Reorganisation of brain networks in frontotemporal dementia and progressive supranuclear palsy.

The disruption of large-scale brain networks is increasingly recognised as a consequence of neurodegenerative dementias. We assessed adults with behavioural variant frontotemporal dementia and progressive supranuclear palsy using magnetoencephalography during an auditory oddball paradigm. Network connectivity among bilateral temporal, frontal and parietal sources was examined using dynamic causal modelling. We found evidence for a systematic change in effective connectivity in both diseases. Compared with healthy subjects, who had focal modulation of intrahemispheric frontal-temporal connections, the patient groups showed abnormally extensive and inefficient networks. The changes in connectivity were accompanied by impaired responses of the auditory cortex to unexpected deviant tones (MMNm), despite normal responses to standard stimuli. Together, these results suggest that neurodegeneration in two distinct clinical syndromes with overlapping profiles of prefrontal atrophy, causes a similar pattern of reorganisation of large-scale networks. We discuss this network reorganisation in the context of other focal brain disorders and the specific vulnerability of functional brain networks to neurodegenerative disease

Perseveration and choice in Parkinson's disease: the impact of progressive frontostriatal dysfunction on action decisions.

We have previously shown that patients with Parkinson's disease (PD) perseverate in their choice of action relative to healthy controls, and that this is affected by dopaminergic medication (Hughes LE, Barker RA, Owen AM, Rowe JB. 2010. Parkinson's disease and healthy aging: Independent and interacting effects on action selection. Hum Brain Mapp. 31:1886-1899). To understand further the neural basis of these phenomena, we used a new task that manipulated the options to repeat responses. Seventeen patients with idiopathic PD were studied both "on" and "off" dopaminergic medication and 18 healthy adults were scanned twice as controls. All subjects performed a right-handed 3-choice button press task, which controlled the availability of repeatable responses. The frequency of choosing to repeat a response (a form of perseveration) in patients was related to dopamine therapy and disease severity as a "U-shaped" function. For repetitive trials, this "U-shaped" relationship was also reflected in the BOLD response in the caudate nuclei and ventrolateral prefrontal cortex. Our results support a U-shaped model of optimized cortico-striatal circuit function and clearly demonstrate that flexibility in response choice is modulated by an interaction of dopamine and disease severity

Adaptation of the DEMQOL-Proxy for routine use in care homes: a cross sectional study of the reliability and validity of DEMQOL-CH

Objective: To investigate the routine use of a measure of quality of life (QoL) in care homes and assess its psychometric properties when used by care staff Design: A cross-sectional two-phase study. Setting and participants: Data were collected from care staff in seven care homes in East Sussex, England. Method: Phase 1: The ability of care staff from two care homes to use the DEMQOL-Proxy without interviewer-administration was assessed using agreement analysis between a selfand interviewer-administered version of the instrument. Based on these findings, DEMQOLProxy was adapted into a new version, DEMQOL-CH, for use as a self-administered instrument in care homes. We assessed agreement between the new DEMQOL-CH and DEMQOL-Proxy to ensure DEMQOL-CH was used correctly. Phase 2: A preliminary assessment of the psychometric properties of DEMQOL-CH when used routinely was completed in a further five care homes. Results: Phase 1: Nineteen care staff from two care homes completed QoL measurements for residents. Systematic error was identified when staff self-completed the DEMQOL-Proxy without an interviewer. We modified the DEMQOL-Proxy to create DEMQOL-CH; this reduced the error, producing a version that could be used more accurately by care staff. Phase 2: Eleven care staff from five care homes rated resident QoL routinely. DEMQOL-CH showed acceptable psychometric properties with satisfactory reliability and validity and a clear factor structure. Conclusions: The research presents positive preliminary data on the acceptability, feasibility and performance of routine QoL measurement in care homes using an adapted version of DEMQOL-Proxy, the DEMQOL-CH. Results provide evidence to support the concept that routine measurement of QoL may be possible in care homes. Research is needed to refine and test the methodology and instrument further, and to explore the potential for benefits to residents, staff, and care homes in larger and more representative populations

Psychometric properties and feasibility of use of dementia specific quality of life instruments for use in care settings: a systematic review

Background: Over 400,000 people live in care home settings in the UK. One way of understanding and improving the quality of care provided is by measuring and understanding the quality of life (QoL) of those living in care homes. This review aimed to identify and examine the psychometric properties including feasibility of use of dementia-specific QoL measures developed or validated for use in care settings. Design: Systematic review. Methods: Instruments were identified using four electronic databases (PubMed, PsycINFO, Web of Science, and CINAHL) and lateral search techniques. Searches were conducted in January 2017. Studies which reported on the development and/or validation of dementia specific QoL instruments for use in care settings written in English were eligible for inclusion. The methodological quality of the studies was assessed using the COSMIN checklist. Feasibility was assessed using a checklist developed specifically for the review. Results: Six hundred and sixteen articles were identified in the initial search. After de-duplication, screening and further lateral searches were performed, 25 studies reporting on 9 dementia-specific QoL instruments for use in care home settings were included in the review. Limited evidence was available on the psychometric properties of many instruments identified. Higher-quality instruments were not easily accessible or had low feasibility of use. Conclusions: Few high-quality instruments of QoL validated for use in care home settings are readily or freely available. This review highlights the need to develop a well-validated measure of QoL for use within care homes that is also feasible and accessible

The prefrontal cortex achieves inhibitory control by facilitating subcortical motor pathway connectivity

Communication between the prefrontal cortex and subcortical nuclei underpins the control and inhibition of behavior. However, the interactions in such pathways remain controversial. Using a stop-signal response inhibition task and functional imaging with analysis of effective connectivity, we show that the lateral prefrontal cortex influences the strength of communication between regions in the frontostriatal motor system. We compared 20 generative models that represented alternative interactions between the inferior frontal gyrus, presupplementary motor area (preSMA), subthalamic nucleus (STN), and primary motor cortex during response inhibition. Bayesian model selection revealed that during successful response inhibition, the inferior frontal gyrus modulates an excitatory influence of the preSMA on the STN, thereby amplifying the downstream polysynaptic inhibition from the STN to the motor cortex. Critically, the strength of the interaction between preSMA and STN, and the degree of modulation by the inferior frontal gyrus, predicted individual differences in participants’ stopping performance (stop-signal reaction time). We then used diffusion-weighted imaging with tractography to assess white matter structure in the pathways connecting these three regions. The mean diffusivity in tracts between preSMA and the STN, and between the inferior frontal gyrus and STN, also predicted individual differences in stopping efficiency. Finally, we found that white matter structure in the tract between preSMA and STN correlated with effective connectivity of the same pathway, providing important cross-modal validation of the effective connectivity measures. Together, the results demonstrate the network dynamics and modulatory role of the prefrontal cortex that underpin individual differences in inhibitory control

A network analysis of potential antecedents and consequences of pain-related activity avoidance and activity engagement in adolescents

Objective This study sets out to identify potential daily antecedents and consequences of pain-related activity avoidance and engagement behavior in adolescents with chronic pain. Methods Adolescents (N = 65, Mage = 14.41) completed baseline self-reports and a diary for 14 days. Afternoon and evening reports were used to infer a network structure of within-day associations between pain intensity, pain-related fear, pain catastrophizing, affect, and pain-related activity avoidance and engagement behavior. Baseline psychological flexibility was examined as a potential resilience factor. Results Activity avoidance in the evening was predicted by pain-related fear and avoidance earlier that afternoon. Activity engagement was predicted by positive affect and activity engagement in the afternoon. Pain-related behavior in the afternoon was not related to subsequent changes in pain intensity, pain-related fear, pain catastrophizing, or affect. Pain-related fear in the afternoon was predictive of increased levels of pain and pain catastrophizing in the evening. Both pain-related fear and pain catastrophizing in the evening were predicted by negative affect in the afternoon. Psychological flexibility was associated with lower levels of daily activity avoidance and buffered the negative association between pain intensity and subsequent activity engagement. Conclusions This study provides insight into unique factors that trigger and maintain activity avoidance and engagement and into the role of psychological flexibility in pediatric pain. Future work should focus on both risk and resilience factors and examine the role of psychological flexibility in chronic pediatric pain in greater detail

Investigating how parental instructions and protective responses mediate the relationship between parental psychological flexibility and pain-related behavior in adolescents with chronic pain : a daily diary study

Background: Parental behavior can influence how well adolescents cope with chronic pain. Previous research has largely focused on how parents negatively impact adolescent functioning. Yet more recent work suggests that parents - and particularly parental psychological flexibility - can foster better adolescent pain-related functioning. In this study we examined if parental protective responses and instructions to engage in activities in the presence of pain mediate the impact of parental psychological flexibility and acceptance of adolescent pain on adolescents' daily pain-related behavior. Method: Fifty-six adolescents with chronic pain (Mage = 14.5 years, 86% girls) and one of their parents (93% mothers) were recruited at initial evaluation at two pediatric pain clinics in the US. Parents completed baseline questionnaires assessing psychologically flexible parenting and acceptance of adolescent pain. Next, parents and adolescents completed a 14-day self-report diary assessing adolescent activity-avoidance and activity-engagement in the presence of pain (adolescent report), and parental protective responses and instructions for their adolescent to engage in activities (parent report). Results: Psychologically flexible parenting and acceptance of adolescent pain in parents were indirectly related to lower daily adolescent activity-avoidance, via their negative association with daily parental protective responses. Positive associations also emerged between baseline psychologically flexible parenting and overall levels of adolescent activity-engagement via its negative association with overall levels of parental protectiveness across the 14-day period. Psychologically flexible parenting and parental acceptance of adolescent pain were also indirectly related to daily decreases in adolescent activity-avoidance via their association with daily increases in parental activity-engagement instructions. These baseline parental resilience factors were also positively related to overall levels of parental engagement instructions, a route via which an indirect association with both higher overall activity-engagement as well as higher overall activity-avoidance in the adolescent was observed. Conclusion: Our findings suggest an (indirect) adaptive role of parental psychological flexibility on adolescent daily pain-related behavior via its impact on parental protective behavior. If our findings replicate, they would suggest that these parental behaviors could be targeted in pain treatments that include both adolescents and their parents. Future research could further examine the impact of parental instructions on pain-related behavior in adolescents with chronic pain

Transcriptional profiling reveals extraordinary diversity among skeletal muscle tissues

Skeletal muscle comprises a family of diverse tissues with highly specialized functions. Many acquired diseases, including HIV and COPD, affect specific muscles while sparing others. Even monogenic muscular dystrophies selectively affect certain muscle groups. These observations suggest that factors intrinsic to muscle tissues influence their resistance to disease. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use RNAseq to profile mRNA expression in skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. We detect mRNA expression of hundreds of putative myokines that may underlie the endocrine functions of skeletal muscle. We identify candidate genes that may drive tissue specialization, including Smarca4, Vegfa, and Myostatin. By demonstrating the intrinsic diversity of skeletal muscles, these data provide a resource for studying the mechanisms of tissue specialization

The impact of neurodegeneration on network connectivity: a study of change detection in frontotemporal dementia.

The neural response to unpredictable auditory events is suggested to depend on frontotemporal interactions. We used magnetoencephalography in patients with behavioral variant frontotemporal dementia to study change detection and to examine the impact of disease on macroscopic network connectivity underlying this core cognitive function. In patients, the amplitudes of auditory cortical responses to predictable standard tones were normal but were reduced for unpredictable deviant tones. Network connectivity, in terms of coherence among frontal, temporal, and parietal sources, was also abnormal in patients. In the beta frequency range, left frontotemporal coherence was reduced. In the gamma frequency range, frontal interhemispheric coherence was reduced whereas parietal interhemispheric coherence was enhanced. These results suggest impaired change detection resulting from dysfunctional frontotemporal interactions. They also provide evidence of a rostro-caudal reorganization of brain networks in disease. The sensitivity of magnetoencephalography to cortical network changes in behavioral variant frontotemporal dementia enriches the understanding of neurocognitive systems as well as showing potential for studies of experimental therapies for neurodegenerative disease.This work has been supported by the Wellcome Trust (088324), the Medical Research Council’s Cognition and Brain Sciences Unit (MC-A060-5PQ30), and the NIHR Cambridge Comprehensive Biomedical Research Centr

Hierarchical Organization of Frontotemporal Networks for the Prediction of Stimuli across Multiple Dimensions.

Brain function can be conceived as a hierarchy of generative models that optimizes predictions of sensory inputs and minimizes "surprise." Each level of the hierarchy makes predictions of neural events at a lower level in the hierarchy, which returns a prediction error when these expectations are violated. We tested the generalization of this hypothesis to multiple sequential deviations, and we identified the most likely organization of the network that accommodates deviations in temporal structure of stimuli. Magnetoencephalography of healthy human participants during an auditory paradigm identified prediction error responses in bilateral primary auditory cortex, superior temporal gyrus, and lateral prefrontal cortex for deviation by frequency, intensity, location, duration, and silent gap. We examined the connectivity between cortical sources using a set of 21 generative models that embedded alternate hypotheses of frontotemporal network dynamics. Bayesian model selection provided evidence for two new features of functional network organization. First, an expectancy signal provided input to the prefrontal cortex bilaterally, related to the temporal structure of stimuli. Second, there are functionally significant lateral connections between superior temporal and/or prefrontal cortex. The results support a predictive coding hypothesis but go beyond previous work in demonstrating the generalization to multiple concurrent stimulus dimensions and the evidence for a temporal expectancy input at the higher level of the frontotemporal hierarchy. We propose that this framework for studying the brain's response to unexpected events is not limited to simple sensory tasks but may also apply to the neurocognitive mechanisms of higher cognitive functions and their disorders.This work was supported by the Medical Research Council (Grant MC-A060-5PQ30 and a doctoral training award to H.N.P.), the Wellcome Trust (Grants 088324 and 103838 to J.B.R. and L.E.H., Biomedical Research Fellowship WT093811MA to T.A.B.), and the James F. McDonnell Foundation 21st Century Science Initiative: Understanding Human Cognition.This is the final version of the article. It first appeared from Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.5095-14.201