Multi‐scale network regression for brain‐phenotype associations

Brain networks are increasingly characterized at different scales, including summary statistics, community connectivity, and individual edges. While research relating brain networks to behavioral measurements has yielded many insights into brain‐phenotype relationships, common analytical approaches only consider network information at a single scale. Here, we designed, implemented, and deployed Multi‐Scale Network Regression (MSNR), a penalized multivariate approach for modeling brain networks that explicitly respects both edge‐ and community‐level information by assuming a low rank and sparse structure, both encouraging less complex and more interpretable modeling. Capitalizing on a large neuroimaging cohort (n = 1, 051) , we demonstrate that MSNR recapitulates interpretable and statistically significant connectivity patterns associated with brain development, sex differences, and motion‐related artifacts. Compared to single‐scale methods, MSNR achieves a balance between prediction performance and model complexity, with improved interpretability. Together, by jointly exploiting both edge‐ and community‐level information, MSNR has the potential to yield novel insights into brain‐behavior relationships.     

Use of catechol‐O‐methyltransferase inhibition to minimize L‐3,4‐dihydroxyphenylalanine‐induced dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned macaque

L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia is a complication of dopaminergic treatment in Parkinson's disease. Lowering the L‐DOPA dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low‐dose L‐DOPA (LDl) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol‐O‐methyltransferase (COMT) inhibition, as an add‐on to LDl, might be a means to achieve this goal. Cynomolgus macaques were administered 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Dyskinesia was established by chronic treatment with L‐DOPA. Two doses of L‐DOPA were identified – high‐dose L‐DOPA (LDh), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and LDl, which was sub‐threshold for providing significant antiparkinsonian benefit, without dyskinesia. LDh and LDl were administered in acute challenges in combination with vehicle and, for LDl, with the COMT inhibitor entacapone (5, 15 and 45 mg/kg). The duration of antiparkinsonian benefit (ON‐time), parkinsonism and dyskinesia were determined. The ON‐time after LDh was ～170 min and the ON‐time after LDl alone (～98 min) was not significantly different to vehicle (～37 min). In combination with LDl, entacapone significantly increased the ON‐time (5, 15 and 45 mg/kg being ～123, ～148 and ～180 min, respectively). The ON‐time after LDl/entacapone 45 mg/kg was not different to that after LDh. However, whereas the percentage ON‐time that was compromised by disabling dyskinesia was ～56% with LDh, it was only ～31% with LDl/entacapone 45 mg/kg. In addition to the well‐recognized action of COMT inhibition to reduce wearing‐OFF, the data presented suggest that COMT inhibition in combination with low doses of L‐DOPA has potential as a strategy to alleviate dyskinesia.     

Pre‐hospital notification reduced the door‐to‐needle time for iv t‐PA in acute ischaemic stroke

Background and purpose: Intrahospital delay is the most serious obstacle in thrombolysis in acute ischaemic stroke (AIS). We implemented the pre‐hospital notification system from the emergency medical information system in our metropolitan area to reduce intrahospital delay. Methods: From October 2007, we implemented a 24‐h hotline system between our stroke center and the Korean Emergency Medical Information System in Busan. We compared processing times and clinical outcomes amongst patients after using intravenous tissue type plasminogen activator (iv t‐PA) with and without the hotline system. Results: After the pre‐hospital notification system was implemented, the rate of iv t‐PA use increased from 6.5% to 14.3%. Time of onset in patients with pre‐hospital notification was much longer than in patients without (121.5 ± 34.8 min vs. 74.7 ± 38.5 min, P < 0.01) notification but door‐to‐needle time was significantly reduced (28.9 ± 11.4 min vs. 47.7 ± 22.8 min, P < 0.01). However, there were no significant differences in 90‐day clinical outcomes between the two groups. Conclusions: The pre‐hospital notification system reduced intrahospital processing times which led to increased iv t‐PA use after AIS. However, the improvement of clinical outcomes in thrombolysis might require organization of not only intrahospital processes but of outside processes such as the early recognition and rapid dispatch of patients with suspected AIS.     

A hierarchical method for whole‐brain connectivity‐based parcellation

In modern neuroscience there is general agreement that brain function relies on networks and that connectivity is therefore of paramount importance for brain function. Accordingly, the delineation of functional brain areas on the basis of diffusion magnetic resonance imaging (dMRI) and tractography may lead to highly relevant brain maps. Existing methods typically aim to find a predefined number of areas and/or are limited to small regions of grey matter. However, it is in general not likely that a single parcellation dividing the brain into a finite number of areas is an adequate representation of the function‐anatomical organization of the brain. In this work, we propose hierarchical clustering as a solution to overcome these limitations and achieve whole‐brain parcellation. We demonstrate that this method encodes the information of the underlying structure at all granularity levels in a hierarchical tree or dendrogram. We develop an optimal tree building and processing pipeline that reduces the complexity of the tree with minimal information loss. We show how these trees can be used to compare the similarity structure of different subjects or recordings and how to extract parcellations from them. Our novel approach yields a more exhaustive representation of the real underlying structure and successfully tackles the challenge of whole‐brain parcellation. Hum Brain Mapp 35:5000–5025, 2014. © 2014 Wiley Periodicals, Inc .     

Deficits in Psychological Well‐Being and Quality‐of‐Life in Minor Depression: Implications for DSM‐V

Objective: To examine deficits in psychological well‐being (PWB) and quality‐of‐life (QOL) in minor depressive disorder (Min D). Method: Ninety‐three subjects entering a treatment study for Min D were assessed using the QOL, Enjoyment and satisfaction questionnaire (Q‐LES‐Q), and the Psychological Well‐Being Scale (PWBS). Scores were compared with major depressive disorder (MDD) and normative community samples. Results: Even though subjects had mild depressive severity, Q‐LES‐Q total scores for the Min D sample averaged nearly two standard deviations below the community norm. Almost 40% of Min D cases had Q‐LES‐Q scores in the lowest 1% of the population. Responses to most Q‐LES‐Q items were closer to subjects with MDD than to community norms. Mean standardized PWB scores were extremely low for subscales of Environmental Mastery and Self‐Acceptance, low for Purpose in Life and Positive Relations with others, but within the normal range for Personal Growth and Autonomy. QOL and PWB measures had low correlations with depressive symptom severity, and scores were similar in the presence or absence of a prior history of MDD. Conclusions: Mild depressive symptoms with Min D are associated with major deficits in QOL and PWB measures of environmental mastery and poor self‐acceptance. Our findings suggest that diminished QOL and PWB may be intrinsic cognitive aspects of Min D with or without a history of MDD. It may be unnecessary in the DSM IV‐TR to exclude the diagnosis of Min D if a subject has had a past episode of MDD. ? Minor depression exists along a continuum of depression. ? Deficits in psychological well‐being and quality‐of‐life in minor depression are severe. ? No difference in these measures if minor depression existed with or without a history of major depression.     

Exercise modifies α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor expression in striatopallidal neurons in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned mouse

The α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic‐acid‐type glutamate receptor (AMPAR) plays a critical role in modulating experience‐dependent neuroplasticity, and alterations in AMPAR expression may underlie synaptic dysfunction and disease pathophysiology. Using the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of dopamine (DA) depletion, our previous work showed exercise increases total GluA2 subunit expression and the contribution of GluA2‐containing channels in MPTP mice. The purpose of this study was to determine whether exercise‐dependent changes in AMPAR expression after MPTP are specific to the striatopallidal (D₂R) or striatonigral (D₁R) medium spiny neuron (MSN) striatal projection pathways. Drd₂‐eGFP‐BAC transgenic mice were used to delineate differences in AMPAR expression between striatal D₂R‐MSNs and D₁R‐MSNs. Striatal AMPAR expression was assessed by immunohistochemical (IHC) staining, Western immunoblotting (WB) of preparations enriched for postsynaptic density (PSD), and alterations in the current–voltage relationship of MSNs. We found DA depletion results in the emergence of GluA2‐lacking AMPARs selectively in striatopallidal D₂R‐MSNs and that exercise reverses this effect in MPTP mice. Exercise‐induced changes in AMPAR channels observed after DA depletion were associated with alterations in GluA1 and GluA2 subunit expression in postsynaptic protein, D₂R‐MSN cell surface expression, and restoration of corticostriatal plasticity. Mechanisms regulating experience‐dependent changes in AMPAR expression may provide innovative therapeutic targets to increase the efficacy of treatments for basal ganglia disorders, including Parkinson's disease. © 2013 Wiley Periodicals, Inc.     

Comparison of a non‐stationary voxelation‐corrected cluster‐size test with TFCE for group‐Level MRI inference

Two powerful methods for statistical inference on MRI brain images have been proposed recently, a non‐stationary voxelation‐corrected cluster‐size test (CST) based on random field theory and threshold‐free cluster enhancement (TFCE) based on calculating the level of local support for a cluster, then using permutation testing for inference. Unlike other statistical approaches, these two methods do not rest on the assumptions of a uniform and high degree of spatial smoothness of the statistic image. Thus, they are strongly recommended for group‐level fMRI analysis compared to other statistical methods. In this work, the non‐stationary voxelation‐corrected CST and TFCE methods for group‐level analysis were evaluated for both stationary and non‐stationary images under varying smoothness levels, degrees of freedom and signal to noise ratios. Our results suggest that, both methods provide adequate control for the number of voxel‐wise statistical tests being performed during inference on fMRI data and they are both superior to current CSTs implemented in popular MRI data analysis software packages. However, TFCE is more sensitive and stable for group‐level analysis of VBM data. Thus, the voxelation‐corrected CST approach may confer some advantages by being computationally less demanding for fMRI data analysis than TFCE with permutation testing and by also being applicable for single‐subject fMRI analyses, while the TFCE approach is advantageous for VBM data. Hum Brain Mapp 38:1269–1280, 2017. © 2016 Wiley Periodicals, Inc.     

Randomized,placebo‐controlled trial of incobotulinumtoxina for upper‐limb post‐stroke spasticity

Introduction: Efficacy and safety of incobotulinumtoxinA in post‐stroke upper‐limb spasticity were studied. Methods: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non‐primary patterns were flexible within predefined ranges. Results: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least‐squares mean change ± standard error: –0.9 ± 0.06 (n = 171) vs. –0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1‐point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. Conclusions: IncobotulinumtoxinA significantly improved upper‐limb spasticity and associated disability, and was well‐tolerated. Muscle Nerve 53: 415–421, 2016     

B cell depletion therapy for new‐onset opsoclonus‐myoclonus

Twelve immunotherapy‐naïve children with opsoclonus‐myoclonus syndrome and CSF B cell expansion received rituximab, adrenocorticotropic hormone (ACTH), and IVIg. Motor severity lessened 73% by 6 mo and 81% at 1 yr (P < 0.0001). Opsoclonus and action myoclonus disappeared rapidly, whereas gait ataxia and some other motor components improved more slowly. ACTH dose was tapered by 87%. Reduction in total CSF B cells was profound at 6 mo (‐93%). By study end, peripheral B cells returned to 53% of baseline and serum IgM levels to 63%. Overall clinical response trailed peripheral B cell and IgM depletion, but improvement continued after their levels recovered. All but one non‐ambulatory subject became ambulatory without additional chemotherapy; two relapsed and remitted; four had rituximab‐related or possibly related adverse events; and two had low‐titer human anti‐chimeric antibody. Combination of rituximab with conventional agents as initial therapy was effective and safe. A controlled trial with long‐term safety monitoring is indicated. © 2009 Movement Disorder Society     

View‐centralized multi‐atlas classification for Alzheimer's disease diagnosis

Multi‐atlas based methods have been recently used for classification of Alzheimer's disease (AD) and its prodromal stage, that is, mild cognitive impairment (MCI). Compared with traditional single‐atlas based methods, multiatlas based methods adopt multiple predefined atlases and thus are less biased by a certain atlas. However, most existing multiatlas based methods simply average or concatenate the features from multiple atlases, which may ignore the potentially important diagnosis information related to the anatomical differences among different atlases. In this paper, we propose a novel view (i.e., atlas) centralized multi‐atlas classification method, which can better exploit useful information in multiple feature representations from different atlases. Specifically, all brain images are registered onto multiple atlases individually, to extract feature representations in each atlas space. Then, the proposed view‐centralized multi‐atlas feature selection method is used to select the most discriminative features from each atlas with extra guidance from other atlases. Next, we design a support vector machine (SVM) classifier using the selected features in each atlas space. Finally, we combine multiple SVM classifiers for multiple atlases through a classifier ensemble strategy for making a final decision. We have evaluated our method on 459 subjects [including 97 AD, 117 progressive MCI (p‐MCI), 117 stable MCI (s‐MCI), and 128 normal controls (NC)] from the Alzheimer's Disease Neuroimaging Initiative database, and achieved an accuracy of 92.51% for AD versus NC classification and an accuracy of 78.88% for p‐MCI versus s‐MCI classification. These results demonstrate that the proposed method can significantly outperform the previous multi‐atlas based classification methods. Hum Brain Mapp 36:1847–1865, 2015. © 2015 Wiley Periodicals, Inc .     

Protein kinase Cγ is a signaling molecule required for the developmental speeding of α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate receptor kinetics

A key step in the maturation of glutamate synapses is the developmental speeding of α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate receptor (AMPA‐R) kinetics, which occurs via a switch in receptor subtypes. However, the molecular components required for the switch in receptors are unknown. Here, we used the zebrafish preparation to show that activation of protein kinase C (PKC)γ is necessary for the developmental speeding of AMPA‐R kinetics. Targeted knockdown of PKCγ with an antisense morpholino oligonucleotide [PKCγ‐morpholino (PKCγ‐MO)], prevents the normal speeding up of AMPA‐R kinetics in Mauthner cells. PKCγ‐MO‐injected embryos are incapable of trafficking AMPA‐Rs following application of phorbol 12‐myristate 13‐acetate or PKCγ. PKCγ‐MO‐injected embryos do not hatch or exhibit the C‐start escape response. Increasing synaptic activity (33 h post‐fertilization embryos) by application of an elevated K⁺ medium or by application of N‐methyl‐d ‐aspartate induces rapid PKCγ‐dependent trafficking of fast AMPA‐Rs to synapses. Our findings reveal that PKCγ is a molecular link underlying the developmental speeding of AMPA‐Rs in zebrafish Mauthner cells.     

Mega‐dose phenobarbital therapy for super‐refractory status epilepticus

Aims. To evaluate the efficacy and safety of mega‐dose phenobarbital (MDPB; enteral or parenteral phenobarbital >10 mg/kg/day) for treating super‐refractory status epilepticus (SRSE; continuous or recurrent status epilepticus for ≥24 hours after the onset of continuous anaesthetic treatment) in adult patients. Methods. Adult patients with SRSE who were treated with MDPB in our institution from March 2005 to September 2014 were reviewed. We collected data on basic demographics, clinical features, functional status, anticonvulsant treatment, and possible adverse events. SRSE outcome was divided into six categories: successful therapy, initial failure, breakthrough seizures, withdrawal seizures, intolerable side effects, and death during treatment. Results. Ten adult patients with SRSE received MDPB. Median age at seizure onset was 38 years (range: 18‐59), and half were male. All patients had no history of seizures and had symptoms suggestive of viral encephalitis. Median duration of status epilepticus was 17.5 days (range: 6–60) and anaesthetics were used for a median of 14.0 days (range: 2–54) before MDPB. Successful control of SRSE was achieved in half of the patients, however, only one of ten patients was able to fully recover at discharge. Median duration of the MDPB was 45.5 days and the maximum serum phenobarbital level reached a median of 151.5 μg/ml. Patients with successful MDPB therapy had normal brain imaging (80% vs. 0%; p=0.048) and better functional outcome at discharge and after three months of follow‐up. Infection was the most critical complication, along with cardiorespiratory depression. Conclusion. MDPB is a therapeutic option for control of SRSE when other choices are exhausted.     

Proteasome inhibitors for malignancy‐related lambert‐eaton myasthenic syndrome

Lambert‐Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by autoantibodies against presynaptic voltage‐gated calcium channels that impair neuromuscular transmission. Malignancies, especially small cell lung cancer (SCLC), have been associated with LEMS and account for approximately 60% of cases, making malignancy management a central step in LEMS therapy. In addition, immunosuppressive therapy is also recommended for symptomatic control. Interestingly, both pathological and epidemiological data suggest that the autoimmune response can inhibit progression of tumors in malignancy‐associated LEMS. Thus, conventional broad‐spectrum immunosuppressants may not be effective agents for treatment of LEMS, especially in those with malignancy‐associated LEMS. Recent preclinical and clinical studies have indicated that proteasome inhibitors can eliminate antibody‐producing cells efficiently, block dendritic cell maturation, and have anti‐tumor activity. We hypothesize that proteasome inhibitors may be promising agents for treatment of malignancy‐related LEMS. Muscle Nerve 49 :325–328, 2014