Synthesis and evaluation of antibody-drug conjugates with high drug-to-antibody ratio using dimaleimide-DM1 as a linker- payload.

The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.

Oligomeric amyloid-ß targeted contrast agent for MRI evaluation of Alzheimer's disease mouse models.

Background: Oligomeric amyloid beta (oAß) is a toxic factor that acts in the early stage of Alzheimer's disease (AD) and may initiate the pathologic cascade. Therefore, detecting oAß has a crucial role in the early diagnosis, monitoring, and treatment of AD. Purpose: The purpose of this study was to evaluate MRI signal changes in different mouse models and the time-dependent signal changes using our novel gadolinium (Gd)-dodecane tetraacetic acid (DOTA)- ob5 aptamer contrast agent. Methods: We developed an MRI contrast agent by conjugating Gd-DOTA-DNA aptamer called ob5 to evaluate its ability to detect oAß deposits in the brain using MRI. A total of 10 control mice, 9 3xTg AD mice, and 11 APP/PS/Tau AD mice were included in this study, with the age of each model being 16 or 36 weeks. A T1-weighted image was acquired at the time points before (0 min) and after injection of the contrast agent at 5, 10, 15, 20, and 25 min. The analyses were performed to compare MRI signal differences among the three groups and the time-dependent signal differences in different mouse models. Results: Both 3xTg AD and APP/PS/Tau AD mouse models had higher signal enhancement than control mice at all scan-time points after injection of our contrast media, especially in bilateral hippocampal areas. In particular, all Tg AD mouse models aged 16 weeks showed a higher contrast enhancement than those aged 36 weeks. For 3xTg AD and APP/PS/Tau AD groups, the signal enhancement was significantly different among the five time points (0 min, 5 min, 10 min, 15 min, 20 min, and 25 min) in multiple ROI areas, typically in the bilateral hippocampus, left thalamus, and left amygdala. Conclusion: The findings of this study suggest that the expression of the contrast agent in different AD models demonstrates its translational flexibility across different species. The signal enhancement peaked around 15-20 min after injection of the contrast agent. Therefore, our novel contrast agent targeting oAß has the potential ability to diagnose early AD and monitor the progression of AD.

Therapeutic effects of a novel electrode for transcranial direct current stimulation in ischemic stroke mice.

Rationale: Non-invasive transcranial direct current stimulation (tDCS), a promising stimulation tool to modulate a wide range of brain disorders, has major limitations, such as poor cortical stimulation intensity and focality. We designed a novel electrode for tDCS by conjugating a needle to a conventional ring-based high-definition (HD) electrode to enhance cortical stimulation efficacy. Method: HD-tDCS (43 µA/mm2, charge density 51.6 kC/m2, 20 min) was administered to male C57BL/6J mice subjected to early-stage ischemic stroke. Behavioral tests were employed to determine the therapeutic effects, and the underlying mechanisms of HD-tDCS were determined by performing RNA sequencing and other biomedical analyses. Results: The new HD-tDCS application, showing a higher electric potential and spatial focality based on computational modeling, demonstrated better therapeutic effects than conventional HD-tDCS in alleviating motor and cognitive deficits, with a decrease in infarct volume and inflammatory response. We assessed different electrode configurations in the new HD electrode; the configurations variously showed potent therapeutic effects, ameliorating neuronal death in the peri-infarct region via N-methyl-D-aspartate-dependent sterol regulatory element-binding protein 1 signaling and related inflammatory factors, further alleviating motor and cognitive deficits in stroke. Conclusion: This new HD-tDCS application showed better therapeutic effects than those with conventional HD-tDCS in early-stage stroke via the amelioration of neuronal death in the penumbra. It may be applied in the early stages of stroke to alleviate neurological impairment.

Effects of Alterations in Resting-State Neural Networks on the Severity of Neuropathic Pain after Spinal Cord Injury.

Neuropathic pain (NP) following spinal cord injury (SCI) is refractory to pain control strategies, and the underlying neuronal mechanisms remain poorly understood. This study aimed to determine the brain regions engaged in maintaining a spontaneous resting state and the link between those regions and the severity of NP in patients with incomplete SCI. Seventy-three subjects (41 patients and 32 age- and sex-matched healthy controls) participated in this retrospective study. Regarding the neurological level of injury, patients with incomplete SCI experienced at-level or below-level NP. The severity of NP was evaluated using a visual analog scale (VAS), and patients were divided into mild and moderate-severe NP groups based on VAS scores. Graph theory and fractional amplitude of low-frequency fluctuation (fALFF) analyses were performed to compare resting-state functional magnetic resonance imaging (fMRI) analysis results among the three groups. Graph theory analysis was performed through a region of interest (ROI)-to-ROI analysis and then fALFF analysis was performed in the brain regions demonstrating significant differences among the three groups analyzed using the graph theory. We evaluated whether the brain regions showing significant differences using graph theory and fALFF correlated with the VAS scores. Patients with moderate-severe NP showed reduced node degree and fALFF in the left middle frontal gyrus compared with those with mild NP and healthy controls. Furthermore, patients with severe NP demonstrated increased average path lengths and reduced fALFF values in the posterior cingulate gyrus. This study found that changes in intrinsic oscillations of fMRI signals in the middle frontal gyrus and posterior cingulate gyrus were significant considering the severity of NP.

Performance evaluation of SimPET-L and SimPET-XL: MRI-compatible small-animal PET systems with rat-body imaging capability.

BACKGROUND: SimPET-L and SimPET-XL have recently been introduced with increased transaxial fields of view (FOV) compared with their predecessors (SimPET™ and SimPET-X), enabling whole-body positron emission tomography (PET) imaging of rats. We conducted performance evaluations of SimPET-L and SimPET-XL and rat-body imaging with SimPET-XL to demonstrate the benefits of increased axial and transaxial FOVs. PROCEDURES: The detector blocks in SimPET-L and SimPET-XL consist of two 4 × 4 silicon photomultiplier arrays coupled with 20 × 9 array lutetium oxyorthosilicate crystals. SimPET-L and SimPET-XL have an inner diameter (bore size) of 7.6 cm, and they are composed of 40 and 80 detector blocks yielding axial lengths of 5.5 and 11 cm, respectively. Each system was evaluated according to the National Electrical Manufacturers Association NU4-2008 protocol. Rat imaging studies, such as 18F-NaF and 18F-FDG PET, were performed using SimPET-XL. RESULTS: The radial resolutions at the axial center measured using the filtered back projection, 3D ordered-subset expectation maximization (OSEM), and 3D OSEM with point spread functions correction were 1.7, 0.82, and 0.82 mm FWHM in SimPET-L and 1.7, 0.91, and 0.91 mm FWHM in SimPET-XL, respectively. The peak sensitivities of SimPET-L and SimPET-XL were 6.30% and 10.4% for an energy window of 100-900 keV and 4.44% and 7.25% for a window of 250-750 keV, respectively. The peak noise equivalent count rate with an energy window of 250-750 keV was 249 kcps at 44.9 MBq for SimPET-L and 349 kcps at 31.3 MBq for SimPET-XL. In SimPET-L, the uniformity was 4.43%, and the spill-over ratios in air- and water-filled chambers were 5.54% and 4.10%, respectively. In SimPET-XL, the uniformity was 3.89%, and the spill-over ratio in the air- and water-filled chambers were 3.56% and 3.60%. Moreover, SimPET-XL provided high-quality images of rats. CONCLUSION: SimPET-L and SimPET-XL show adequate performance compared with other SimPET systems. In addition, their large transaxial and long axial FOVs provide imaging capability for rats with high image quality.

Tumor-treating fields as a proton beam-sensitizer for glioblastoma therapy.

Few advances in GBM treatment have been made since the initiation of the Stupp trials in 2005. Experimental studies on immunotherapy drugs, molecular inhibitors, radiation dosage escalation and vascular growth factor blockers have all failed to provide satisfactory outcomes. TTFields therapy, on the other hand, have emerged as a viable substitute to therapies like radiation in GBM patients having a highly immunosuppressive tumor microenvironment. To enhance the biofunctional impacts, we explored the combination events with TTFields and proton treatment in this study. We conducted a cell viability test, a cell death detection evaluation, a ROS analysis, a three-dimensional (3D) culture system, and a migration assay. The combination of proton radiation and TTFields therapy laid a substantial anticancer impact on the F98 and U373 as compared to the consequences of either of these therapies used separately. The combination proton beam therapy used by TTFields was very successful in curbing GBM from migrating. GBM cell metastasis is restricted by TTFields combined proton by downregulating the MAPK, NF-κB, and PI3K/AKT indicating pathways, caused by reduced EMT marker expression. These findings furnish biological proof for the molecular grounds of TTFields in combination with proton used for GBM therapy.

Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging.

Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.

Dysfunction of anterior insula in the non- affected hemisphere in patients with post- stroke depression: A resting-state fMRI study.

BACKGROUND: Post-stroke depression (PSD) is a consequential neuropsychiatric sequela that occurs after stroke. However, the pathophysiology of PSD are not well understood yet. OBJECTIVE: To explore alterations in functional connectivity (FC) between anterior insula and fronto-cortical and other subcortical regions in the non-affected hemisphere in patients with PSD compared to without PSD and healthy control. METHODS: Resting-state FC was estimated between the anterior insula and cortical and subcortical brain regions in the non-affected hemisphere in 13 patients with PSD, 12 patients without PSD, and 13 healthy controls. The severity of depressive mood was measured by the Beck Depression Inventory (BDI)-II. RESULTS: Patients with PSD showed significant differences in FC scores between the anterior insula and the superior frontal, middle frontal, and orbitofrontal gyrus in the non-affected hemisphere than healthy control or patients without PSD (P< 0.05). In post-hoc, patients with PSD showed higher FC scores between the anterior insula and the superior frontal region than patients without PSD (P< 0.05). Furthermore, alterations in FC of the superior frontal, middle frontal, and orbitofrontal gyrus were positively correlated with depression severity, as measured with the BDI-II (P< 0.001).

Correction: Oh, J.Y., et al. Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells, Cancers 2019, 11, 1812.

The authors wish to make the following corrections to this paper [...].

Interhemispheric Functional Connectivity in the Primary Motor Cortex Assessed by Resting-State Functional Magnetic Resonance Imaging Aids Long-Term Recovery Prediction among Subacute Stroke Patients with Severe Hand Weakness.

This study aimed to evaluate the usefulness of interhemispheric functional connectivity (FC) as a predictor of motor recovery in severe hand impairment and to determine the cutoff FC level as a clinically useful parameter. Patients with stroke (n = 22; age, 59.9 ± 13.7 years) who presented with unilateral severe upper-limb paresis and were confirmed to elicit no motor-evoked potential responses were selected. FC was measured using resting-state functional magnetic resonance imaging (rsfMRI) scans at 1 month from stroke onset. The good recovery group showed a higher FC value than the poor recovery group (p = 0.034). In contrast, there was no statistical difference in FC value between the good recovery and healthy control groups (p = 0.182). Additionally, the healthy control group showed a higher FC value than that shown by the poor recovery group (p = 0.0002). Good and poor recovery were determined based on Brunnstrom stage of upper-limb function at 6 months as the standard, and receiver operating characteristic curve indicated that a cutoff score of 0.013 had the greatest prognostic ability. In conclusion, interhemispheric FC measurement using rsfMRI scans may provide useful clinical information for predicting hand motor recovery during stroke rehabilitation.

Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells.

Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation bisphosphonate that inhibits osteoclast-mediated bone resorption and has shown efficacy in treating bone metastases in patients with various types of solid tumors. Here, we sought to clarify the mechanisms through which ZOL inhibits OS cell proliferation. ZOL treatment inhibited OS cell proliferation, viability, and colony formation. Autophagy inhibition by RNA interference against Beclin-1 or ATG5 inhibited ZOL-induced OS cell death. ZOL induced autophagy by repressing the protein kinase B/mammalian target of rapamycin/p70S6 kinase pathway and extracellular signal-regulated kinase signaling-dependent autophagy in OS cell lines and patient-derived OS cells. Microarrays of miRNA showed that ZOL increased the levels of miR-212-3p, which is known to play an important role in autophagy, in OS in vitro and in vivo systems. Collectively, our data provided mechanistic insight into how increased miR-212-3p through ZOL treatment induces autophagy synergistically in OS cells, providing a preclinical rationale for conducting a broad-scale clinical evaluation of ZOL + miR-212-3p in treating OS.

Power Spectral Density Analysis of Long-Term Motor Recovery in Patients With Subacute Stroke.

BACKGROUND: Prognostic measures of long-term motor recovery are important in patients with stroke presenting with severe hemiplegia. OBJECTIVE: We aimed to investigate whether initial power spectral density (PSD) analysis of resting-state functional magnetic resonance (fMRI) data can provide a sensitive prognostic predictor in patients with subacute stroke with severe hand disability. METHODS: Twelve patients with good recovery, 14 patients with poor recovery, and 12 healthy subjects were included. PSD analysis was performed using resting-state fMRI data. Contralesional and ipsilesional PSD in the motor cortex were measured. Pearson correlation analysis was performed to assess a possible association between the difference in ipsilesional versus contralesional PSD and motor outcomes. A receiver operating characteristic (ROC) curve was constructed to estimate the discriminative value of the difference between the ipsilesional PSD and the contralesional PSD for good versus poor recovery. RESULTS: There were no differences in PSD between the contralesional and ipsilesional hemispheres in the good recovery group ( P = .77). In contrast, there were significant differences in PSD between the 2 hemispheres in the poor recovery group ( P = .07). The difference in PSD between the 2 hemispheres had a positive correlation with post Brunnstrom stage scores. ROC analysis showed that the difference in PSD between the 2 hemispheres was sensitive in discriminating good versus poor recovery. CONCLUSION: The present study suggests that PSD in the motor cortex may be a sensitive predictor of late-onset motor recovery following stroke.

[18F]FET PET is a useful tool for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic glioblastoma mouse model.

O-2-18F-fluoroethyl-l-tyrosine ([18F]FET) has been widely used for glioblastomas (GBM) in clinical practice, although evaluation of its applicability in non-clinical research is still lacking. The objective of this study was to examine the value of [18F]FET for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic mouse model of GBM. Human U87MG cells were implanted into nude mice and then bevacizumab, a representative anti-angiogenic drug, was administered. We monitored the effect of anti-angiogenic agents using multiple imaging modalities, including bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT). Among these imaging methods analyzed, only [18F]FET uptake showed a statistically significant decrease in the treatment group compared to the control group (P=0.02 and P=0.03 at 5 and 20 mg/kg, respectively). This indicates that [18F]FET PET is a sensitive method to monitor the response of GBM bearing mice to anti-angiogenic drug. Moreover, [18F]FET uptake was confirmed to be a significant parameter for predicting the prognosis of anti-angiogenic drug (P=0.041 and P=0.007, on Days 7 and 12, respectively, on Pearson's correlation; P=0.048 and P=0.030, on Days 7 and 12, respectively, on Cox regression analysis). However, results of BLI or MRI were not significantly associated with survival time. In conclusion, this study suggests that [18F]FET PET imaging is a pertinent imaging modality for sensitive monitoring and accurate prediction of treatment response to anti-angiogenic agents in an orthotopic model of GBM.

Recovery of Proprioception in the Upper Extremity by Robotic Mirror Therapy: a Clinical Pilot Study for Proof of Concept.

A novel robotic mirror therapy system was recently developed to provide proprioceptive stimulus to the hemiplegic arm during a mirror therapy. Validation of the robotic mirror therapy system was performed to confirm its synchronicity prior to the clinical study. The mean error angle range between the intact arm and the robot was 1.97 to 4.59 degrees. A 56-year-old male who had right middle cerebral artery infarction 11 months ago received the robotic mirror therapy for ten 30-minute sessions during 2 weeks. Clinical evaluation and functional magnetic resonance imaging (fMRI) studies were performed before and after the intervention. At the follow-up evaluation, the thumb finding test score improved from 2 to 1 for eye level and from 3 to 1 for overhead level. The Albert's test score on the left side improved from 6 to 11. Improvements were sustained at 2-month follow-up. The fMRI during the passive motion revealed a considerable increase in brain activity at the lower part of the right superior parietal lobule, suggesting the possibility of proprioception enhancement. The robotic mirror therapy system may serve as a useful treatment method for patients with supratentorial stroke to facilitate recovery of proprioceptive deficit and hemineglect.

Neuromodulatory effects of offline low-frequency repetitive transcranial magnetic stimulation of the motor cortex: A functional magnetic resonance imaging study.

Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) can modulate cortical excitability and is thought to influence activity in other brain areas. In this study, we investigated the anatomical and functional effects of rTMS of M1 and the time course of after-effects from a 1-Hz subthreshold rTMS to M1. Using an "offline" functional magnetic resonance imaging (fMRI)-rTMS paradigm, neural activation was mapped during simple finger movements after 1-Hz rTMS over the left M1 in a within-subjects repeated measurement design, including rTMS and sham stimulation. A significant decrease in the blood oxygen level dependent (BOLD) signal due to right hand motor activity during a simple finger-tapping task was observed in areas remote to the stimulated motor cortex after rTMS stimulation. This decrease in BOLD signal suggests that low frequency subthreshold rTMS may be sufficiently strong to elicit inhibitory modulation of remote brain regions. In addition, the time course patterns of BOLD activity showed this inhibitory modulation was maximal approximately 20 minutes after rTMS stimulation.

Volume-normalized transfer constant as an imaging biomarker for chronic inflammatory arthritis: A dynamic contrast enhanced MRI study.

PURPOSE: Proper diagnosis and treatment of rheumatoid arthritis are extremely important to optimize treatment outcomes. Dynamic contrast-enhanced MRI (DCE-MRI) may be used as a biomarker to detect inflammatory changes in synovial joints and to discriminate active and inactive stages of the disease. The aim of this study was to investigate vascular permeability changes associated with inflammatory arthritis progression and its treatment. METHODS: Arthritis was induced in DBA/1J mice by immunization with type-II collagen emulsified in complete Freund's adjuvant. Severity of arthritis was monitored using the clinical arthritis index. MR images of mice were obtained at different stages of arthritis progression and at 3 weeks after methotrexate treatment. Immunohistochemical staining using an anti-CD31 antibody was used to assess vessel density. RESULTS: Volume-normalized transfer constant increased progressively until the active stage of arthritis was reached, and thereafter declined gradually. The pattern of volume-normalized transfer constant changes quantified using DCE-MRI correlated with vascular densities and immunohistochemical findings. Furthermore, volume-normalized transfer constant and densities decreased significantly in a dose-dependent manner after treatment with methotrexate. CONCLUSION: Volume-normalized transfer constant assessed by DCE-MRI can be used as an imaging biomarker for tracking disease progression and for monitoring therapeutic efficacy in inflammatory arthritis. Magn Reson Med 76:926-934, 2016. © 2016 Wiley Periodicals, Inc.

Altered executive function in the welders: A functional magnetic resonance imaging study.

Chronic exposure to manganese (Mn) can lead to impairments in motor and cognitive functions. Several recent studies reported Mn-induced executive dysfunction. The present study compared the neural correlates of ongoing executive function of welders and healthy controls. Fifty-three welders and 44 healthy controls were enrolled. Participants were given functional magnetic resonance imaging (fMRI) scans and performed two modified versions of the Wisconsin Card Sorting Task (WCST) that differed in cognitive demand, and a task that established a high-level baseline (HLB) condition. Card Sorting Test and Word-Color Test were also used to assess executive performance. Neural activation of the bilateral superior-frontal cortex, right-inferior parietal cortex, and bilateral insula cortex were greater in healthy controls than in welders when contrasting the difficult version of the WCST with the HLB. There were also correlations between executive functions by the Card Sorting Test and Word-Color Test, and brain activation in the insula cortex using the WCST. Our results indicated that welders had altered neural processing related to executive function in the prefrontal cortex under conditions of high cognitive demand. Welders also had less activation of the insula cortex, a part of a larger network comprising the lateral prefrontal cortex and parietal cortex.

Synthesis, Magnetic Properties, Map Images, and Water Proton Relaxivities of D-Glucuronic Acid Coated Ln2O3 Nanoparticles (Ln = Ho and Er).

T2 MRI contrast agents cannot be synthesized by using molecules but nanoparticles because appreciable magnetic moments at room temperature are needed. Recently, some of lanthanide (Ln) oxide nanoparticles have shown decent magnetic moments at room temperature and even at ultrasmall particle diameters. In this study, we explored D-glucuronic acid coated Ln2O3 nanoparticles (Ln = Ho and Er) with ultrasmall particle diameters. They showed decent magnetic moments at room temperature and as a result, appreciable transverse water proton relaxivities (r2s) at 1.5 tesla MR field. Clear dose-dependent contrast enhancements in R2 map images were observed in both samples. These results showed that D-glucuronic acid coated Ln2O3 nanoparticles (Ln = Ho and Er) would be potential T2 MRI contrast agents at high MR fields.

Altered executive function in the lead-exposed brain: A functional magnetic resonance imaging study.

INTRODUCTION: It is well known that lead exposure induces neurotoxic effects, which can result in dysfunction in a variety of cognitive capacities including executive function. However, few studies have used fMRI to examine the direct neural correlates of executive function in participants with past lead exposure. Therefore, this study aimed to investigate possible alterations in the neural correlates of executive function in the previously lead-exposed brain. METHODS: Forty-three lead-exposed and 41 healthy participants were enrolled. During the fMRI scans, participants performed two modified versions of the Wisconsin Card Sorting Task (WCST) differing in cognitive demand, and a task that established a high-level baseline condition (HLB). RESULTS: The neural activation of left dorsolateral prefrontal cortex was greater in healthy controls than in participants with lead exposure when contrasting the difficult version of the WCST with the HLB. Moreover, cortical activation was found to be inversely associated with blood lead concentration after controlling for covariates. DISCUSSION: These data suggest that lead exposure can induce functional abnormalities in distributed cortical networks related to executive function, and that lead-induced neurotoxicity may be persistent rather than transient.

Change of Brain Functional Connectivity in Patients With Spinal Cord Injury: Graph Theory Based Approach.

OBJECTIVE: To investigate the global functional reorganization of the brain following spinal cord injury with graph theory based approach by creating whole brain functional connectivity networks from resting state-functional magnetic resonance imaging (rs-fMRI), characterizing the reorganization of these networks using graph theoretical metrics and to compare these metrics between patients with spinal cord injury (SCI) and age-matched controls. METHODS: Twenty patients with incomplete cervical SCI (14 males, 6 females; age, 55±14.1 years) and 20 healthy subjects (10 males, 10 females; age, 52.9±13.6 years) participated in this study. To analyze the characteristics of the whole brain network constructed with functional connectivity using rs-fMRI, graph theoretical measures were calculated including clustering coefficient, characteristic path length, global efficiency and small-worldness. RESULTS: Clustering coefficient, global efficiency and small-worldness did not show any difference between controls and SCIs in all density ranges. The normalized characteristic path length to random network was higher in SCI patients than in controls and reached statistical significance at 12%-13% of density (p<0.05, uncorrected). CONCLUSION: The graph theoretical approach in brain functional connectivity might be helpful to reveal the information processing after SCI. These findings imply that patients with SCI can build on preserved competent brain control. Further analyses, such as topological rearrangement and hub region identification, will be needed for better understanding of neuroplasticity in patients with SCI.