Impaired Inhibition Research Articles

Similarity and difference in large-scale functional network alternations between behavioral addictions and substance use disorder: a comparative meta-analysis.

Behavioral addiction (BA) and substance use disorder (SUD) share similarities and differences in clinical symptoms, cognitive functions, and behavioral attributes. However, little is known about whether and how functional networks in the human brain manifest commonalities and differences between BA and SUD. Voxel-wise meta-analyses of resting-state functional connectivity (rs-FC) were conducted in BA and SUD separately, followed by quantitative conjunction analyses to identify the common and distinct alterations across both the BA and SUD groups. A total of 92 datasets with 2444 addicted patients and 2712 healthy controls (HCs) were eligible for the meta-analysis. Our findings demonstrated that BA and SUD exhibited common alterations in rs-FC between frontoparietal network (FPN) and other high-level neurocognitive networks (i.e. default mode network (DMN), affective network (AN), and salience network (SN)) as well as hyperconnectivity between SN seeds and the Rolandic operculum in SSN. In addition, compared with BA, SUD exhibited several distinct within- and between-network rs-FC alterations mainly involved in the DMN and FPN. Further, altered within- and between-network rs-FC showed significant association with clinical characteristics such as the severity of addiction in BA and duration of substance usage in SUD. The common rs-FC alterations in BA and SUD exhibited the relationship with consistent aberrant behaviors in both addiction groups, such as impaired inhibition control and salience attribution. By contrast, the distinct rs-FC alterations might suggest specific substance effects on the brain neural transmitter systems in SUD.

Differential neurocognitive profiles in adult attention-deficit/hyperactivity disorder subtypes revealed by the Cambridge Neuropsychological Test Automated Battery.

Adult attention-deficit/hyperactivity disorder (aADHD) represents a heterogeneous entity incorporating different subgroups in terms of symptomatology, course, and neurocognition. Although neurocognitive dysfunction is generally associated with aADHD, its severity, association with self-reported symptoms, and differences between subtypes remain unclear. We investigated 61 outpatients (65.6% male, mean age 31.5 ± 9.5) diagnosed using DSM-5 criteria together with age-, sex-, and education-matched healthy controls (HC) (n = 58, 63.8% male, mean age 32.3 ± 9.6). Neurocognitive alterations were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and compared between groups using the generalized linear model (GLM) method. Multivariate effects were tested by principal component analysis combined with multivariate pattern analysis. Self-reported symptom severity was tested for correlations with neurocognitive performance. GLM analyses revealed nominally significant differences between the aADHD and HC groups in several domains, however, only the Rapid Visual Information Processing measures survived correction, indicating impaired sustained attention and response inhibition in the aADHD group. Comparison of the predominantly inattentive and the hyperactive-impulsive/combined subtypes yielded nominally significant differences with higher levels of dysfunction in the inattentive group. In the stepwise discriminant analysis aADHD and HC groups were best separated with 2 factors representing sustained attention and reaction time. We found only weak correlations between symptom severity and CANTAB factors. aADHD patients are neuropsychologically heterogeneous and subtypes show different neurocognitive profiles. Differences between the aADHD and HC groups were driven primarily by the inattentive subtype. Sustained attention and its factor derivative showed the most significant alterations in aADHD patients.

Hypercoagulability impairs plaque stability in diabetes-induced atherosclerosis

Abstract Introduction Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Atherosclerosis among diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Methadology Female ApoE-/- or TMPro/Pro ApoE-/- mice (age 6 to 8 weeks) were fed a normal chow diet and were made diabetic (DM) by injecting streptozotocin, reflecting type 1 DM. After 22 weeks of age, the body weight of the mice was measured, and the mice were sacrificed. Plasma and tissue samples were analysed for different parameters. Results Here, we demonstrate that atherosclerotic plaque stability is reduced in hyperglycemic mice expressing dysfunctional TM (TMPro/Pro mice), which have a pro-coagulant phenotype due to impaired thrombin inhibition and markedly reduced aPC generation. The vessel lumen and plaque size of atherosclerotic lesions in the truncus brachiocephalic were decreased in diabetic TMPro/Pro ApoE-/- mice compared to diabetic ApoE-/- mice. While lipid accumulation in lesions of diabetic TMPro/Pro ApoE-/- mice was lower than that in diabetic ApoE-/- mice, morphometric analyses revealed more prominent signs of instable plaques, such as a larger necrotic core area and decreased fibrous cap thickness in diabetic TMPro/Pro ApoE-/- mice. Congruently, more macrophages and fewer smooth muscle cells were observed within lesions of diabetic TMPro/Pro ApoE-/- mice. Conclusion Thus, impaired TM function reduces plaque stability, a characteristic of hyperglycemia-associated plaques, thus suggesting the crucial role of impaired TM function in mediating diabetes-associated atherosclerosis.

Enhanced reactive inhibition in adolescents with non-suicidal self-injury disorder.

To investigate whether the core of the pathophysiology underlying non-suicidal self-injury (NSSI) relates to poor impulse control due to impaired motor inhibition (i.e. the ability to inhibit a preplanned motor response). We conducted a case-control study to compare the proficiency of two domains of motor inhibition, that is, reactive and proactive inhibition, by giving the reaching arm version of the stop-signal task and a go-only task to 28 drug-naive adolescents with NSSI disorder (NSSID) (mean age [SD] 15 years 8 months [1 year 4 months]; three males and 25 females) and 28 typically developing adolescents (mean age 15 years 8 months [1 year 5 months]; three males and 25 females). Reactive inhibition, as determined by the duration of the stop-signal reaction time, was enhanced in adolescents with NSSID compared to typically developing controls (194.2 [22.5 ms] vs 217.5 [17.3 ms], p < 0.001). By contrast, proactive inhibition was similar in both groups. Lastly, the level of impulsivity, assessed using the Barratt Impulsiveness Scale Version 11, did not differ between typically developing adolescents and adolescents with NSSID. However, adolescents with NSSID were more impulsive than controls in a subscale of the UPPS-P Impulsive Behavior Scale. NSSID is not driven by heightened motor impulsivity. Instead, adolescents with NSSID exhibited greater proficiency in reactive inhibition, a proxy for motor impulsivity. We suggest that the enhancement of reactive inhibition strengthens action control, allowing adolescents to suppress their self-protection instinct and perform NSSI behaviours.

Ultrasound-Induced Prenatal Stress: New Possibilities for Modeling Mental Disorders

The development of animal models of mental disorders is an important task since such models are useful for studying the neurobiological mechanisms of psychopathologies and for trial of new therapeutic drugs. One way to model pathologies of the nervous system is to impair fetal neurodevelopment through stress of the pregnant future mother, or prenatal stress (PS). The use of variable frequency ultrasound (US) in rodents is a promising method of imitating psychological stress, to which women in modern society are most often subjected. The aim of our study was to investigate the effect of PS induced by exposure to variable frequency ultrasound (US PS) throughout the gestational period on the adult rat offspring, namely, to identify features of behavioral alterations and neurochemical brain parameters that can be associated with certain mental disorders in humans, to determine the possibility of creating a new model of psychopathology. Our study included a study of some behavioral characteristics of male and female rats in the elevated plus maze, open-field test, object recognition test, social interaction test, sucrose preference test, latent inhibition test, Morris water maze, forced swimming test, acoustic startle reflex, and prepulse inhibition tests. We also determined the activity of the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems in the hippocampus and frontal cortex by HPLC-ED. Concentration of norepinephrine, dopamine, DOPAC, serotonin, and HIAA, as well as DOPAC/dopamine and HIAA/serotonin ratios were determined. A correlation analysis of behavioral and neurochemical parameters in male and female rats was performed based on the data obtained. The results of the study showed that US PS altered the behavioral phenotype of the rat offspring. US PS increased the level of anxious behavior, impaired orientation-research behavior, increased grooming activity, decreased the desire for social contacts, shifted behavioral reactions from social interaction to interaction with inanimate objects, impaired latent inhibition, and decreased the startle reflex. US PS activated the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems of the rat frontal cortex and hippocampus. A correlation between neurochemical and behavioral parameters was revealed. Our study showed that US PS leads to a certain dysfunction on behavioral and neurochemical levels in rats that is most closely associated with symptoms of schizophrenia or autism. We hypothesize that this could potentially be an indicator of face validity for a model of psychopathology based on neurodevelopmental impairment.

Pivotal role of Slitrk1 in adult striatal cholinergic neurons in mice: Implication in Tourette syndrome.

The SLIT and NTRK-like 1 (SLITRK1) gene mutation and striatal cholinergic interneurons (ChIs) loss are associated with Tourette syndrome (TS). ChIs comprise only 1-2% of total neurons but send dense arbors of fibers in the stratum, making it the most ACh-abundant brain region. Here, mice receiving Slitrk1 siRNA bilateral microinjection in the dorsal striatum, Slitrk1-knockdown (KD) mice, exhibit TS-like haloperidol-sensitive stereotypic tic behaviors and impaired prepulse inhibition, as well as delayed sensorimotor response, compared with scrambled siRNA-treated controls. These TS-like characteristics correlate with lower striatal Slitrk1 protein levels, fewer Slitrk1-containing ChIs, and fewer activated ChIs in Slitrk1-KD mice. Based on their electrophysiological properties, Slitrk1-negative ChIs are less excitable than Slitrk1-positive ChIs. Slitrk1-KD mice have lower evoked acetylcholine and dopamine levels, higher tonic dopamine levels, and downregulated dopamine transporters in the striatum, increased apomorphine-induced climbing behaviors, and impaired methamphetamine-induced hyperlocomotion compared with controls. These results suggest that Slitrk1 is pivotal in maintaining striatal ChIs activity and subsequent dopaminergic transmission for normal motor functioning. Furthermore, conditional striatal Slitrk1-KD mice may serve as a translational modality with aspects of TS phenomenology. This article is protected by copyright. All rights reserved.

Quantitative GABA magnetic resonance spectroscopy as a measure of motor learning function in the motor cortex after subarachnoid hemorrhage.

The neural mechanisms underlying gross and fine motor dysfunction after subarachnoid hemorrhage (SAH) remain unknown. The γ-aminobutyric acid (GABA) deficit hypothesis proposes that reduced neuronal GABA concentrations and the subsequent lack of GABA-mediated inhibition cause motor impairment after SAH. This study aimed to explore the correlation between GABA levels and a behavioral measure of motor performance in patients with SAH. Motor cortical GABA levels were assessed in 40 patients with SAH and 10 age-matched healthy controls using proton magnetic resonance spectroscopy. The GABA and N-acetylasparate (NAA) ratio was measured in the normal gray matter within the primary motor cortex. The relationship between GABA concentration and hand-motor performance was also evaluated. Results showed significantly lower GABA levels in patients with SAH's left motor cortex than in controls (GABA/NAA ratio: 0.282 ± 0.085 vs. 0.341 ± 0.031, respectively; p = 0.041). Reaction times (RTs), a behavioral measure of motor performance potentially dependent on GABAergic synaptic transmission, were significantly longer in patients than in controls (936.8 ± 303.8 vs. 440.2 ± 67.3 ms, respectively; p < 0.001). Moreover, motor cortical GABA levels and RTs exhibited a significant positive linear correlation among patients (r = 0.572, rs = 0.327, p = 0.0001). Therefore, a decrease in GABA levels in the primary motor cortex after SAH may lead to impaired cortical inhibition of neuronal function and indicates that GABA-mediated synaptic transmission in the motor cortex is critical for RT.

Impaired immunosuppressive effect of bone marrow mesenchymal stem cell-derived exosomes on T cells in aplastic anemia

BackgroundPrevious studies have verified the dysfunction of mesenchymal stem cells (MSCs) for immunoregulation in acquired aplastic anemia (AA) patients. Exosomes derived from MSCs can partially substitute MSCs acting as immune regulator. Dysfunction of exosomes (Exos) derived from AA-MSC (AA-Exos) may play a key role in immunologic dissonance.MethodIn this study, CD3 + T cells were collected and cocultured with AA-Exos and exosomes derived from HD-MSC (HD-Exos). The proliferation, differentiation and activation of CD3 + T cells were detected to compare the immunosuppressive effects between AA-Exos and HD-Exos. An immune-mediated murine model of AA was structured to compare the therapeutic effect of AA-Exos and HD-Exos. Furthermore, total RNA including miRNA from exosomes we purified and total RNA of CD3 + T cells were extracted for RNA-seq in order to construct the miRNA–mRNA network for interactions and functional analysis.ResultsAA-Exos had impaired inhibition effects on CD3 + T cells in terms of cell proliferation, activation and differentiation compared with exosomes from HD-Exos. HD-Exos showed a more effective rescue of AA mice compared to AA-Exos. Importantly, we found some differentially expressed miRNA involved in immune response, such as miR-199, miR-128 and miR-486. The Gene Ontology analysis of differentially expressed genes (DEGs) revealed involvement of various cellular processes, such as lymphocyte chemotaxis, lymphocyte migration and response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes analysis illustrated upregulation of critical pathways associated with T cell function after coculturing with AA-Exos compared with HD-Exos, such as graft-versus-host disease, Th17 cell differentiation and JAK-STAT signaling pathway. A miRNA–mRNA network was established to visualize the interaction between them.ConclusionIn summary, AA-Exos had impaired immunosuppressive effect on T cells, less ability to rescue AA mice and differently expressed miRNA profile, which might partly account for the pathogenesis of AA as well as provide a new target of AA treatment.

Exploring Cognitive-Pragmatic Heterogeneity Following Acquired Brain Injury: A Cluster Analysis of Hint Comprehension.

Difficulties understanding nonliteral language (especially hints) are frequently reported following acquired brain injury (ABI). Several cognitive mechanisms, such as context processing, executive functions, and theory of mind (ToM), may underlie these disorders. However, their role remains controversial, mainly because of the characteristic heterogeneity of this population. Therefore, our study aimed to identify cognitive-pragmatic profiles in individuals with ABI. A new task of hint comprehension, manipulating executive demand, markers of hints, and ToM and neuropsychological tests were administered to 33 participants with frontal ABI and 33 control participants. Cluster analysis, a method sensitive to profile heterogeneity, was applied and coupled with error analysis. We highlighted two cognitive-pragmatic profiles. One subgroup of participants with ABI exhibited contextual insensitivity, leading them to infer the utterance meaning based on linguistic decoding alone-literal meaning. This difficulty in understanding hints was associated with deficits in working memory, inhibition, and ToM. The second subgroup of participants with ABI showed difficulty with literal statements, associated with impaired inhibition and ToM. In addition, the two subgroups differed only on the ToM task. This result suggests that various types of ToM deficit (misunderstanding vs. incorrect attribution of mental states) could contribute to the variability of the pragmatic profiles observed (difficulties in interpreting hints vs. literal statements). The experimental design adopted in this study provides valuable insight into the explanatory hypotheses of nonliteral language comprehension disorders and has important clinical implications. https://doi.org/10.23641/asha.24069516.

Locus Coeruleus Integrity Is Linked to Response Inhibition Deficits in Parkinson's Disease and Progressive Supranuclear Palsy.

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetization-transfer-weighted imaging of the LC. Parameters of "race models" of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer nondecision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioral modeling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioral changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimization of noradrenergic treatment is likely to benefit from stratification according to LC integrity.SIGNIFICANCE STATEMENT Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson's disease and progressive supranuclear palsy. We used cognitive modeling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson's disease and progressive supranuclear palsy.

Automatic Positive and Negative Emotion Regulation in Adolescents with Major Depressive Disorder

Introduction: Adolescents with major depressive disorder (MDD) exhibit hypoactivity to positive stimuli and hyperactivity to negative stimuli in terms of neural responses. Automatic emotion regulation (AER) activates triple networks (i.e., the central control network, default mode network, and salience network). Based on previous studies, we hypothesized that adolescents with MDD exhibit dissociable spatiotemporal deficits during positive and negative AER. Methods: We first collected EEG data from 32 adolescents with MDD and 35 healthy adolescents while they performed an implicit emotional Go/NoGo task. Then, we characterized the spatiotemporal dynamics of cortical activity during AER. Results: In Go trials, MDD adolescents exhibited reduced N2 amplitudes, enhanced theta power for positive pictures, and stronger bottom-up information flow from the left orbitofrontal cortex (OFC) to the right superior frontal gyrus compared to top-down information flow than the controls. In contrast, in NoGo trials, MDD adolescents exhibited elevated P3 amplitudes, enhanced theta power, and stronger top-down information flows from the right middle frontal gyrus to the right OFC and the left insula than the controls. Conclusion: Overall, adolescents with MDD exhibited impaired automatic attention to positive emotions and impaired automatic response inhibition. These findings have potential implications for the clinical treatment of adolescents with MDD.

Reduced Cholecystokinin-Expressing Interneuron Input Contributes to Disinhibition of the Hippocampal CA2 Region in a Mouse Model of Temporal Lobe Epilepsy.

A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and CA2 pyramidal neurons (PNs). A role for CA2 in seizure generation was suggested based on findings of a reduction in CA2 synaptic inhibition (Williamson and Spencer, 1994) and the presence of interictal-like spike activity in CA2 in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus (PILO-SE) mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study, we explored the cellular basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches in PILO-SE male and female mice. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive (CCK+) interneurons and a functional impairment of CCK+ interneuron-mediated inhibition of CA2 PNs. We also found a disruption in the perisomatic perineuronal net in the CA2 stratum pyramidale. Such pathologic alterations may contribute to an enhanced excitation of CA2 PNs and CA2-dependent seizure activity in the PILO-SE mouse model.SIGNIFICANCE STATEMENT Impaired synaptic inhibition in hippocampal circuits has been identified as a key feature that contributes to the emergence and propagation of seizure activity in human patients and animal models of temporal lobe epilepsy (TLE). Among the hippocampal subfields, the CA2 region is particularly resilient to seizure-associated neurodegeneration and has been suggested to play a key role in seizure activity in TLE. Here we report that perisomatic inhibition of CA2 pyramidal neurons mediated by cholecystokinin-expressing interneurons is selectively reduced in acute hippocampal slices from epileptic mice. Parvalbumin-expressing interneurons, in contrast, appear relatively conserved in epileptic mice. These findings advance our understanding of the cellular mechanisms underlying inhibitory disruption in hippocampal circuits in a mouse model of spontaneous recurring seizures.

94 Citrullination of C1-inhibitor as a mechanism of impaired complement inhibition in rheumatoid arthritis

94 Citrullination of C1-inhibitor as a mechanism of impaired complement inhibition in rheumatoid arthritis

A frontal transcallosal inhibition loop mediates interhemispheric balance in visuospatial processing

Interhemispheric communication through the corpus callosum is required for both sensory and cognitive processes. Impaired transcallosal inhibition causing interhemispheric imbalance is believed to underlie visuospatial bias after frontoparietal cortical damage, but the synaptic circuits involved remain largely unknown. Here, we show that lesions in the mouse anterior cingulate area (ACA) cause severe visuospatial bias mediated by a transcallosal inhibition loop. In a visual-change-detection task, ACA callosal-projection neurons (CPNs) were more active with contralateral visual field changes than with ipsilateral changes. Unilateral CPN inactivation impaired contralateral change detection but improved ipsilateral detection by altering interhemispheric interaction through callosal projections. CPNs strongly activated contralateral parvalbumin-positive (PV+) neurons, and callosal-input-driven PV+ neurons preferentially inhibited ipsilateral CPNs, thus mediating transcallosal inhibition. Unilateral PV+ neuron activation caused a similar behavioral bias to contralateral CPN activation and ipsilateral CPN inactivation, and bilateral PV+ neuron activation eliminated this bias. Notably, restoring interhemispheric balance by activating contralesional PV+ neurons significantly improved contralesional detection in ACA-lesioned animals. Thus, a frontal transcallosal inhibition loop comprising CPNs and callosal-input-driven PV+ neurons mediates interhemispheric balance in visuospatial processing, and enhancing contralesional transcallosal inhibition restores interhemispheric balance while also reversing lesion-induced bias.

The role of GABAB receptors in the subcortical pathways of the mammalian auditory system.

GABAB receptors are G-protein coupled receptors for the inhibitory neurotransmitter GABA. Functional GABAB receptors are formed as heteromers of GABAB1 and GABAB2 subunits, which further associate with various regulatory and signaling proteins to provide receptor complexes with distinct pharmacological and physiological properties. GABAB receptors are widely distributed in nervous tissue, where they are involved in a number of processes and in turn are subject to a number of regulatory mechanisms. In this review, we summarize current knowledge of the cellular distribution and function of the receptors in the inner ear and auditory pathway of the mammalian brainstem and midbrain. The findings suggest that in these regions, GABAB receptors are involved in processes essential for proper auditory function, such as cochlear amplifier modulation, regulation of spontaneous activity, binaural and temporal information processing, and predictive coding. Since impaired GABAergic inhibition has been found to be associated with various forms of hearing loss, GABAB dysfunction could also play a role in some pathologies of the auditory system.

Intracortical and intercortical networks in patients after stroke: a concurrent TMS-EEG study

BackgroundConcurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) recording provides information on both intracortical reorganization and networking, and that information could yield new insights into post-stroke neuroplasticity. However, a comprehensive investigation using both concurrent TMS-EEG and motor-evoked potential-based outcomes has not been carried out in patients with chronic stroke. Therefore, this study sought to investigate the intracortical and network neurophysiological features of patients with chronic stroke, using concurrent TMS-EEG and motor-evoked potential-based outcomes.MethodsA battery of motor-evoked potential-based measures and concurrent TMS-EEG recording were performed in 23 patients with chronic stroke and 21 age-matched healthy controls.ResultsThe ipsilesional primary motor cortex (M1) of the patients with stroke showed significantly higher resting motor threshold (P = 0.002), reduced active motor-evoked potential amplitudes (P = 0.001) and a prolonged cortical silent period (P = 0.007), compared with their contralesional M1. The ipsilesional stimulation also produced a reduction in N100 amplitude of TMS-evoked potentials around the stimulated M1 (P = 0.007), which was significantly correlated with the ipsilesional resting motor threshold (P = 0.011) and motor-evoked potential amplitudes (P = 0.020). In addition, TMS-related oscillatory power was significantly reduced over the ipsilesional midline-prefrontal and parietal regions. Both intra/interhemispheric connectivity and network measures in the theta band were significantly reduced in the ipsilesional hemisphere compared with those in the contralesional hemisphere.ConclusionsThe ipsilesional M1 demonstrated impaired GABA-B receptor-mediated intracortical inhibition characterized by reduced duration, but reduced magnitude. The N100 of TMS-evoked potentials appears to be a useful biomarker of post-stroke recovery.

Lack of functional brain connectivity was associated with poor inhibition in children with attention-deficit/hyperactivity disorder using near-infrared spectroscopy.

The present study aimed to evaluate the characteristics of functional brain connectivity in the resting state in children with attention deficit hyperactivity disorder (ADHD) and to assess the association between the connectivity and inhibition function using near-infrared spectroscopy (NIRS). In total, 34 children aged 6-13 diagnosed with ADHD were recruited from Hangzhou Seventh People's Hospital. In comparison, 37 healthy children were recruited from a local primary school as controls matched by age and sex. We used NIRS to collect information on brain images. The Stroop test assessed inhibition function. We compared the differences in functional brain connectivity in two groups by analyzing the resting-state brain network. Pearson partial correlation analysis was applied to evaluate the correlation between functional brain connectivity and inhibition in all the children. Compared with the control group, results of NIRS images analysis showed that children with ADHD had significantly low functional brain connectivity in regions of the orbitofrontal cortex, left dorsolateral prefrontal cortex, left pre-motor and supplementary motor cortex, inferior prefrontal gyrus, and right middle temporal gyrus (p = 0.006). Inhibition function of children with ADHD was negatively correlated with functional brain connectivity (p = 0.009), while such correlation was not found in the control group. The present study demonstrated that children with ADHD had relatively low connectivity in several brain regions measured at the resting state. Our results supported the evidence that lack of functional brain connectivity was associated with impaired inhibition function in children with ADHD.

Systemic immune profile in Prader-Willi syndrome: elevated matrix metalloproteinase and myeloperoxidase and reduced macrophage inhibitory factor

BackgroundPrader-Willi syndrome (PWS) is a rare genetic neurodevelopmental syndrome with highly increased risk of obesity and cardiovascular disease (CVD). Recent evidence suggests that inflammation is implicated in the pathogenesis. Here we investigated CVD related immune markers to shed light on pathogenetic mechanisms.MethodsWe performed a cross-sectional study with 22 participants with PWS and 22 healthy controls (HC), and compared levels of 21 inflammatory markers that reflect activity in different aspects of CVD related immune pathways and analyzed their association with clinical CVD risk factors.ResultsSerum levels of matrix metalloproteinase 9 (MMP-9) was (median (range)) 121 (182) ng/ml in PWS versus 44 (51) ng/ml in HC, p = 1 × 10-9), myeloperoxidase (MPO) was 183 (696) ng/ml versus 65 (180) ng/ml, p = 1 × 10-5) and macrophage inhibitory factor (MIF) was 46 (150) ng/ml versus 121 (163) ng/ml (p = 1 × 10-3), after adjusting for age and sex. Also other markers tended to be elevated (OPG, sIL2RA, CHI3L1, VEGF) but not significantly after Bonferroni correction (p > 0.002). As expected PWS had higher body mass index, waist circumference, leptin, C-reactive protein, glycosylated hemoglobin (HbA1c), VAI and cholesterol, but MMP-9, MPO and MIF remained significantly different in PWS after adjustment for these clinical CVD risk factors.ConclusionPWS had elevated levels of MMP-9 and MPO and of reduced levels of MIF, which were not secondary to comorbid CVD risk factors. This immune profile suggests enhanced monocyte/neutrophil activation, impaired macrophage inhibition with enhanced extracellular matrix remodeling. These findings warrant further studies targeting these immune pathways in PWS.

Distinct effects of different neurofeedback protocols on the neural mechanisms of response inhibition in ADHD

ObjectiveIn attention deficit/hyperactivity disorder (ADHD), impaired response inhibition is frequently observed. A promising non-pharmacological treatment is electroencephalography (EEG)-neurofeedback (NF) training. However, the widely used theta-down/beta-up regulation (↓θ↑β) NF protocol may not be optimal for targeting these deficits. We examined how neurofeedback protocols training the upregulation of theta and/or beta power affect inhibitory control in children and adolescents with ADHD. Methods64 patients with ADHD took part in the three NF trainings. Aside from parent-reported ADHD symptoms and behavioural performance data, neurophysiological parameters collected via a Go/Nogo task and corrected to account for intraindividual variability were compared in a pre-post design and to an ADHD (n = 20) as well as a typically developing control group (n = 24). ResultsThe examined NF protocols resulted in similar improvements in response inhibition with the neurophysiological mechanisms differing substantially. The upregulation of theta led to a specific Nogo-P3 increase, while training beta upregulation as well as the combined protocol resulted in less specific effects. ConclusionsThis study shows distinct effects of different theta/beta-neurofeedback protocols on the neural mechanisms underlying improvements in response inhibition in patients with ADHD. SignificanceThese effects shed further light on the oscillatory dynamics underlying cognitive control in ADHD and how these may be targeted in neurofeedback treatments.

Shared genetic etiology between ADHD, task-related behavioral measures and brain activation during response inhibition in a youth ADHD case–control study

Impaired response inhibition is commonly present in individuals with attention-deficit/hyperactivity disorder (ADHD) and their unaffected relatives, suggesting impaired response inhibition as a candidate endophenotype in ADHD. Therefore, we explored whether behavioral and neural correlates of response inhibition are related to polygenic risk scores for ADHD (PRS-ADHD). We obtained functional magnetic resonance imaging of neural activity and behavioral measures during a stop-signal task in the NeuroIMAGE cohort, where inattention and hyperactivity-impulsivity symptoms were assessed with the Conners Parent Rating Scales. Our sample consisted of 178 ADHD cases, 103 unaffected siblings, and 173 controls (total N = 454; 8–29 years), for whom genome-wide genotyping was available. PRS-ADHD was constructed using the PRSice-2 software. We found PRS-ADHD to be associated with ADHD symptom severity, a slower and more variable response to Go-stimuli, and altered brain activation during response inhibition in several regions of the bilateral fronto-striatal network. Mean reaction time and intra-individual reaction time variability mediated the association of PRS-ADHD with ADHD symptoms (total, inattention, hyperactivity-impulsivity), and activity in the left temporal pole and anterior parahippocampal gyrus during failed inhibition mediated the relationship of PRS-ADHD with hyperactivity-impulsivity. Our findings indicate that PRS-ADHD are related to ADHD severity on a spectrum of clinical, sub-threshold, and normal levels; more importantly, we show a shared genetic etiology of ADHD and behavioral and neural correlates of response inhibition. Given the modest sample size of our study, future studies with higher power are warranted to explore mediation effects, suggesting that genetic liability to ADHD may adversely affect attention regulation on the behavioral level and point to a possible response inhibition-related mechanistic pathway from PRS-ADHD to hyperactivity-impulsivity.