Masako Nagashima

Clinically-oriented monitoring of acute effects of methylphenidate on cerebral hemodynamics in ADHD children using fNIRS

OBJECTIVE Attention Deficit Hyperactivity Disorder (ADHD), a common developmental syndrome with inattention, hyperactivity, and impulsivity, is typically treated with the psychostimulant drug, methylphenidate (MPH). We explored the feasibility of using functional near-infrared spectroscopy (fNIRS) to search for a clinically implementable biological marker for the acute MPH effect on ADHD children. METHODS Following an MPH washout period, twelve ADHD children performed a go/no-go task before and 1.5 h after MPH intake. fNIRS was used to monitor the lateral prefrontal cortical hemodynamics of ADHD children performing a go/no-go task. RESULTS There was no significant activation in the lateral prefrontal cortices examined before MPH intake. However, after MPH intake, significant MPH-elicited activation (oxygenated hemoglobin signal increase) was detected in the right lateral prefrontal cortex (LPFC) implicated with response inhibition functions. There was a large significant correlation between increases in task performance and activation in the right LPFC. CONCLUSIONS The improved cognitive performance was associated with activation in the right LPFC, which might serve as a biological marker to monitor the effect of MPH in ADHD children. SIGNIFICANCE MPH-effect assessment in ADHD children using fNIRS can be performed within a 3 h stay at a hospital during a single visit, and thus may be integrated into clinical practice.

Right prefrontal activation as a neuro-functional biomarker for monitoring acute effects of methylphenidate in ADHD children: An fNIRS study

An objective biomarker is a compelling need for the early diagnosis of attention deficit hyperactivity disorder (ADHD), as well as for the monitoring of pharmacological treatment effectiveness. The advent of fNIRS, which is relatively robust to the body movements of ADHD children, raised the possibility of introducing functional neuroimaging diagnosis in younger ADHD children. Using fNIRS, we monitored the oxy-hemoglobin signal changes of 16 ADHD children (6 to 13 years old) performing a go/no-go task before and 1.5 h after MPH or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. 16 age- and gender-matched normal controls without MPH administration were also monitored. Relative to control subjects, unmedicated ADHD children exhibited reduced activation in the right inferior frontal gyrus (IFG) and middle frontal gyrus (MFG) during go/no-go tasks. The reduced right IFG/MFG activation was acutely normalized after MPH administration, but not after placebo administration. The MPH-induced right IFG/MFG activation was significantly larger than the placebo-induced activation. Post-scan exclusion rate was 0% among 16 right-handed ADHD children with IQ > 70. We revealed that the right IFG/MFG activation could serve as a neuro-functional biomarker for monitoring the acute effects of methylphenidate in ADHD children. fNIRS-based examinations were applicable to ADHD children as young as 6 years old, and thus would contribute to early clinical diagnosis and treatment of ADHD children.

Individual classification of ADHD children by right prefrontal hemodynamic responses during a go/no-go task as assessed by fNIRS

While a growing body of neurocognitive research has explored the neural substrates associated with attention deficit hyperactive disorder (ADHD), an objective biomarker for diagnosis has not been established. The advent of functional near-infrared spectroscopy (fNIRS), which is a noninvasive and unrestrictive method of functional neuroimaging, raised the possibility of introducing functional neuroimaging diagnosis in young ADHD children. Previously, our fNIRS-based measurements successfully visualized the hypoactivation pattern in the right prefrontal cortex during a go/no-go task in ADHD children compared with typically developing control children at a group level. The current study aimed to explore a method of individual differentiation between ADHD and typically developing control children using multichannel fNIRS, emphasizing how spatial distribution and amplitude of hemodynamic response are associated with inhibition-related right prefrontal dysfunction. Thirty ADHD and thirty typically developing control children underwent a go/no-go task, and their cortical hemodynamics were assessed using fNIRS. We explored specific regions of interest (ROIs) and cut-off amplitudes for cortical activation to distinguish ADHD children from control children. The ROI located on the border of inferior and middle frontal gyri yielded the most accurate discrimination. Furthermore, we adapted well-formed formulae for the constituent channels of the optimized ROI, leading to improved classification accuracy with an area under the curve value of 85% and with 90% sensitivity. Thus, the right prefrontal hypoactivation assessed by fNIRS would serve as a potentially effective biomarker for classifying ADHD children at the individual level.

Acute neuropharmacological effects of atomoxetine on inhibitory control in ADHD children: A fNIRS study

The object of the current study is to explore the neural substrate for effects of atomoxetine (ATX) on inhibitory control in school-aged children with attention deficit hyperactivity disorder (ADHD) using functional near-infrared spectroscopy (fNIRS). We monitored the oxy-hemoglobin signal changes of sixteen ADHD children (6–14 years old) performing a go/no-go task before and 1.5 h after ATX or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. Sixteen age- and gender-matched normal controls without ATX administration were also monitored. In the control subjects, the go/no-go task recruited the right inferior and middle prefrontal gyri (IFG/MFG), and this activation was absent in pre-medicated ADHD children. The reduction of right IFG/MFG activation was acutely normalized after ATX administration but not placebo administration in ADHD children. These results are reminiscent of the neuropharmacological effects of methylphenidate to up-regulate reduced right IFG/MFG function in ADHD children during inhibitory tasks. As with methylphenidate, activation in the IFG/MFG could serve as an objective neuro-functional biomarker to indicate the effects of ATX on inhibitory control in ADHD children. This promising technique will enhance early clinical diagnosis and treatment of ADHD in children, especially in those with a hyperactivity/impulsivity phenotype.

MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus

Deletion of the monoamine oxidase (MAO)-A and MAO-B was detected in two male siblings and in their mother. The approximately 800-kb deletion, extending from about 43.0MB to 43.8MB, was detected by array comparative genomic hybridization analysis. The MAOA and MAOB genes were included in the deletion, but the adjacent Norrie disease gene, NDP, was not deleted. The boys had short stature, hypotonia, severe developmental delays, episodes of sudden loss of muscle tone, exiting behavior, lip-smacking and autistic features. The serotonin levels in their cerebrospinal fluid were extremely elevated. Another set of siblings with this deletion was reported previously. We propose recognition of MAOA/B deletion syndrome as a distinct disorder.

Neuropharmacological effect of atomoxetine on attention network in children with attention deficit hyperactivity disorder during oddball paradigms as assessed using functional near-infrared spectroscopy.

Abstract. The current study aimed to explore the neural substrate for atomoxetine effects on attentional control in school-aged children with attention deficit hyperactivity disorder (ADHD) using functional near-infrared spectroscopy (fNIRS), which can be applied to young children with ADHD more easily than conventional neuroimaging modalities. Using fNIRS, we monitored the oxy-hemoglobin signal changes of 15 ADHD children (6 to 14 years old) performing an oddball task before and 1.5 h after atomoxetine or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. Fifteen age-, gender-, and intelligence quotient-matched normal controls without atomoxetine administration were also monitored. In the control subjects, the oddball task recruited the right prefrontal and inferior parietal cortices. The right prefrontal and parietal activation was normalized after atomoxetine administration in ADHD children. This was in contrast to our previous study using a similar protocol showing methylphenidate-induced normalization of only the right prefrontal function. fNIRS allows the detection of differential neuropharmacological profiles of both substances in the attentional network: the neuropharmacological effects of atomoxetine to upregulate the noradrenergic system reflected in the right prefrontal and inferior parietal activations and those of methylphenidate to upregulate the dopamine system reflected in the prefrontal cortex activation.

A case of severe movement disorder with GNAO1 mutation responsive to topiramate.

We report the case of a 19-year-old female patient who had progressive chorea associated with a GNAO1 mutation. Chorea was refractory to multiple anticonvulsants, and the patient suffered from tiapride-induced neuroleptic malignant syndrome. After identification of a GNAO1 missense mutation at the age of 18years, topiramate treatment was initiated and the frequency of chorea decreased dramatically. The efficacy of topiramate may have been related to the inhibitory modulation of voltage-activated Ca2+ channels. Given the side effects and complications associated with neuroleptics and deep brain stimulation, respectively, topiramate is recommended for the first-line management of severe chorea associated with a GNAO1 mutation.

Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation

Leigh syndrome, which is a common phenotype of pediatric mitochondrial disease, is a progressive neurodegenerative disease. The typical neuroimaging findings of Leigh syndrome include bilateral symmetric lesions in the basal ganglia and/or the brainstem. However, there are a few reports on spinal cord involvement in patients with Leigh syndrome. In the present case, magnetic resonance imaging (MRI) obtained during infancy revealed symmetric lesions in the substantia nigra of a patient with Leigh syndrome with an NDUFA1 mutation; lesions of the bilateral putamen and brainstem were subsequently observed. Additionally, our patient presented large and extended spinal cord lesions. Therefore, this case is suggesting that we should consider the occurrence of spinal cord lesions as an atypical finding in Leigh syndrome.

A semi-learning algorithm for noise rejection: an fNIRS study on ADHD children

In pediatrics studies, the quality of functional near infrared spectroscopy (fNIRS) signals is often reduced by motion artifacts. These artifacts likely mislead brain functionality analysis, causing false discoveries. While noise correction methods and their performance have been investigated, these methods require several parameter assumptions that apparently result in noise overfitting. In contrast, the rejection of noisy signals serves as a preferable method because it maintains the originality of the signal waveform. Here, we describe a semi-learning algorithm to detect and eliminate noisy signals. The algorithm dynamically adjusts noise detection according to the predetermined noise criteria, which are spikes, unusual activation values (averaged amplitude signals within the brain activation period), and high activation variances (among trials). Criteria were sequentially organized in the algorithm and orderly assessed signals based on each criterion. By initially setting an acceptable rejection rate, particular criteria causing excessive data rejections are neglected, whereas others with tolerable rejections practically eliminate noises. fNIRS data measured during the attention response paradigm (oddball task) in children with attention deficit/hyperactivity disorder (ADHD) were utilized to evaluate and optimize the algorithm’s performance. This algorithm successfully substituted the visual noise identification done in the previous studies and consistently found significantly lower activation of the right prefrontal and parietal cortices in ADHD patients than in typical developing children. Thus, we conclude that the semi-learning algorithm confers more objective and standardized judgment for noise rejection and presents a promising alternative to visual noise rejection

fNIRS-based neuropharmacological assessment of Methylphenidate and Atomoxetine on inhibition and attention network in pediatric attention deficit/hyperactivity disorder

T aim of this study was to evaluate the bioequivalence of a fixed-dose repaglinide/metformin combination (FDC) tablet at a dose of 2/500 mg with co-administration of equivalent doses of repaglinide (2 mg) and metformin (500 mg) as individual (EDI) tablets in healthy Korean male volunteers.This study was conducted as an open-label, randomized, single-dose, 2-period 2-squence crossover design in 48 healthy Korean male volunteers who received an FDC tablet or EDI tablets after a 12-hour overnight fast in each period. Plasma concentrations of repaglinide and metformin up to 24 hours were determined using a UPLC-MS/MS method. The pharmacokinetic parameters such as AUC0-t, AUC0-∞, Cmax, Tmax and t1/2, were analyzed. Analysis of variance was carried out using logarithmically transformed AUC0-t, AUC0-∞ and Cmax. The formulations were considered bioequivalent if the log-transformed ratios of AUC0–t, AUC0–∞, and Cmax were within the predetermined bioequivalence range (80-125%) established by the US Food and Drug Administration. Tolerability was assessed throughout the study. No significant sequence effect was detected. The point estimates (90% CIs) for AUC0-t, AUC0-∞ and Cmax based on EDI tablets were 1.101 (1.023-1.185), 1.099 (1.022-1.184) and 1.126 (1.015-1.249) for repaglinide, and 0.952 (0.896-1.011), 0.950 (0.897-1.007) and 0.984 (0.927-1.045) for metformin, respectively, satisfying the bioequivalence criteria of 80-125% as proposed by the US FDA. This single-dose study found that both Repaglinide and Metformin in a fixed-dose combination tablet were bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg in these fasting, healthy Korean male volunteers.I resistance plays important roles during the initiation and pathogenesis of the disease. Thus, treatment of T2DM targeted on insulin resistance is one of the major strategies. Unfortunately, current clinical insulin sensitizer agent thiazolidinediones (TZDs), which are validated to be potent agonist of nuclear receptor PPARγ, are beset by adverse side effects evoked by full PPARγ agonism. Aimed to develop the safe and efficient insulin sensitizer, researchers proposed the concept of selective PPARγ modulator (sPPARγM), which is believed to retain potent insulin sensitizing activity yet minimize side effects derived from full PPARγ agonism. However, the sPPARγM developed slowly because of the tardiness of the mechanism on the selective modulation of PPARγ. Recent studies demonstrated that liands activated PPARγ mediated insulin sensitizing effect dependent on the inhibition of CDK5 mediated phosphorylation at serine 273 of PPARγ (pSer273PPARγ) in adipose depots but independent on classical full agonism related transcriptional activity, which provides an explicit avenue to develop novel sPPARγM. In this study, we found that a novel non-TZD compound L312 interacts with PPARγ. Evaluation of activity indicated that L312 showed equal binding affinity with pioglitazone to PPARγ but displayed a very different modulation of PPARγ activity. In db/db mice, L312 considerably improve insulin resistance and lipid variables compared to TZD, yet with reduced side effects such as weight gain and fluid retention. Molecular mechanism revealed that L312 effectively inhibited pSer273PPARγ and exerted a selective gene expression profile in epididymal WAT. In conclusion, we determined that L312 is novel sPPARγM with potent inhibition of pSer273PPARγ and suggested that L312 may represent a novel template for designing sPPARγM with advantages over current TZDs.R developments in cancer biology have identified the existence of a sub-population of cells—cancer stem cells—that are immune to most traditional therapies (e.g., chemotherapy and radiotherapy) and have the ability to repair their damaged DNA. Here, we show the resistance of hepatocarcinoma stem cells and glioblastoma multiform stem cells to both radiation and therapy. Also, we show the efficiency of the conjugated iron oxide nanoparticles for the in vivo disruption of Notch signaling by the gamma secretase inhibitor DAPT [N-(N-((3,5-Difluorophenacetyl))-L-alanyl)-S-phenylglycerin t-butyl ester. By introducing these targeted conjugated nanoparticles, detection, targeting, and destruction of the Hepatocarcinoma and glioblastoma stem cells was achieved. An efficient alternative treatment for the incurable disease of cancer could be provided.Article history: This study was aimed to evaluate the in vitro complexation nature and strength of complex which may be formed due to interaction between Amoxicillin and Calcium chloride (CaCl2). The interaction of Amoxicillin and Calcium chloride (fused) has been studied in aqueous systems at a fixed temperature (37 ± 0.5) °C and under different pH (pH 2.4 and pH 7.4) by using some physical methods as spectral observation, Jobs method of continuous variation, Ardons method. From spectrophotometric study, Amoxicillin gives a sharp peak at 272 nm when Calcium chloride mixed with Amoxicillin in 1:1 ratio the intensity of the peak of Amoxicillin change remarkably due to interaction. The jobs plot was obtained by plotting absorbance difference against the mole fraction of the each drug at pH 2.4 and pH 7.4. Amoxicillin forms strong 1:1 complex with Calcium chloride and reverse V Shaped curves indicate the formation of 1:1 complexes of Amoxicillin with Calcium chloride. These may indicate strong kinetics of complexation between Amoxicillin with Calcium chloride. The value of stability constant for the complexation of Amoxicillin with calcium chloride at pH 2.4 and pH 7.4 were obtained from the spectral data using Ardons plot. The value of stability constant for the drug-metal system at pH 2.4 and pH 7.4 are 5.54 and 6.67 respectively. At pH 2.4 it is found that Amoxicillin form relatively stable complex with Calcium chloride (stability constant 6.67) is high in comparison to pH 7.4. It can therefore be concluded that a careful consideration is needed during concurrent administration of Amoxicillin with Calcium chloride.A deficit/hyperactivity disorder (ADHD) is among the most frequent neurodevelopmental disorders. Atomoxetine (ATX) and methylphenidate (MPH) have been recommended as primary medication choices to treat inhibitionand attention-related dysfunctions in ADHD children. This study used functional near-infrared spectroscopy (fNIRS) to explore the efficacy of both medications in school-aged children with ADHD for inhibitory and attention task performance. fNIRS is a promising tool, offering robust advantages such as its compactness, affordable price, tolerance to body motion and accessibility. We monitored the oxy-hemoglobin changes in ADHD children (6 to 14 years old) during go/nogo or oddball tasks before and 1.5 h after ATX, MPH or placebo administration, in a randomized, double-blind, placebo-controlled experiment. Age-, genderand IQ-matched healthy controls, who did not receive medications or a placebo, were also monitored. In the control subjects, the go/nogo task modulated the right inferior and middle prefrontal gyri (IFG/MFG) and the oddball task modulated the right IFG/MFG and inferior parietal cortex (IPL). In ADHD children, these activations were absent in pre-medicated conditions. The reduction in the right IFG/MFG activation was normalized by both ATX and MPH for go/nogo and oddball tasks, but the right IPL was normalized only by ATX in the oddball task. These results led us to conclude that fNIRS could visualize the differential neuropharmacological effects of both substances in the inhibitory and attentional networks: ATX to up-regulate the noradrenergic system reflected in the right IFG/MFG and IPL activations, and MPH to up-regulate the dopamine system reflected in the IFG/MFG activations.G a bioactive compound found in many Traditional Chinese medicine and Ayurvedic herbs. It was recently shown to be in abundance in the rind waste of the fruit Nephelium lappaceum. We have shown in our laboratories, using both in vitro and in vivo studies, the ability of this compound extracted from Nephelium lappaceum to effectively enhance glucose uptake, reduce insulin resistance, reduce obesity among other uses. Others have shown the anti-hypertensive ability of the compound.