Cognitive Flexibility: A Default Mode Perspective

The intra/extradimensional set-shifting task (IED) provides a reliable assessment of cognitive flexibility, the shifting of attention to select behaviorally relevant stimuli in a given context. Impairments in this domain were previously reported in patients with altered neurotransmitter systems such as schizophrenia and Parkinson's disease. Consequently, corticostriatal connections were implicated in the mediation of this function. In addition, parts of the default mode network (DMN), namely the medial prefrontal and posterior cingulate/precuneus cortices, are also being progressively described in association with set-shifting paradigms. Nevertheless, a definitive link between cognitive flexibility and DMN connectivity remains to be established. To this end, we related resting state functional magnetic resonance imaging (fMRI)-based functional connectivity of DMN with IED task performance in a healthy population, measured outside the scanner. The results demonstrated that greater posterior cingulate cortex/precuneus (DMN) connectivity with the ventromedial striatopallidum at rest correlated with fewer total adjusted errors on the IED task. This finding points to a relationship between DMN and basal ganglia connectivity for cognitive flexibility, further highlighting this network's potential role in adaptive human cognition.The Evelyn Trust (RUAG/018) supported this research. Additionally, DV received funding from the Yousef Jameel Academic Program; DKM is funded by the NIHR Cambridge Biomedical Centre (RCZB/004), and an NIHR Senior Investigator Award (RCZB/014), and EAS is supported by the Stephen Erskine Fellowship Queens’ College, Cambridge. We would also like to thank Dr. Guy Williams and Victoria Lupson and the rest of the staff in the Wolfson Brain Imaging Centre (WBIC) at Addenbrooke’s Hospital for their assistance in scanning. Finally, we thank all the participants for their contribution to this studyThis is the author accepted manuscript. The final version is available from Mary Ann Liebert via http://dx.doi.org/10.1089/brain.2015.038

Default Mode Dynamics for Global Functional Integration.

UNLABELLED: The default mode network (DMN) has been traditionally assumed to hinder behavioral performance in externally focused, goal-directed paradigms and to provide no active contribution to human cognition. However, recent evidence suggests greater DMN activity in an array of tasks, especially those that involve self-referential and memory-based processing. Although data that robustly demonstrate a comprehensive functional role for DMN remains relatively scarce, the global workspace framework, which implicates the DMN in global information integration for conscious processing, can potentially provide an explanation for the broad range of higher-order paradigms that report DMN involvement. We used graph theoretical measures to assess the contribution of the DMN to global functional connectivity dynamics in 22 healthy volunteers during an fMRI-based n-back working-memory paradigm with parametric increases in difficulty. Our predominant finding is that brain modularity decreases with greater task demands, thus adapting a more global workspace configuration, in direct relation to increases in reaction times to correct responses. Flexible default mode regions dynamically switch community memberships and display significant changes in their nodal participation coefficient and strength, which may reflect the observed whole-brain changes in functional connectivity architecture. These findings have important implications for our understanding of healthy brain function, as they suggest a central role for the DMN in higher cognitive processing. SIGNIFICANCE STATEMENT: The default mode network (DMN) has been shown to increase its activity during the absence of external stimulation, and hence was historically assumed to disengage during goal-directed tasks. Recent evidence, however, implicates the DMN in self-referential and memory-based processing. We provide robust evidence for this network's active contribution to working memory by revealing dynamic reconfiguration in its interactions with other networks and offer an explanation within the global workspace theoretical framework. These promising findings may help redefine our understanding of the exact DMN role in human cognition.This research was supported by the Evelyn Trust (RUAG/018). In addition, DV received funding from the Yousef Jameel Academic Program; DKM is supported by the NIHR Cambridge Biomedical Centre (RCZB/004), and an NIHR Senior Investigator Award (RCZB/014), and EAS is funded by the Stephen Erskine Fellowship Queens’ College Cambridge.This is the author accepted manuscript. The final version is available from Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.2135-15.201

Spectral Diversity in Default Mode Network Connectivity Reflects Behavioral State.

Default mode network (DMN) functional connectivity is thought to occur primarily in low frequencies (<0.1 Hz), resulting in most studies removing high frequencies during data preprocessing. In contrast, subtractive task analyses include high frequencies, as these are thought to be task relevant. An emerging line of research explores resting fMRI data at higher-frequency bands, examining the possibility that functional connectivity is a multiband phenomenon. Furthermore, recent studies suggest DMN involvement in cognitive processing; however, without a systematic investigation of DMN connectivity during tasks, its functional contribution to cognition cannot be fully understood. We bridged these concurrent lines of research by examining the contribution of high frequencies in the relationship between DMN and dorsal attention network at rest and during task execution. Our findings revealed that the inclusion of high frequencies alters between network connectivity, resulting in reduced anticorrelation and increased positive connectivity between DMN and dorsal attention network. Critically, increased positive connectivity was observed only during tasks, suggesting an important role for high-frequency fluctuations in functional integration. Moreover, within-DMN connectivity during task execution correlated with RT only when high frequencies were included. These results show that DMN does not simply deactivate during task execution and suggest active recruitment while performing cognitively demanding paradigms

Methylphenidate-mediated motor control network enhancement in patients with traumatic brain injury.

PRIMARY OBJECTIVE: To investigate functional improvement late (>6 months) after traumatic brain injury (TBI). To this end, we conducted a double-blind, placebo-controlled experimental medicine study to test the hypothesis that a widely used cognitive enhancer would benefit patients with TBI. RESEARCH DESIGN: We focused on motor control function using a sequential finger opposition fMRI paradigm in both patients and age-matched controls. METHODS AND PROCEDURES: Patients' fMRI and DTI scans were obtained after randomised administration of methylphenidate or placebo. Controls were scanned without intervention. To assess differences in motor speed, we compared reaction times from the baseline condition of a sustained attention task. MAIN OUTCOMES AND RESULTS: Patients' reaction times correlated with wide-spread motor-related white matter abnormalities. Administration of methylphenidate resulted in faster reaction times in patients, which were not significantly different from those achieved by controls. This was also reflected in the fMRI findings in that patients on methylphenidate activated the left inferior frontal gyrus significantly more than when on placebo. Furthermore, stronger functional connections between pre-/post-central cortices and cerebellum were noted for patients on methylphenidate. CONCLUSIONS: Our findings suggest that residual functionality in patients with TBI may be enhanced by a single dose of methylphenidate.The study was funded by the Evelyn Trust- grant number 06/20. C.D. was funded by the Clinical Academic Research Awards organized by the East of England Multi Professional Deanery. B.J.S. consults for Cambridge Cognition, Otsuka, Servier and Lundbeck. She holds a grant from Janssen/J&J and has share options in Cambridge Cognition. D.K.M. is supported by the Neuroscience Theme of the NIHR Cambridge Biomedical Research Centre and NIHR Senior Investigator awards, and by Framework Program 7 funding from the European Commission (TBIcare). He has received lecture and consultancy fees and support for research from Glaxo SmithKline, Solvay and Linde. E.A.S. is funded by the Stephen Erskine Fellowship, Queens' College, Cambridge, UK

Dynamic Changes in White Matter Abnormalities Correlate With Late Improvement and Deterioration Following TBI: A Diffusion Tensor Imaging Study.

OBJECTIVE: Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient trajectories over the entire disease narrative, from ictus to late outcome. METHODS: Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior. RESULTS: Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior. CONCLUSIONS: These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point

Mild traumatic brain injury recovery: a growth curve modelling analysis over 2 years

Background An improved understanding of the trajectory of recovery after mild traumatic brain injury is important to be able to understand individual patient outcomes, for longitudinal patient care and to aid the design of clinical trials. Objective To explore changes in health, well-being and cognition over the 2 years following mTBI using latent growth curve (LGC) modelling. Methods Sixty-one adults with mTBI presenting to a UK Major Trauma Centre completed comprehensive longitudinal assessment at up to five time points after injury: 2 weeks, 3 months, 6 months, 1 year and 2 years. Results Persisting problems were seen with neurological symptoms, cognitive issues and poor quality of life measures including 28% reporting incomplete recovery on the Glasgow Outcome Score Extended at 2 years. Harmful drinking, depression, psychological distress, disability, episodic memory and working memory did not improve significantly over the 2 years following injury. For other measures, including the Rivermead Post-Concussion Symptoms and Quality of Life after Brain Injury (QOLIBRI), LGC analysis revealed significant improvement over time with recovery tending to plateau at 3–6 months. Interpretation Significant impairment may persist as late as 2 years after mTBI despite some recovery over time. Longitudinal analyses which make use of all available data indicate that recovery from mTBI occurs over a longer timescale than is commonly believed. These findings point to the need for long-term management of mTBI targeting individuals with persisting impairment

Mild traumatic brain injury recovery: a growth curve modelling analysis over 2 years

Background: An improved understanding of the trajectory of recovery after mild traumatic brain injury is important to be able to understand individual patient outcomes, for longitudinal patient care and to aid the design of clinical trials. Objective: To explore changes in health, well-being and cognition over the 2 years following mTBI using latent growth curve (LGC) modelling. Methods Sixty-one adults with mTBI presenting to a UK Major Trauma Centre completed comprehensive longitudinal assessment at up to five time points after injury: 2 weeks, 3 months, 6 months, 1 year and 2 years. Results: Persisting problems were seen with neurological symptoms, cognitive issues and poor quality of life measures including 28% reporting incomplete recovery on the Glasgow Outcome Score Extended at 2 years. Harmful drinking, depression, psychological distress, disability, episodic memory and working memory did not improve significantly over the 2 years following injury. For other measures, including the Rivermead Post-Concussion Symptoms and Quality of Life after Brain Injury (QOLIBRI), LGC analysis revealed significant improvement over time with recovery tending to plateau at 3-6 months. Interpretation Significant impairment may persist as late as 2 years after mTBI despite some recovery over time. Longitudinal analyses which make use of all available data indicate that recovery from mTBI occurs over a longer timescale than is commonly believed. These findings point to the need for long-term management of mTBI targeting individuals with persisting impairment.</div