Subcellular localization of PD-L1 and cell-cycle-dependent expression of nuclear PD-L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy.

The programmed cell death 1 ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) axis is primarily associated with immunosuppression in cytotoxic T lymphocytes (CTLs). However, mounting evidence is supporting the thesis that PD-L1 not only functions as a ligand but mediates additional cellular functions in tumor cells. Moreover, it has been demonstrated that PD-L1 is not exclusively localized at the cellular membrane. Subcellular fractionation revealed the presence of PD-L1 in various cellular compartments of six well-characterized head and neck cancer (HNC) cell lines, including the nucleus. Via Western blotting, we detected PD-L1 in its well-known glycosylated/deglycosylated state at 40-55 kDa. In addition, we detected previously unknown PD-L1 variants with a molecular weight at approximately 70 and > 150 kDa exclusively in nuclear protein fractions. These in vitro findings were confirmed with primary tumor samples from head and neck squamous cell carcinoma (HNSCC) patients. Furthermore, we demonstrated that nuclear PD-L1 variant expression is cell-cycle-dependent. Immunofluorescence staining of PD-L1 in different cell cycle phases of synchronized HNC cells supported these observations. Mechanisms of nuclear PD-L1 trafficking remain less understood; however, proximity ligation assays showed a cell-cycle-dependent interaction of the cytoskeletal protein vimentin with PD-L1, whereas vimentin could serve as a potential shuttle for nuclear PD-L1 transportation. Mass spectrometry after PD-L1 co-immunoprecipitation, followed by gene ontology analysis, indicated interaction of nuclear PD-L1 with proteins involved in DNA remodeling and messenger RNA (mRNA) splicing. Our results in HNC cells suggest a highly complex regulation of PD-L1 and multiple tumor cell-intrinsic functions, independent of immune regulation. These observations bear significant implications for the therapeutic efficacy of immune checkpoint inhibition.

Influence of the macrodesign of an implant and the sleeve system on the accuracy of template-guided implant placement: A prospective clinical study.

STATEMENT OF PROBLEM: Three-dimensional (3D) implant planning facilitates determining the optimal position and number of implants, in terms of function and esthetics, by taking into account adjacent structures. Template-guided implant placement is an established procedure for implementing this planning, although the accuracy between the planned and the actual implant position is subject to many influences. The influences of the macrodesign of the implants and the sleeve materials used have rarely been investigated clinically. PURPOSE: The purpose of this prospective clinical study was to investigate the accuracy of template-guided implant placement according to the macrodesign of different implants and the design of the drill sleeve. MATERIAL AND METHODS: Implants were placed in 60 participants within 3 groups (n=20): tapered implant with a metal sleeve (T-MS), tapered implant with a polymeric sleeve (T-PS), and progressive tapered implant with a polymeric sleeve (XT-PS). After overlaying the 3D implant planning image with the postoperative intraoral scan, deviations were 2-dimensionally related to the implant shoulder (S) and the apex (A) in terms of height (2DHS/2DHA), mesiodistal (2DSmd/2DAmd) and buccolingual (2DSbo/2DAbo), as well as 3-dimensionally on the implant shoulder (3DS), on the apex (3DA), and on the axis deviation (Axis). The groups were compared by using the analysis of variance. The Tukey post hoc test was performed for normally distributed data to identify significant differences among groups (α=.05). RESULTS: The errors for 2DSmd and 2DSbo were 0.26 to 0.40 mm across all groups. The 3DS group varied between 0.67 and 0.87 mm. No significant differences were found in terms of the material of the sleeves or the macrodesign of the implants (P>.05). Significant differences were found for 2DHS (P=.029) and 2DHA (P=.016) between the groups with the different sleeves. Group T-PS showed the least height deviation. CONCLUSIONS: In terms of height deviation, significant differences were found among the groups, with deviations depending on the implant type and the sleeve type. Overall, the method showed a high level of accuracy, providing good predictability of the prosthetic rehabilitation.

Changes in Secondary Healthcare Use Over Retirement Transition: Examining Social Differences With Swedish Register Data.

Background: Despite its relevance for healthcare expenditures and public health, few studies have examined how secondary healthcare use changes during the retirement transition. We therefore use Swedish register data to examine whether retirement is associated with intensified secondary healthcare use overall and for specific subgroups based on gender and education. Methods: The sample was all individuals registered in Sweden who retired from paid work in 2010. We used Generalised Estimating Equations models to analyse changes in two indicators of secondary healthcare use, namely specialist visits and hospitalisation, from 3 years prior to 5 years after retirement. Results: Retirement is not associated with changes in specialist visits or hospitalisation per se. Three years before retirement, women were more likely to visit a specialist but less likely to be hospitalised than men; these gender differences disappeared approximately 1 year before retirement. Women with high education were more likely to visit a specialist than women with low education across the entire retirement transition, particularly post-retirement. Significant differences with regard to specialist visits between male educational groups only emerged 12 months after retirement. There were no educational differences with regard to hospitalisation. Conclusions: We conclude that secondary healthcare use in Sweden does not generally change with retirement. However, over the course of retirement gender differences in secondary healthcare use tend to decrease and within-gender educational differences tend to increase. We interpret the results as reflecting the role of labour market institutions in contributing to gender differences but repressing educational differences in secondary healthcare use.

Development of healthcare use across contemporary retirement pathways: results from a register based cohort study.

AIM: We aimed to understand the interplay between retirement pathways and healthcare use in the postponed and structurally changing context of retirement. METHODS: Based on Swedish register data on income and healthcare use, we applied combined sequence and cluster analysis to identify typical pathways into retirement and analysed their relation to healthcare use developments. RESULTS: We detected five distinct pathways into retirement. Level of healthcare use was significantly higher for the pathway via disability pensions. We saw an overall increase in healthcare use across the retirement process that was related to age rather than to the different pathways. CONCLUSIONS: Level of healthcare use at the beginning of the retirement process may be related to selection into different pathways of retirement. We did not find clear evidence across several healthcare measures that different pathways lead to different developments in healthcare use.

Differential Expression of PD-L1 during Cell Cycle Progression of Head and Neck Squamous Cell Carcinoma.

The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.

Accuracy of Computer-Assisted Dynamic Navigation as a Function of Different Intraoral Reference Systems: An In Vitro Study.

The aim of this in vitro study was to determine whether the process chain influences the accuracy of a computer-assisted dynamic navigation procedure. Four different data integration workflows using cone-beam computed tomography (CBCT), conventional impressions, and intraoral digitization with and without reference markers were analyzed. Digital implant planning was conducted using data from the CBCT scans and 3D data of the oral models. The restoration of the free end of the lower jaw was simulated. Fifteen models were each implanted with two new teeth for each process chain. The models were then scanned with scan bodies screwed onto the implants. The deviations between the planned and achieved implant positions were determined. The evaluation of all 120 implants resulted in a mean angular deviation of 2.88 ± 2.03°. The mean 3D deviation at the implant shoulder was 1.53 ± 0.70 mm. No significant differences were found between the implant regions. In contrast, the workflow showed significant differences in various parameters. The position of the reference marker affected the accuracy of the implant position. The in vitro examination showed that precise implantation is possible with the dynamic navigation system used in this study. The results are of the same order of magnitude that can be achieved using static navigation methods. Clinical studies are yet to confirm the results of this study.

Accuracy of Computer-Assisted Dynamic Navigation in Implant Placement with a Fully Digital Approach: A Prospective Clinical Trial.

BACKGROUND: This prospective clinical study aimed to investigate a possible deviation between the digitally planned implant position and the position achieved using dynamic navigation. The aim of the study was to establish clinical effectiveness and precision of implantation using dynamic navigation. METHODS: Twenty consecutive patients received an implant (iSy-Implantat, Camlog, Wimsheim, Germany). One screw implant was placed in one jaw with remaining dentition of at least six teeth. The workflow was fully digital. Digital implant planning was conducted using cone-beam computed tomography (CBCT) and an intraoral scan of the actual condition. Twenty implants were subsequently placed using a dynamic computer-assisted procedure. The clinical situation of the implant position was recorded using an intraoral scan. Using these data, models were produced via 3D printing, and CBCTs of these models were made using laboratory analogs. Deviations of the achieved implant position from the planned position were determined using evaluation software. RESULTS: The evaluation of 20 implants resulted in a mean angle deviation of 2.7° (95% CI 2.2-3.3°). The 3D deviation at the implant shoulder was 1.83 mm (95% CI 1.34-2.33 mm). No significant differences were found for any of the parameters between the implantation in the upper or lower jaw and an open or flapless procedure (p-value < 0.05). CONCLUSION: The clinical trial showed that sufficiently precise implantation was possible with the dynamic navigation system used here. Dynamic navigation can improve the quality of implant positioning. In particular, the procedure allows safe positioning of the implants in minimally invasive procedures, which usually cannot be performed freehand in this form. A clinical benefit and effectiveness can be determined from the results.

Putting cumulative (dis)advantages in context: Comparing the role of educational inequality in later-life functional health trajectories in England and Germany.

BACKGROUND: The cumulative (dis)advantage (CAD) perspective more and more is examined in a comparative way, to highlight the role of context in generating inequality over the life course. This study adds to this field of research by examining trajectories of activities of daily living (ADL) in later life by educational level in a country comparison of England and Germany, emphasizing differing institutional conditions. METHOD: Data used are the English Longitudinal Study of Ageing (ELSA; 11,352 individuals) and the German subsample of the Survey of Health and Retirement in Europe (SHARE; 5,573 individuals). Using population averaged Poisson panel regression models, 12-year trajectories of six birth cohorts are investigated, covering the age range of 50 to 90 years. RESULTS: Respondents in England have a higher level of limitations at age 50, and more limited increases over age than in Germany. An educational gradient exists in both countries at age 50. Notably, the educational gradient increases for more recently born cohorts, but declines with increasing age in England, while in Germany educational differences increase for more recently born cohort only. DISCUSSION: The current study indicates that CAD processes between educational groups are context sensitive. While England showed convergence of disparities with increasing age, in Germany no differential development was found.

Level and change in economic, social, and personal resources for people retiring from paid work and other labour market statuses.

Well-being in retirement is thought to depend on person's level of resources and how his or her resources change during retirement. However, to date few studies have directly investigated resource trajectories during retirement. The current study therefore examines how economic, personal, and social-relational resources change during the retirement transition for people retiring from paid employment and for people retiring from other, non-working labour market statuses (e.g. disability pension, homemaker, unemployment). Based on four representative baseline samples of the German Ageing Survey (1996, 2002, 2008, and 2014) and their respective 6-year follow-up interviews, we identified N = 586 retirees. We then used dual change score models to separately estimate the level and change in income, health, activity, family and non-family network size, and social support for people retiring from paid work (n = 384) and people retiring from other statuses (n = 202) adjusted for age, gender, education, region, period, and time since retirement. Overall, we found that resources changed only modestly during the retirement transition. Resource changes did, however, differ by last labour market status and sociodemographic characteristics. Income and social support declined and family networks increased for both those retiring from paid work and those retiring from other statuses. Leisure activities increased only for those retiring from paid work. No changes in health or non-family networks were observed. People with many resources before retirement also had many resources after retirement. We conclude that retirement affects resources less than researchers often expect. Accordingly, differences based on labour market remain despite retirement.

Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation.

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.

Pathways to retirement: Are they related to patterns of short- and long-term subjective well-being?

We examine the association between pathways to retirement and patterns of subjective well-being in Germany. We argue that short-term development of subjective well-being is related to social status changes while long-term development of subjective well-being is related to resources and changes in life circumstances. Importantly, we expect that how a person's social status changes and his/her access to resources post-retirement both depend on the person's specific pathway to retirement, resulting in distinct patterns of subjective well-being post-retirement. Based on data from the German Socio-Economic Panel, we categorized people as retiring from employment, short- or long-term unemployment, labour market inactivity or due to disability. We then used dual-change score models to compare trajectories of life satisfaction ten years before to ten years after the retirement transition. For people retiring from employment, life satisfaction did not change in the short term but developed more positively in the long term. In comparison, people retiring from unemployment or due to disability experienced a short-term increase in life satisfaction but had more negative long-term trajectories of life satisfaction. We found no retirement-related changes in life satisfaction for people retiring from inactivity. The findings suggest that different pathways to retirement are related to distinct patterns of subjective well-being and highlight the importance of late-life employment biographies for quality of life post-retirement.

Comparison of non-invasive assessment of liver fibrosis in patients with alpha1-antitrypsin deficiency using magnetic resonance elastography (MRE), acoustic radiation force impulse (ARFI) Quantification, and 2D-shear wave elastography (2D-SWE).

PURPOSE: Although it has been known for decades that patients with alpha1-antitrypsin deficiency (AATD) have an increased risk of cirrhosis and hepatocellular carcinoma, limited data exist on non-invasive imaging-based methods for assessing liver fibrosis such as magnetic resonance elastography (MRE) and acoustic radiation force impulse (ARFI) quantification, and no data exist on 2D-shear wave elastography (2D-SWE). Therefore, the purpose of this study is to evaluate and compare the applicability of different elastography methods for the assessment of AATD-related liver fibrosis. METHODS: Fifteen clinically asymptomatic AATD patients (11 homozygous PiZZ, 4 heterozygous PiMZ) and 16 matched healthy volunteers were examined using MRE and ARFI quantification. Additionally, patients were examined with 2D-SWE. RESULTS: A high correlation is evident for the shear wave speed (SWS) determined with different elastography methods in AATD patients: 2D-SWE/MRE, ARFI quantification/2D-SWE, and ARFI quantification/MRE (R = 0.8587, 0.7425, and 0.6914, respectively; P≤0.0089). Four AATD patients with pathologically increased SWS were consistently identified with all three methods-MRE, ARFI quantification, and 2D-SWE. CONCLUSION: The high correlation and consistent identification of patients with pathologically increased SWS using MRE, ARFI quantification, and 2D-SWE suggest that elastography has the potential to become a suitable imaging tool for the assessment of AATD-related liver fibrosis. These promising results provide motivation for further investigation of non-invasive assessment of AATD-related liver fibrosis using elastography.

Out of society? Retirement affects perceived social exclusion in Germany.

BACKGROUND: Perceived social exclusion (PSE) depends on individual access to resources (e.g. income and social networks) and recognition of a social status. Working provides individuals with both resources and a social status. This situation leaves the non-working population at a severe social disadvantage, which might partly be remedied by retirement. OBJECTIVE: We expected to find differential effects on PSE when individuals retire. For individuals working until retirement the transition might be mostly associated with a loss of resources (leading to an increase in PSE) and for individuals not working before retirement the transition might be more strongly associated with an increase in social status (leading to a decrease in PSE). MATERIAL AND METHODS: We used longitudinal data from the German Panel Study of Labor Market and Social Security (PASS) to estimate fixed effects panel regression models for 790 men and women experiencing the transition to retirement (4110 observations). Models were estimated separately for retired persons who worked or did not work prior to retirement. RESULTS: At retirement those working prior to the transition reported lower levels of PSE than those not working. As expected retirement increased PSE for those previously working and for those not previously working retirement decreased PSE in the short term. Both effects remained stable after compensating for resource changes due to retirement. CONCLUSION: Retirement reduced the differences in PSE between previously working and non-working groups. For those previously working retirement seemed to depict a loss of social acceptance whereas for those previously not working retirement seemed to indicate a reduction of stigmatization. The previous effect of the labor market, however, continued to affect individuals in retirement for a long time.

[Pursuing the triple aim: evaluation of the integrated care system Gesundes Kinzigtal: population health, patient experience and cost-effectiveness]. / Triple Aim - Evaluation in der Integrierten Versorgung Gesundes Kinzigtal - Gesundheitszustand, Versorgungserleben und Wirtschaftlichkeit.

BACKGROUND: The integrated care system Gesundes Kinzigtal (ICSGK), one of the most comprehensive population-based ICS in Germany, started its work nearly 9 years ago. The ICSGK is pursuing the Triple Aim: improving the health of the population, improving the individual's experience of care, and at the same time reducing the per capita costs of care. OBJECTIVES: To evaluate the impact of the ICSGK on the Triple Aim. MATERIALS AND METHODS: The ICSGK is being evaluated externally and internally via a mix of diverse quantitative and qualitative methods. This paper presents selected results for each Triple Aim dimension. RESULTS AND CONCLUSIONS: Regarding population health, most of the quality indicators examined by the external scientific evaluation show positive development. For example, the prevalence of patients with fractures among all insurants with osteoporosis is presented. In 2011, this prevalence was approximately 26 % in the "Kinzigtal" population (aged ≥ 20 years old) in comparison to 33 % in the control group. As far as patient experience is concerned, to the question "Would you recommend becoming a member of Gesundes Kinzigtal to your friends or relatives?" 92.1 % of those questioned answered "Yes, for sure" or "Yes, probably." Twenty-four percent of those questioned further stated that they would now live "more healthy" than before enrolment in the ICSGK. In the subgroup of questioned insurants who had objective agreements with their doctors 45.4 % answered in this way. On the subject of cost-effectiveness, for both participating socil health insurance schemes, cost savings relative to the costs normally expected for the ICSGK population concerned are observed every year. In the seventh intervention year (2012) the total is 4.56 million Euros for the AOK Baden-Württemberg (BW), which is a contribution margin of 146 Euros per insurant for the 31.156 insurants concerned (LKK BW = 322 Euros per insurant relative to cost savings). The results presented in this paper indicate positive effects in all three Triple Aim dimensions. Further longitudinal studies are recommended to validate those first results together with a detailed analysis to obtain in-depth insights into the specific influence of subcomponents of the total intervention.

Pharmaco-MEG evidence for attention related hyper-connectivity between auditory and prefrontal cortices in ADHD.

The ability to attend to particular stimuli while ignoring others is crucial in goal-directed activities and has been linked with prefrontal cortical regions, including the dorsolateral prefrontal cortex (DLPFC). Both hyper- and hypo-activation in the DLPFC has been reported in patients with attention-deficit/hyperactivity disorder (ADHD) during many different cognitive tasks, but the network-level effects of such aberrant activity remain largely unknown. Using magnetoencephalography (MEG), we examined functional connectivity between regions of the DLPFC and the modality-specific auditory cortices during an auditory attention task in medicated and un-medicated adults with ADHD, and those without ADHD. Participants completed an attention task in two separate sessions (medicated/un-medicated), and each session consisted of two blocks (attend and no-attend). All MEG data were coregistered to structural MRI, corrected for head motion, and projected into source space. Subsequently, we computed the phase coherence (i.e., functional connectivity) between DLPFC regions and the auditory cortices. We found that un-medicated adults with ADHD exhibited greater phase coherence in the beta (14-30Hz) and gamma frequency (30-56Hz) range in attend and no-attend conditions compared to controls. Stimulant medication attenuated these differences, but did not fully eliminate them. These results suggest that aberrant bottom-up processing may engulf executive resources in ADHD.

Histone deacetylase inhibitors modulate interleukin 6-dependent CD4+ T cell polarization in vitro and in vivo.

Histone deacetylase (HDAC) inhibitors have been associated primarily with an anti-proliferative effect in vitro and in vivo. Recent data provide evidence for an anti-inflammatory potency of HDAC inhibitors in models of experimental colitis. Because the balance of T cell subpopulations is critical for the balance of the mucosal immune system, this study explores the regulatory potency of HDAC inhibitors on T cell polarization as a mechanistic explanation for the observed anti-inflammatory effects. Although HDAC inhibition suppressed the polarization toward the pro-inflammatory T helper 17 (Th17) cells, it enhanced forkhead box P3 (FoxP3)(+) regulatory T cell polarization in vitro and in vivo at the site of inflammation in the lamina propria. This was paralleled by a down-regulation of the interleukin 6 receptor (IL-6R) on naïve CD4(+) T cells on the mRNA as well as on the protein level and changes in the chromatin acetylation at the IL6R gene and its promoter. Downstream of the IL-6R, HDAC inhibition was followed by a decrease in STAT3 phosphorylation as well as retinoic acid receptor-related orphan receptor γT (RORγT) expression, thus identifying the IL-6/STAT3/IL-17 pathway as an important target of HDAC inhibitors. These results directly translated to experimental colitis, where IL-6R expression was suppressed in naïve T cells, paralleled by a significant reduction of Th17 cells in the lamina propria of ITF2357-treated animals, resulting in the amelioration of disease. This study indicates that, in experimental colitis, inhibition of HDAC exerts an anti-inflammatory potency by directing T helper cell polarization via targeting the IL-6 pathway.

Estimating the passage of minutes: deviant oscillatory frontal activity in medicated and unmedicated ADHD.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common and extensively treated psychiatric disorder in children, which often persists into adulthood. The core diagnostic symptoms include inappropriate levels of hyperactivity, impulsivity, and/or pervasive inattention. Another crucial aspect of the disorder involves aberrations in temporal perception, which have been well documented in behavioral studies and, recently, have been the focus of neuroimaging studies. These functional magnetic resonance imaging studies have shown reduced activation in anterior cingulate and prefrontal cortices in ADHD using a time-interval discrimination task, whereby participants distinguish intervals differing by only hundreds of milliseconds. METHOD: We used magnetoencephalography (MEG) to evaluate the cortical network serving temporal perception during a continuous, long-duration (in minutes) time estimation experiment. Briefly, medicated and unmedicated persons with ADHD, and a control group responded each time they estimated 60 s had elapsed for an undisclosed amount of time in two separate MEG sessions. All MEG data were transformed into regional source activity, and subjected to spectral analyses to derive amplitude estimates of gamma-band activity. RESULTS: Compared to controls, unmedicated patients were less accurate time estimators and had weaker gamma activity in the anterior cingulate, supplementary motor area, and left prefrontal cortex. After medication, these patients exhibited small but significant increases in gamma across these same neural regions and significant improvements in time estimation accuracy, which correlated with the gamma activity increases. CONCLUSION: We found deficient gamma activity in brain areas known to be crucial for timing functions, which may underlie the day-to-day abnormalities in time perception that are common in ADHD.

Atypical coupling between posterior regions of the default mode network in attention-deficit/hyperactivity disorder: a pharmaco-magnetoencephalography study.

BACKGROUND: Dysfunction in the default mode network (DMN), a group of cortical areas more active during the resting state, has been linked to attentional deficits and symptoms associated with attention-deficit/hyperactivity disorder (ADHD). Prior imaging studies have shown decreased functional connectivity between DMN nodes in patients with ADHD, primarily between anterior and posterior regions. Using magnetoencephalography (MEG), we evaluated phase coherence (i.e., functional connectivity) among regions of the DMN in healthy controls and adults with ADHD before and after stimulant therapy. METHODS: We obtained a resting-state MEG recording for all participants. Magnetoencephalography data were transformed into a ~30 node regional source model using inverse spatial filtering, including regions corresponding to the DMN. We computed the zero-lag phase coherence between these regions pairwise for 5 distinct frequency bands, and we assessed group and medication effects. RESULTS: Twelve adults with and 13 without ADHD participated in our study. Functional connectivity was stronger between particular node pairs and showed frequency-specific effects. Unmedicated patients showed reduced phase locking between posterior cingulate/precuneus regions (PCC) and right inferior parietal cortices (RIPL), and between medial prefrontal regions (MPFC) and the left inferior parietal region (LIPL) and the PCC. Unmedicated patients had increased phase locking between the RIPL and LIPL regions compared with controls. Administration of stimulants improved phase locking abnormalities along the MPFC-PCC and LIPL-RIPL pathways in patients with ADHD. LIMITATIONS: Modest sample size and lack of duration of patient treatment history may limit the generalizability of our findings. CONCLUSION: Adults with ADHD exhibit hyper- and hypoconnectivity between regions of the DMN during rest, which were suppressed after stimulant medication administration.

Broadband neurophysiological abnormalities in the medial prefrontal region of the default-mode network in adults with ADHD.

Previous investigations of the default-mode network (DMN) in persons with attention-deficit/hyperactivity disorder (ADHD) have shown reduced functional connectivity between the anterior and posterior aspects. This finding was originally demonstrated in adults with ADHD, then in youth with ADHD, and has been tentatively linked to ultra low frequency oscillations within the DMN. The current study evaluates the specificity of DMN abnormalities to neuronal oscillations in the ultra low frequency range, and examines the regional specificity of these DMN aberrations in medicated and unmedicated adults with, and those without ADHD. An individually matched sample of adults with and without ADHD completed 6-minute sessions of resting-state magnetoencephalography (MEG). Participants with ADHD were known responders to stimulant medications and completed two sessions (predrug/postdrug). MEG data were coregistered to the participant's MRI, corrected for head motion, fitted to a regional-level source model, and subjected to spectral analyses to extract neuronal population activity in regions of the DMN. The unmedicated adults with ADHD exhibited broadband deficits in medial prefrontal cortices (MPFC), but not other DMN regions compared to adults without ADHD. Unmedicated patients also showed abnormal cross-frequency coupling in the gamma range between the MPFC and posterior cingulate areas, and disturbed balance within the DMN as activity in posterior regions was stronger than frontal regions at beta and lower frequencies, which dissipated at higher γ-frequencies. Administration of pharmacotherapy significantly increased prefrontal alpha activity (8-14 Hz) in adults with ADHD, and decreased the cross-frequency gamma coupling. These results indicate that neurophysiological aberrations in the DMN of patients with ADHD are not limited to ultra slow oscillations, and that they may be primarily attributable to abnormal broadband activity in the MPFC.

Gamma-frequency neuronal activity is diminished in adults with attention-deficit/hyperactivity disorder: a pharmaco-MEG study.

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder affecting approximately 4-7% of children and persisting in 2-5% of adults. The core symptoms include pervasive inattention and inappropriate levels of hyperactivity-impulsivity. High-frequency gamma activity has been implicated in the temporal binding of stimulus properties across cortical areas, and is known to be crucial for complex information processing and attentional processes in particular. Thus, we evaluated the amplitude of gamma-frequency neural responses in adults with and those without ADHD, and tested whether stimulant medications, the most common treatment for ADHD, modulate gamma activity in affected adults. Participants underwent two sessions (~75 min apart) of auditory stimulation using stimuli known to elicit 40 Hz gamma-band responses as magnetoencephalography data were acquired. Between sessions, the ADHD group (who were in maintenance therapy) were administered their daily stimulant medication and both groups were told to relax. The primary results indicated that gamma activity was weaker in the ADHD group during session one (pre-drug), but not session two (post-drug), and that gamma activity significantly increased following stimulant administration in adults with ADHD. These results suggest that ADHD is associated with reduced cortical gamma activity and that stimulants may ameliorate this abnormality.