Premovement activity in the mesocortical system links peak force but not initiation of force generation under incentive motivation.

Motivation facilitates motor performance; however, the neural substrates of the psychological effects on motor performance remain unclear. We conducted a functional magnetic resonance imaging experiment while human subjects performed a ready-set-go task with monetary incentives. Although subjects were only motivated to respond quickly, increasing the incentives improved not only reaction time but also peak grip force. However, the trial-by-trial correlation between reaction time and peak grip force was weak. Extensive areas in the mesocortical system, including the ventral midbrain (VM) and cortical motor-related areas, exhibited motivation-dependent activity in the premovement "Ready" period when the anticipated monetary reward was displayed. This premovement activity in the mesocortical system correlated only with subsequent peak grip force, whereas the activity in motor-related areas alone was associated with subsequent reaction time and peak grip force. These findings suggest that the mesocortical system linking the VM and motor-related regions plays a role in controlling the peak of force generation indirectly associated with incentives but not the initiation of force generation.

The dorsal premotor cortex encodes the step-by-step planning processes for goal-directed motor behavior in humans.

The dorsal premotor cortex (PMd) plays an essential role in visually guided goal-directed motor behavior. Although there are several planning processes for achieving goal-directed behavior, the separate neural processes are largely unknown. Here, we created a new visuo-goal task to investigate the step-by-step planning processes for visuomotor and visuo-goal behavior in humans. Using functional magnetic resonance imaging, we found activation in different portions of the bilateral PMd during each processing step. In particular, the activated area for rule-based visuomotor and visuo-goal mapping was located at the ventrorostral portion of the bilateral PMd, that for action plan specification was at the dorsocaudal portion of the left PMd, that for transformation was at the rostral portion of the left PMd, and that for action preparation was at the caudal portion of the bilateral PMd. Thus, the left PMd was involved throughout all of the processes, but the right PMd was involved only in rule-based visuomotor and visuo-goal mapping and action preparation. The locations related to each process were generally spatially separated from each other, but they overlapped partially. These findings revealed that there are functional subregions in the bilateral PMd in humans and these subregions form a functional gradient to achieve goal-directed behavior.

Frequency-specific task modulation of human brain functional networks: A fast fMRI study.

How coherent neural oscillations are involved in task execution is a fundamental question in neuroscience. Although several electrophysiological studies have tackled this issue, the brain-wide task modulation of neural coherence remains uncharacterized. Here, with a fast fMRI technique, we studied shifts of brain-wide neural coherence across different task states in the ultraslow frequency range (0.01-0.7 Hz). First, we examined whether the shifts of the brain-wide neural coherence occur in a frequency-dependent manner. We quantified the shift of a region's average neural coherence by the inter-state variance of the mean coherence between the region and the rest of the brain. A clustering analysis based on the variance's spatial correlation between frequency components revealed four frequency bands (0.01-0.15 Hz, 0.15-0.37 Hz, 0.37-0.53 Hz, and 0.53-0.7 Hz) showing band-specific shifts of the brain-wide neural coherence. Next, we investigated the similarity of the inter-state variance's spectra between all pairs of regions. We found that regions showing similar spectra correspond to those forming functional modules of the brain network. Then, we investigated the relationship between identified frequency bands and modules' inter-state variances. We found that modules showing the highest variance are those made up of parieto-occipital regions at 0.01-0.15 Hz, while it is replaced with another consisting of frontal regions above 0.15 Hz. Furthermore, these modules showed specific shifting patterns of the mean coherence across states at 0.01-0.15 Hz and above 0.15 Hz, suggesting that identified frequency bands differentially contribute to neural interactions during task execution. Our results highlight that usage of the fast fMRI enables brain-wide investigation of neural coherence up to 0.7 Hz, which opens a promising track for assessment of the large-scale neural interactions in the ultraslow frequency range.

Quantitative Evaluations of Geometrical Distortion Corrections in Cortical Surface-Based Analysis of High-Resolution Functional MRI Data at 7T.

BACKGROUND: Although 7T functional MRI (fMRI) provides better signal-to-noise ratio and higher spatial resolution than 3T fMRI, geometric distortions become more challenging because fMRI is more susceptible to distortions than structural MRI. Accurate alignment of 7T fMRI to structural MRI data is critical for precise cortical surface-based analysis. PURPOSE: To quantify the effectiveness of distortion corrections of 7T fMRI data. STUDY TYPE: Prospective. SUBJECTS: Fifteen healthy individuals aged 19-26 years (mean: 21.9 years). FIELD STRENGTH/SEQUENCE: Multiband gradient-echo echo-planar imaging sequence at 7T; 3D T1 /T2 -weighted sequences (magnetization prepared rapid acquisition with gradient echo [MPRAGE] and sampling perfection with application optimized contrast using different flip angle evolution [SPACE]) at 3T. ASSESSMENT: fMRI data at 7T were registered to cortical surfaces reconstructed from 3T structural data acquired in the same subjects. Distortions induced by B0 inhomogeneity and gradient nonlinearity (B0 and gradient distortions) were evaluated as cortical fallout (misregistration of noncortical areas) and displacement (misregistration along gray matter). STATISTICAL TESTS: Repeated measures analyses of variance with post-hoc t-tests with Bonferroni correction. RESULTS: The accuracy of fully corrected fMRI images based on the intensity distribution was 89.2%. Without any corrections, 9.7% of vertices in the whole surfaces were fallout and the average displacement was 0.96 mm for the rest of the vertices. B0 and gradient distortion corrections significantly reduced the fallout (to 2.1% and 8.7%) and displacement (to 0.29 mm and 0.86 mm). These corrections were effective even around regions with moderate distortions (the somatosensory and visual cortices for B0 distortion, and the anterior frontal, inferior temporal, and posterior occipital cortices for gradient distortion). DATA CONCLUSION: B0 distortion correction is crucial for surface-based analysis of fine-resolution fMRI at 7T. Gradient distortion correction should be considered when regions of interest include regions distant from the isocenter of scanners. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY STAGE: 1.

Corticosteroid Withdrawal after Complete Resection of Recurrent IgG4-Related Ophthalmic Disease.

Corticosteroids are the first-line treatment for immunoglobulin G4-related ophthalmic disease (IgG4-ROD). However, the therapeutic effect of corticosteroids is unpredictable, and recurrences occur frequently. We present a case of a 60-year-old woman with IgG4-ROD of the lacrimal fossa. She was first treated with oral prednisolone, which was tapered within three months. However, proptosis recurred two months after prednisolone withdrawal. En bloc excision of the lesion was performed via the eyelid crease approach. The patient is lesion-free without corticosteroids at 18 months after surgery. Complete resection can be a powerful strategy for IgG4-ROD if a well-defined lesion is located in accessible areas.

Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia.

Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.

Elucidating the Quenching Mechanism of Tris(2,2'-bipyridyl)ruthenium(II) Complex in the Water-Glycerol Binary System Based on the Microscopic Structure of the Media.

Kinetic studies on the photochemical quenching reaction of the tris(2,2'-bipyridyl) ruthenium(II) complex ([Ru(bpy)3]2+) in water-glycerol binary media were conducted based on the Einstein-Smoluchowski (E-S) theory. Dynamic and static quenching behaviors were analyzed by comparing results from time-resolved spectroscopy and emission spectroscopy. While the dynamic quenching reaction aligns well with the E-S theory, static quenching was observed, leading to a notable increase in the overall photoquenching reaction rate constant. Employing chromatography and infrared spectroscopy, we correlated the microscopic molecular structure of the binary solvent system and the solvation environment around the emitters with the reaction mechanism. This correlation was found to correspond to ion pair formation and the confinement effect of the emitter, respectively.

Barium-induced toxic anterior segment syndrome.

Toxic anterior segment syndrome (TASS) is a rapid-onset inflammation of the eye following uneventful ocular surgery. We report a case of TASS following Baerveldt glaucoma implant (BGI) surgery. Inductively coupled plasma-mass spectrometry (ICP-MS) identified barium in the eye and in the eluate from the bleb of the BGI. We attribute TASS in our patient to the dissolution of barium from the BGI and its entry into the eye, where it causes severe inflammation.

Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin.

We demonstrate a physiological role for tumstatin, a cleavage fragment of the alpha3 chain of type IV collagen (Col IValpha3), which is present in the circulation. Mice with a genetic deletion of Col IValpha3 show accelerated tumor growth associated with enhanced pathological angiogenesis, while angiogenesis associated with development and tissue repair are unaffected. Supplementing Col IValpha3-deficient mice with recombinant tumstatin to a normal physiological concentration abolishes the increased rate of tumor growth. The suppressive effects of tumstatin require alphaVbeta3 integrin expressed on pathological, but not on physiological, angiogenic blood vessels. Mice deficient in matrix metalloproteinase-9, which cleaves tumstatin efficiently from Col IValpha3, have decreased circulating tumstatin and accelerated growth of tumor. These results indicate that MMP-generated fragments of basement membrane collagen can have endogenous function as integrin-mediated suppressors of pathologic angiogenesis and tumor growth.

Novel corneal morphological alterations in Vogt-Koyanagi-Harada disease.

PURPOSE: To determine whether visual function, especially when dependent on the anterior segment of ocular tissue, is altered during high-dose steroid treatment for Vogt-Koyanagi-Harada disease (VKH). STUDY DESIGN: Retrospective case series METHODS: This case series included 18 eyes of 18 patients with VKH who received high-dose steroid therapy as initial treatment. All patients underwent anterior swept-source optical coherent tomography (CASIA-2) examinations during their clinical course to measure the central corneal thickness (CCT), average central corneal power (ACCP), maximum curvature (Kmax) and anterior chamber depth (ACD). RESULTS: The treatment duration was classified into the initial phase (earliest initial phase eIP; 0-1 month, initial phase: IP; 1-3months), middle phase (MP; 3-6 months), and late phase (LP; 6-9 months). The CCT decreased significantly after treatment (eIP vs. IP, p<0.01, eIP vs. MP, p<0.01; eIP vs. LP, p<0.01). The CCT at eIP was correlated with the flare value at 0M (R2=0.22). The change in Kmax at MP and LP was correlated with the flare value at 0M. Moreover, CCT at MP was correlated with rate of change in nasal angle open distance (AOD) at IP and rate of change in temporal AOD at IP. CONCLUSIONS: This study was the first to reveal morphological changes in the anterior segment of the eye in VKH using CASIA-2, which may affect visual acuity and the astigmatic axis. It is vital to assess corneal morphology to determine the cause of visual function deterioration in patients with VKH.

Lack of collagen XVIII/endostatin exacerbates immune-mediated glomerulonephritis.

Collagen XVIII is a component of the highly specialized extracellular matrix associated with basement membranes of epithelia and endothelia. In the normal kidney, collagen XVIII is distributed throughout glomerular and tubular basement membranes, mesangial matrix, and Bowman's capsule. Proteolytic cleavage within its C-terminal domain releases the fragment endostatin, which has antiangiogenic properties. Because damage to the glomerular basement membrane (GBM) accompanies immune-mediated renal injury, we investigated the role of collagen XVIII/endostatin in this disorder. We induced anti-GBM glomerulonephritis in collagen XVIII alpha1-null and wild-type mice and compared the resulting matrix accumulation, inflammation, and capillary rarefaction. Anti-GBM disease upregulated collagen XVIII/endostatin expression within the GBM and Bowman's capsule of wild-type mice. Collagen XVIII/endostatin-deficient mice developed more severe glomerular and tubulointerstitial injury than wild-type mice. Collagen XVIII/endostatin deficiency altered matrix remodeling, enhanced the inflammatory response, and promoted capillary rarefaction and vascular endothelial cell damage, but did not affect endothelial proliferation. Supplementing collagen XVIII-deficient mice with exogenous endostatin did not affect the progression of anti-GBM disease. Taken together, these results suggest that collagen XVIII/endostatin preserves the integrity of the extracellular matrix and capillaries in the kidney, protecting against progressive glomerulonephritis.

The integrative role of the M1 in motor sequence learning.

The primary motor cortex (M1) is crucial in motor learning. Whether the M1 encodes the motor engram for sequential finger tapping formed by an emphasis on speed is still inconclusive. The active states of engrams are hard to discriminate from the motor execution per se. As preparatory activity reflects the upcoming movement parameters, we hypothesized that the retrieval of motor engrams generated by different learning modes is reflected as a learning-related increase in the preparatory activity of the M1. To test this hypothesis, we evaluated the preparatory activity during the learning of sequential finger-tapping with the non-dominant left hand using a 7T functional MRI. Participants alternated between performing a tapping sequence as quickly as possible (maximum mode) or at a constant speed of 2 Hz paced by a sequence-specifying visual cue (constant mode). We found a training-related increase in preparatory activity in the network covering the bilateral anterior intraparietal sulcus and inferior parietal lobule extending to the right M1 during the maximum mode and the right M1 during the constant mode. These findings indicate that the M1, as the last effector of the motor output, integrates the motor engram distributed through the networks despite training mode differences.

Cognitive control affects motor learning through local variations in GABA within the primary motor cortex.

The primary motor cortex (M1) is crucial for motor learning; however, its interaction with other brain areas during motor learning remains unclear. We hypothesized that the fronto-parietal execution network (FPN) provides learning-related information critical for the flexible cognitive control that is required for practice. We assessed network-level changes during sequential finger tapping learning under speed pressure by combining magnetic resonance spectroscopy and task and resting-state functional magnetic resonance imaging. There was a motor learning-related increase in preparatory activity in the fronto-parietal regions, including the right M1, overlapping the FPN and sensorimotor network (SMN). Learning-related increases in M1-seeded functional connectivity with the FPN, but not the SMN, were associated with decreased GABA/glutamate ratio in the M1, which were more prominent in the parietal than the frontal region. A decrease in the GABA/glutamate ratio in the right M1 was positively correlated with improvements in task performance (p = 0.042). Our findings indicate that motor learning driven by cognitive control is associated with local variations in the GABA/glutamate ratio in the M1 that reflects remote connectivity with the FPN, representing network-level motor sequence learning formations.

Enhanced structural connectivity within the motor loop in professional boxers prior to a match.

Professional boxers train to reduce their body mass before a match to refine their body movements. To test the hypothesis that the well-defined movements of boxers are represented within the motor loop (cortico-striatal circuit), we first elucidated the brain structure and functional connectivity specific to boxers and then investigated plasticity in relation to boxing matches. We recruited 21 male boxers 1 month before a match (Time1) and compared them to 22 age-, sex-, and body mass index (BMI)-matched controls. Boxers were longitudinally followed up within 1 week prior to the match (Time2) and 1 month after the match (Time3). The BMIs of boxers significantly decreased at Time2 compared with those at Time1 and Time3. Compared to controls, boxers presented significantly higher gray matter volume in the left putamen, a critical region representing motor skill training. Boxers presented significantly higher functional connectivity than controls between the left primary motor cortex (M1) and left putamen, which is an essential region for establishing well-defined movements. Boxers also showed significantly higher structural connectivity in the same region within the motor loop from Time1 to Time2 than during other periods, which may represent the refined movements of their body induced by training for the match.

Low-dose darbepoetin alpha attenuates progression of a mouse model of aristolochic acid nephropathy through early tubular protection.

BACKGROUND/AIM: Aristolochic acid (AA) nephropathy, first reported as Chinese herbs nephropathy, is a rapidly progressive tubulointerstitial nephropathy that results in severe anemia, interstitial fibrosis and end-stage renal disease. Tubulointerstitial injury was studied in a mouse model of AA nephropathy to determine whether low-dose darbepoetin alpha (DPO) treatment prevents acute tubular necrosis and interstitial fibrosis. METHODS: AA was administered to C3H/He mice intraperitoneally and some mice were also treated with 0.1 microg/kg of DPO weekly starting on the day of AA administration or on day 28. At 28, 56 or 84 days, blood and urine samples were collected and mice were sacrificed for histological assessment of the kidneys. RESULTS: AA-treated mice developed anemia, elevation of serum creatinine, severe tubular injury similar to acute tubular necrosis and progressive interstitial fibrosis. Although early treatment with low-dose DPO had minimal effects on the hematocrit, it significantly ameliorated acute tubular injury and interstitial inflammation through increasing the survival of tubular cells. As a result, it contributed to preservation of peritubular capillaries and reduction of interstitial fibrosis. CONCLUSION: Low-dose DPO treatment conferred protection against acute tubular damage and attenuated interstitial fibrosis in a mouse model of AA nephropathy. Early administration of low-dose DPO may prevent the progression of acute tubular necrosis and the subsequent renal fibrosis in human AA nephropathy.

The motor engram as a dynamic change of the cortical network during early sequence learning: An fMRI study.

Neural substrates of motor engrams in the human brain are hard to identify because their dormant states are difficult to discriminate. We utilized eigenvector centrality (EC) to measure the network information that accumulates as an engram during learning. To discriminate engrams formed by emphasis on speed or accuracy, we conducted functional MRI on 58 normal volunteers as they performed a sequential finger-tapping task with the non-dominant left hand. Participants alternated between performing a tapping sequence as quickly as possible (maximum mode) or at a constant speed of 2 Hz, paced by a sequence-specifying visual cue (constant mode). We depicted the formation of the motor engram by characterizing the dormant state as the increase in EC of the resting epoch throughout the training course, and the ecphory, or activated state, as the increment in EC during the task epoch relative to the alternated resting epoch. We found that a network covering the left anterior intraparietal sulcus and inferior parietal lobule represented the engram for the speed of execution, whereas bilateral premotor cortex and right primary motor cortex represented the sequential order of movements. This constitutes the first demonstration of learning-mode specific motor engrams formed by only 30 min of training.

Prosocial behavior toward estranged persons modulates the interaction between midline cortical structures and the reward system.

Good reputation enhances positive self-image, which motivates prosocial behavior, a phenomenon known as indirect reciprocity. Thus, good reputation should promote prosocial behavior toward estranged people to whom affective responses leading to direct reciprocity are suppressed. We predicted that such behaviors involve an interrelationship between self-image, processed in the medial prefrontal cortex (mPFC) and precuneus, and social reward, processed in the reward system. To test our hypothesis, we performed fMRI on 21 participants during a virtual ball-toss game after subjects formed negative impressions (estrangement) or neutral impressions of other players. During some blocks of the game, the other players did not receive tosses, and participants could increase tosses to them (i.e. engage in prosocial behavior). Participants significantly increased tosses to all isolated players; therefore, prosocial behavior occurred irrespective of estrangement. Prosocial behavior toward estranged players enhanced positive self-image and increased activation of the anterior mPFC and precuneus. The precuneus exhibited enhanced functional connectivity with the striatum. Thus, a positive self-image, represented by an interaction between the midline cortical structures and striatum, plays key roles in prosocial behavior toward estranged people.

Qualitative differences in offline improvement of procedural memory by daytime napping and overnight sleep: An fMRI study.

Daytime napping offers various benefits for healthy adults, including enhancement of motor skill learning. It remains controversial whether napping can provide the same enhancement as overnight sleep, and if so, whether the same neural underpinning is recruited. To investigate this issue, we conducted functional MRI during motor skill learning, before and after a short day-nap, in 13 participants, and compared them with a larger group (n=47) who were tested following regular overnight sleep. Training in a sequential finger-tapping task required participants to press a keyboard in the MRI scanner with their non-dominant left hand as quickly and accurately as possible. The nap group slept for 60min in the scanner after the training run, and the previously trained skill was subsequently re-tested. The whole-night sleep group went home after the training, and was tested the next day. Offline improvement of speed was observed in both groups, whereas accuracy was significantly improved only in the whole-night sleep group. Correspondingly, the offline increment in task-related activation was significant in the putamen of the whole-night group. This finding reveals a qualitative difference in the offline improvement effect between daytime napping and overnight sleep.

Neural correlates underlying change in state self-esteem.

State self-esteem, the momentary feeling of self-worth, functions as a sociometer involved in maintenance of interpersonal relations. How others' appraisal is subjectively interpreted to change state self-esteem is unknown, and the neural underpinnings of this process remain to be elucidated. We hypothesized that changes in state self-esteem are represented by the mentalizing network, which is modulated by interactions with regions involved in the subjective interpretation of others' appraisal. To test this hypothesis, we conducted task-based and resting-state fMRI. Participants were repeatedly presented with their reputations, and then rated their pleasantness and reported their state self-esteem. To evaluate the individual sensitivity of the change in state self-esteem based on pleasantness (i.e., the subjective interpretation of reputation), we calculated evaluation sensitivity as the rate of change in state self-esteem per unit pleasantness. Evaluation sensitivity varied across participants, and was positively correlated with precuneus activity evoked by reputation rating. Resting-state fMRI revealed that evaluation sensitivity was positively correlated with functional connectivity of the precuneus with areas activated by negative reputation, but negatively correlated with areas activated by positive reputation. Thus, the precuneus, as the part of the mentalizing system, serves as a gateway for translating the subjective interpretation of reputation into state self-esteem.

Loss of placental growth factor ameliorates maternal hypertension and preeclampsia in mice.

Preeclampsia remains a clinical challenge due to its poorly understood pathogenesis. A prevailing notion is that increased placental production of soluble fms-like tyrosine kinase-1 (sFlt-1) causes the maternal syndrome by inhibiting proangiogenic placental growth factor (PlGF) and VEGF. However, the significance of PlGF suppression in preeclampsia is uncertain. To test whether preeclampsia results from the imbalance of angiogenic factors reflected by an abnormal sFlt-1/PlGF ratio, we studied PlGF KO (Pgf-/-) mice and noted that the mice did not develop signs or sequelae of preeclampsia despite a marked elevation in circulating sFLT-1. Notably, PlGF KO mice had morphologically distinct placentas, showing an accumulation of junctional zone glycogen. We next considered the role of placental PlGF in an established model of preeclampsia (pregnant catechol-O-methyltransferase-deficient [COMT-deficient] mice) by generating mice with deletions in both the Pgf and Comt genes. Deletion of placental PlGF in the context of COMT loss resulted in a reduction in maternal blood pressure and increased placental glycogen, indicating that loss of PlGF might be protective against the development of preeclampsia. These results identify a role for PlGF in placental development and support a complex model for the pathogenesis of preeclampsia beyond an angiogenic factor imbalance.