the findings of these studies collectively suggest that the experience of R/S has specific neurobiological correlates and that these correlates are distinct from non-R/S counterparts. The findings implicate several brain regions potentially associated with R/S development and behavior, including the medial frontal cortex, orbitofrontal cortex, precuneus, posterior cingulate cortex, default mode network, and caudate. This research may suggest future clinical applications and interventions related to R/S and various disorders, including mood, anxiety, psychotic, pain, and vertiginous disorders. Further studies with more rigorous study designs are warranted to elucidate the neurobiological mechanisms of R/S and their potential clinical applications.

scholarly journals Amplification, not spreading limits rate of tau aggregate accumulation in Alzheimer’s disease

2020 ◽  
Author(s):  
Georg Meisl ◽  
Yukun Zuo ◽  
Kieren Allinson ◽  
Timothy Rittman ◽  
Sarah DeVos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Regions ◽  
Replication Rate ◽  
Promising Strategy ◽  
Human Brains ◽  
The Brain ◽  
Tau Aggregate ◽  
Rate Of Accumulation

AbstractBoth the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we are able to quantify their replication rate in human brains. Remarkably, we obtain comparable rates in several different datasets, with 5 different methods of tau quantification, from seed amplification assays in vitro to tau PET studies in living patients. Our results suggest that the overall rate of accumulation of tau in neocortical regions is limited not by spreading between brain regions but by local replication, which doubles the number of seeds every ~5 years. Thus, we propose that limiting local replication constitutes the most promising strategy to control tau accumulation during AD.

scholarly journals Author response: High-throughput microcircuit analysis of individual human brains through next-generation multineuron patch-clamp

2019 ◽  
Author(s):  
Yangfan Peng ◽  
Franz Xaver Mittermaier ◽  
Henrike Planert ◽  
Ulf Christoph Schneider ◽  
Henrik Alle ◽  
...  
Keyword(s):  
Patch Clamp ◽  
High Throughput ◽  
Author Response ◽  
Next Generation ◽  
Human Brains ◽  
Individual Human

A phase I study of high-dose calcitriol in combination with temozolomide for patients (Pts) with metastatic melanoma (MM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9087-9087
Author(s):  
Erin Pettijohn ◽  
Alfred Rademaker ◽  
Brenda K. Martone ◽  
Erica Poast ◽  
Bing Bing Weitner ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Interleukin 2 ◽  
Primary Objective ◽  
Small Sample ◽  
High Dose ◽  
Vdr Gene ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Small Sample Sizes

9087 Background: Temozolomide (Tem) has demonstrated efficacy as an oral alternative for pts with MM on traditional and extended dosing schedules. Calcitriol has known antiproliferative properties in vitro, and has shown synergistic effects with chemotherapy. Additionally, vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and disease progression. Specifically, the VDR genotype tt/ff (Taq1 and Fok1 polymorphisms) has been associated with tumors >3.5mm, though no studies have focused on survival. Methods: Tem 150mg/m2was administered on days 2-8 and 16-22 every 28 days until progression or significant toxicity. Calcitriol was given on days 1 and 15 every 28 days with 3 pts at a dose of 0.2mcg/kg, 3 pts at 0.3mcg/kg, 3 pts at 0.5mcg/kg, and an additional 11 pts at a maximum dose of 0.5mcg/kg. VDR gene analysis was completed on 17/20 pts using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (PFS) and overall survival (OS), both as a whole and by VDR genotype. Results: Twenty pts (males=15) with MM treated with at least one prior systemic therapy or who were not candidates for interleukin-2 (conducted pre BRAF and anti CTLA agents), were accrued. Median age was 58. The regimen was well-tolerated with leukopenia, lymphopenia, thrombocytopenia, anemia, and thrombosis as the most common grade 3 or 4 toxicities at 10% incidence each, less than observed in prior studies (Patel et al Eur J Ca 2011). Obj RR was 10%. Median PFS was 1.8 mo with a mean of 2.7 cycles given. Pts with low-risk VDR genotype non-tt or ff (n= 11) had a median OS of 7.4 mo compared to 3.8 mo for tt or ff or both (n=6)(median ratio=1.95) from time of enrollment, although not statistically significant given small sample sizes. Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated oral regimen in MM. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness. Whether this represents a benefit of the inclusion of calcitriol should be studied further. Clinical trial information: NCT00301067.

scholarly journals MicroRNAs as Salivary Markers for Periodontal Diseases: A New Diagnostic Approach?

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Gerhard Schmalz ◽  
Simin Li ◽  
Ralph Burkhardt ◽  
Sven Rinke ◽  
Felix Krause ◽  
...  
Keyword(s):  
Periodontal Diseases ◽  
Small Sample ◽  
In Vivo Studies ◽  
Case Definitions ◽  
Tissue Samples ◽  
Cancer Types ◽  
Small Sample Sizes ◽  
Noninvasive Markers

The aim of this review is to discuss current findings regarding the roles of miRNAs in periodontal diseases and the potential use of saliva as a diagnostic medium for corresponding miRNA investigations. For periodontal disease, investigations have been restricted to tissue samples and five miRNAs, that is, miR-142-3p, miR-146a, miR-155, miR-203, and miR-223, were repeatedly validated in vivo and in vitro by different validation methods. Particularly noticeable are the small sample sizes, different internal controls, and different case definitions of periodontitis in in vivo studies. Beside of that, the validated miRNAs are associated with inflammation and therefore with various diseases. Furthermore, several studies successfully explored the use of salivary miRNA species for the diagnosis of oral cancer. Different cancer types were investigated and heterogeneous methodology was used; moreover, no overlap of results was found. In conclusion, five miRNAs have consistently been reported for periodontitis; however, their disease specificity, detectability, and expression in saliva and their importance as noninvasive markers are questionable. In principle, a salivary miRNA diagnostic method seems feasible. However, standardized criteria and protocols for preanalytics, measurements, and analysis should be established to obtain comparable results across different studies.

scholarly journals Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
L. Mason ◽  
F. Shic ◽  
T. Falck-Ytter ◽  
B. Chakrabarti ◽  
T. Charman ◽  
...  
Keyword(s):  
Biological Motion ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Case Control ◽  
Small Sample ◽  
Social Brain ◽  
Small Sample Sizes ◽  
Social Communicative ◽  
Perception Of Biological Motion ◽  
And Control

Abstract Background The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. Methods Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). Results The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. Limitations The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. Conclusions Biological motion preference elicits small-to-medium-sized case–control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear.

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