Post-traumatic Confusional State: A Case Definition and Diagnostic Criteria.

In response to the need to better define the natural history of emerging consciousness after traumatic brain injury and to better describe the characteristics of the condition commonly labeled posttraumatic amnesia, a case definition and diagnostic criteria for the posttraumatic confusional state (PTCS) were developed. This project was completed by the Confusion Workgroup of the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest group. The case definition was informed by an exhaustive literature review and expert opinion of workgroup members from multiple disciplines. The workgroup reviewed 2466 abstracts and extracted evidence from 44 articles. Consensus was reached through teleconferences, face-to-face meetings, and 3 rounds of modified Delphi voting. The case definition provides detailed description of PTCS (1) core neurobehavioral features, (2) associated neurobehavioral features, (3) functional implications, (4) exclusion criteria, (5) lower boundary, and (6) criteria for emergence. Core neurobehavioral features include disturbances of attention, orientation, and memory as well as excessive fluctuation. Associated neurobehavioral features include emotional and behavioral disturbances, sleep-wake cycle disturbance, delusions, perceptual disturbances, and confabulation. The lower boundary distinguishes PTCS from the minimally conscious state, while upper boundary is marked by significant improvement in the 4 core and 5 associated features. Key research goals are establishment of cutoffs on assessment instruments and determination of levels of behavioral function that distinguish persons in PTCS from those who have emerged to the period of continued recovery.

Therapeutic trial design for frontotemporal dementia and related disorders.

The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these conditions. To date, no pharmacological interventions have been proven effective in significantly modifying the course of these disorders. This study critically reviews the construct and methodology of previously published randomised controlled trials (RCTs) in FTD spectrum disorders in order to identify limitations and potential reasons for negative results. Moreover, recommendations based on the identified gaps are elaborated in order to guide future clinical trial design. A systematic literature review was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A total of 23 RCTs in cohorts with diagnoses of behavioural and language variants of FTD, corticobasal syndrome and progressive supranuclear palsy syndrome were identified out of the 943 citations retrieved and were included in the qualitative review. Most studies identified were early-phase clinical trials that were small in size, short in duration and frequently underpowered. Diagnoses of populations enrolled in clinical trials were based on clinical presentation and rarely included precision-medicine tools, such as genetic and molecular testing. Uniformity and standardisation of research outcomes in the FTD spectrum are essential. Several elements should be carefully considered and planned in future clinical trials. We anticipate that precision-medicine approaches will be crucial to adequately address heterogeneity in the FTD spectrum research.

Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts.

BACKGROUND: There are few data concerning the association between season and cognition and its neurobiological correlates in older persons-effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects. METHODS AND FINDINGS: We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07-0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07-0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years' difference in age (95% CI 2.1-8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10-1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aß 42 level (amplitude 0.30 SD [95% CI 0.10-0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21-0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27-0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24-0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20-0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere. CONCLUSIONS: Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.

Fifty Years of Prefrontal Cortex Research: Impact on Assessment.

Our knowledge of the functions of the prefrontal cortex, often called executive, supervisory, or control, has been transformed over the past 50 years. After operationally defining terms for clarification, we review the impact of advances in functional, structural, and theoretical levels of understanding upon neuropsychological assessment practice as a means of identifying 11 principles/challenges relating to assessment of executive function. Three of these were already known 50 years ago, and 8 have been confirmed or emerged since. Key themes over this period have been the emergence of the use of naturalistic tests to address issues of "ecological validity"; discovery of the complexity of the frontal lobe control system; invention of new tests for clinical use; development of key theoretical frameworks that address the issue of the role of prefrontal cortex systems in the organization of human cognition; the move toward considering brain systems rather than brain regions; the advent of functional neuroimaging, and its emerging integration into clinical practice. Despite these huge advances, however, practicing neuropsychologists are still desperately in need of new ways of measuring executive function. We discuss pathways by which this might happen, including decoupling the two levels of explanation (information processing; brain structure) and integrating very recent technological advances into the neuropsychologist's toolbox. (JINS, 2017, 23, 755-767).

Small vessel disease is linked to disrupted structural network covariance in Alzheimer's disease.

INTRODUCTION: Cerebral small vessel disease (SVD) is thought to contribute to Alzheimer's disease (AD) through abnormalities in white matter networks. Gray matter (GM) hub covariance networks share only partial overlap with white matter connectivity, and their relationship with SVD has not been examined in AD. METHODS: We developed a multivariate analytical pipeline to elucidate the cortical GM thickness systems that covary with major network hubs and assessed whether SVD and neurodegenerative pathologic markers were associated with attenuated covariance network integrity in mild AD and normal elderly control subjects. RESULTS: SVD burden was associated with reduced posterior cingulate corticocortical GM network integrity and subneocorticocortical hub network integrity in AD. DISCUSSION: These findings provide evidence that SVD is linked to the selective disruption of cortical hub GM networks in AD brains and point to the need to consider GM hub covariance networks when assessing network disruption in mixed disease.

Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations.

INTRODUCTION: Corticobasal syndrome (CBS) resulting from genetic Alzheimer's disease (AD) has been described only once. Whether familial CBS-AD is a distinct clinical entity with its own imaging signature remains unknown. METHODS: Four individuals with CBS from two families underwent detailed assessment. For two individuals, regional atrophy and hypoperfusion were compared to autopsy-confirmed typical late-onset AD and corticobasal degeneration, as well as genetically proven PSEN1 cases with an amnestic presentation. RESULTS: One family harbored a novel mutation in PSEN1:p.Phe283Leu. MRI demonstrated severe parietal, perirolandic, and temporal atrophy, with relative sparing of frontal and ipsilateral hippocampal regions. Autopsy confirmed pure AD pathology. The other family harbored a known PSEN1 mutation:p.Gly378Val. DISCUSSION: This report confirms familial CBS-AD as a distinct clinical entity, with a parietal-perirolandic-temporal atrophy signature. It illustrates the clinical heterogeneity that can occur despite a shared genetic cause and underscores the need for biomarkers such as amyloid imaging during life.

Trail Making Test Elucidates Neural Substrates of Specific Poststroke Executive Dysfunctions.

BACKGROUND AND PURPOSE: Poststroke cognitive impairment is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood, and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. METHODS: One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set shifting (TMT-B-A difference, proportion, quotient scores, and TMT-B set-shifting errors). The TMT was administered to 2 overt ischemic stroke cohorts from a multinational study: (1) a chronic stroke cohort (N=61) and (2) an acute-subacute stroke cohort (N=45). Volumetric quantification of ischemic stroke and white matter hyperintensities was done on magnetic resonance imaging, along with ratings of involvement of cholinergic projections, using the previously published cholinergic hyperintensities projections scale. Damage to the superior longitudinal fasciculus, which colocalizes with some cholinergic projections, was also documented. RESULTS: Multiple linear regression analyses were completed. Although larger infarcts (ß=0.37, P<0.0001) were associated with slower processing speed, cholinergic hyperintensities projections scale severity (ß=0.39, P<0.0001) was associated with all metrics of set shifting. Left superior longitudinal fasciculus damage, however, was only associated with the difference score (ß=0.17, P=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set-shifting errors also had greater cholinergic hyperintensities projections scale severity. CONCLUSIONS: In this multinational stroke cohort study, damage to lateral cholinergic pathways and the superior longitudinal fasciculus emerged as significant neuroanatomical correlates for executive deficits in set shifting.

The Ontario Brain Institute: completing the circle.

The Province of Ontario recognized the pressing need to improve the understanding, diagnosis, and treatment of brain disorders. It also recognized that maximizing the existing strengths through a province-wide integrated approach was a pivotal mechanism. To achieve this, the Province established the Ontario Brain Institute. The goal of this article is to introduce the elements of the Ontario Brain Institute to the neuroscience community: the motivation for establishing it, the philosophy behind its creation, the principles guiding its development, the rapid evolution of its functional structure, the tools available to achieve its vision, and the management structure to ensure success. The singular goal of the Province and the Ontario Brain Institute is a comprehensive system that assures that basic research is embedded in the clinical system and is facilitating product development to accelerate benefits to both health and the economy of health: science with impact.

Theory of mind and recognition of facial emotion in dementia: challenge to current concepts.

Current literature suggests that theory of mind (ToM) and recognition of facial emotion are impaired in behavioral variant frontotemporal dementia (bvFTD). In contrast, studies suggest that ToM is spared in Alzheimer disease (AD). However, there is controversy whether recognition of emotion in faces is impaired in AD. This study challenges the concepts that ToM is preserved in AD and that recognition of facial emotion is impaired in bvFTD. ToM, recognition of facial emotion, and identification of emotions associated with video vignettes were studied in bvFTD, AD, and normal controls. ToM was assessed using false-belief and visual perspective-taking tasks. Identification of facial emotion was tested using Ekman and Friesen's pictures of facial affect. After adjusting for relevant covariates, there were significant ToM deficits in bvFTD and AD compared with controls, whereas neither group was impaired in the identification of emotions associated with video vignettes. There was borderline impairment in recognizing angry faces in bvFTD. Patients with AD showed significant deficits on false belief and visual perspective taking, and bvFTD patients were impaired on second-order false belief. We report novel findings challenging the concepts that ToM is spared in AD and that recognition of facial emotion is impaired in bvFTD.

Object alternation: a novel probe of medial frontal function in frontotemporal dementia.

We studied behavioral variant frontotemporal dementia (bvFTD) using object alternation (OA) as a novel probe of cognition. This task was adopted from animal models and is sensitive to ventrolateral-orbitofrontal and medial frontal function in humans. OA was administered to bvFTD patients, normal controls, and a dementia control group with Alzheimer disease (AD). Two other frontal lobe measures adopted from animal models were administered: delayed response (DR) and delayed alternation (DA). Brain volumes were measured using the semiautomatic brain region extraction method. Compared with the normal controls, bvFTD patients were significantly impaired on OA and DR. For OA and DR, sensitivities and specificities were 100% and 51.5% (cutoff=22.5 errors) and 9.5% and 98% (cutoff=1.5 errors), respectively. Negative predictive value (NPV) for OA was 100% at all prevalence rates. Comparing AD with bvFTD, there were no significant differences on OA, DR, or DA. Nevertheless, positive predictive value (PPV) and NPV were good at all prevalence rates for OA (cutoff=36.5 errors) and DA (cutoff=6 errors); PPV was good for DR (cutoff=9 errors). Error scores above cutoffs favored diagnosis of AD. Performance on OA was significantly related to medial frontal gray matter atrophy. OA, together with DR and DA, may facilitate assessment of bvFTD as a novel probe of medial frontal function.

fMRI investigation of speed-accuracy strategy switching.

Switching between rapid and accurate responses is an important aspect of decision-making. However, the brain mechanisms important to smoothly change the speed-accuracy strategy remain mostly unclear. This issue was addressed here by using functional magnetic resonance imaging (fMRI). On each trial, right-handed healthy participants had to stress speed or accuracy in performing a color discrimination task on a target stimulus according to the instructions given by an initial cue. Participants were capable of trading speed for accuracy and vice versa. Analyses of cue-related fMRI activations revealed a significant recruitment of left middle frontal gyrus and right cerebellum when switching from speed to accuracy. The left superior parietal lobule was activated in the same switching condition but only after the target onset. The anterior cingulate cortex was more recruited, also after target presentation, when speed had to be maintained from one trial to the next. These results are interpreted within a theoretical framework that attributes a role in criterion-setting to the left lateral prefrontal cortex, perceptual evidence accumulation to the superior parietal lobule, and action energization to the anterior cingulate cortex, extending previous findings to the domain of speed-accuracy tradeoff regulations.

Effects of white matter hyperintensities, neuropsychiatric symptoms, and cognition on activities of daily living: Differences between Alzheimer's disease and dementia with Lewy bodies.

Introduction: Disability is common across Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). White matter hyperintensities (WMHs) are prevalent in both diagnoses and associated with disability; both diagnoses show neuropsychiatric symptoms (NPS) and impaired cognition. Methods: In AD and DLB, we examined if WMHs, NPS, and cognition associate with basic and/or instrumental activities of daily living (BADLs and/or IADLs) cross-sectionally, and longitudinally over ≈1.4 years. Results: Across both diagnoses, NPS were not only associated with greater disability in performing both BADLs and IADLs, but were also associated with a decline in the ability to perform BADLs in the AD group. In the DLB group only, higher WMH volume was associated with greater disability in performing both BADLs and IADLs, and was associated with a decline in the ability to perform BADL over time. Discussion: Management of NPS and WMHs, particularly in DLB, might help maintain functionality in dementia patients for longer.

Cognitive and Neuroimaging Profiles of Older Adults With Attention Deficit/Hyperactivity Disorder Presenting to a Memory Clinic.

OBJECTIVE: Some features of attention-deficit/hyperactivity disorder (ADHD) may resemble those of mild cognitive impairment (MCI) in older adults, contributing to diagnostic uncertainty in individuals seeking assessment in memory clinics. We systematically compared cognition and brain structure in ADHD and MCI to clarify the extent of overlap and identify potential features unique to each. METHOD: Older adults from a Cognitive Neurology clinic (40 ADHD, 29 MCI, 37 controls) underwent neuropsychological assessment. A subsample (n = 80) underwent structural neuroimaging. RESULTS: Memory was impaired in both patient groups, but reflected a storage deficit in MCI (supported by relatively smaller hippocampi) and an encoding deficit in ADHD (supported by frontal lobe thinning). Both groups displayed normal executive functioning. Semantic retrieval was uniquely impaired in MCI. CONCLUSION: Although ADHD has been proposed as a dementia risk factor or prodrome, we propose it is rather a pathophysiologically-unique phenotypic mimic acting via overlap in memory and executive performance.

Overrecruitment in the aging brain as a function of task demands: evidence for a compensatory view.

This study used fMRI to investigate the neural effects of increasing cognitive demands in normal aging and their role for performance. Simple and complex go/no-go tasks were used with two versus eight colored letters as go stimuli, respectively. In both tasks, no-go stimuli could produce high conflict (same letter, different color) or low conflict (colored numbers) with go stimuli. Multivariate partial least square analysis of fMRI data showed that older adults overengaged a cohesive pattern of fronto-parietal regions with no-go stimuli under the specific combination of factors which progressively amplified task demands: high conflict no-go trials in the first phase of the complex task. This early neural overrecruitment was positively correlated with a lower error rate in the older group. Thus, the present data suggest that age-related extra-recruitment of neural resources can be beneficial for performance under taxing task conditions, such as when novel, weak, and complex rules have to be acquired.

Task context and frontal lobe activation in the Stroop task.

The ability to step outside a routine--to select a new response over a habitual one--is a cardinal function of the frontal lobes. A large body of neuroimaging work now exists pointing to increased activation within the anterior cingulate when stimuli evoke competing responses (incongruent trials) relative to when responses converge (congruent trials). However, lesion evidence that the ACC is necessary in this situation is inconsistent. We hypothesized that this may be a consequence of different task procedures (context) used in lesion and neuroimaging studies. The present study attempted to reconcile the lesion and the fMRI findings by having subjects perform clinical and experimental versions of the Stroop task during BOLD fMRI acquisition. We examined the relationship of brain activation patterns, specifically within the anterior cingulate and left dorsolateral frontal regions, to congruent and incongruent trial types in different task presentations or contexts. The results confirmed our hypothesis that ACC activity is relatively specific to unblocked-uncued incongruent Stroop conditions that have not been used in large neuropsychological studies. Moreover, the size of the behavioral Stroop interference effect was significantly correlated with activity in ACC and left dorsolateral regions, although in different directions. The current results are discussed in terms of previous proposals for the functional roles of these regions in activating, monitoring, and task setting, and the relation of these findings to the disparate reports in recent case series is considered.

Traumatic brain injury: relation to executive dysfunction and the frontal lobes.

PURPOSE OF REVIEW: This review examines the applicability of a framework of frontal lobe functioning to understand the sequelae of traumatic brain injury (TBI). RECENT FINDINGS: TBI research illustrates the need for improved phenotyping of TBI outcome. The functions of the frontal lobes are divisible into four distinct anatomically discrete categories: executive functions, speed of processing, personality changes, and problems with empathy and social cognition. Research on the outcome after TBI demonstrates several different types of impairment that map onto this framework. SUMMARY: TBI predominantly causes damage to the frontal/temporal regions, regardless of the pathophysiology. Limiting the spotlight to the frontal lobes, a model is presented describing four separate general categories of functions within the frontal lobes, with specific types of processes within each category. A selective review of TBI literature supports the importance of evaluating TBI patients with this framework in mind. In addition, there is growing evidence that rehabilitation of TBI patients must consider this broader approach to direct rehabilitation efforts and improve outcome.

Functions of the frontal lobes: relation to executive functions.

Proceeding from the assumptions that specific frontal regions control discrete functions and that very basic cognitive processes can be systematically manipulated to reveal those functions, recent reports have demonstrated consistent anatomical/functional relationships: dorsomedial for energization, left dorsolateral for task setting, and right dorsolateral for monitoring. There is no central executive. There are, instead, numerous domain general processes discretely distributed across several frontal regions that act in concert to accomplish control. Beyond these functions, there are two additional "frontal" anatomical/functional relationships: ventral-medial/orbital for emotional and behavioral regulation, and frontopolar for integrative-even meta-cognitive-functions.

Planful versus avoidant coping: behavior of individuals with moderate-to-severe traumatic brain injury during a psychosocial stress test.

Many people who sustain traumatic brain injuries (TBI) have poor psychosocial outcomes that have been related to the use of avoidant coping. A major obstacle to understanding the mechanisms of this relationship are the self-report measures by which coping has been traditionally evaluated. The purpose of the present study was to compare coping behavior during a simulated real-world stress test with self-reported coping. People with moderate-to-severe TBI and matched controls completed the Baycrest Psychosocial Stress Test (BPST) where coping behavior was evaluated, and also completed the Ways of Coping Questionnaire (WOC). While there were no group differences in self- or significant-other-reported behavior on the WOC, the TBI group engaged in more avoidant than planful behavior on the BPST, while the control group displayed the opposite pattern of behavior. Moreover, in the control group there were positive relations between behavior on the BPST and self-reported coping on the WOC, but no such relation within the TBI group. Secondary analyses allowed for TBI participants to be characterized as "planners" or "avoiders." This is the first study, to our knowledge, to report behavioral differences in coping post-TBI. Future work investigating the moderators of these differences may have significant implications for rehabilitative intervention.

Coping behaviour following traumatic brain injury: what makes a planner plan and an avoider avoid?

PRIMARY OBJECTIVE: Avoidant coping has consistently been related to negative outcomes following traumatic brain injury (TBI), although the mechanisms of this relationship are not clear. A recent study demonstrated that people with moderate-to-severe TBI engaged in more avoidant than planful coping behaviour during a psychosocial stress test, while their matched healthy counterparts engaged in the opposite pattern. The purpose of the current study was to evaluate the neuropsychological, physiological and psychological differences between planners and avoiders with TBI. METHODS AND PROCEDURES: Eighteen people with moderate-to-severe TBI completed the Baycrest Psychosocial Stress Test (BPST) where coping behaviour was evaluated and physiological measures recorded. Participants also completed a series of questionnaires and a neuropsychological test battery. MAIN OUTCOMES AND RESULTS: Compared to avoiders, planners had better executive function, were more psychologically and physiologically reactive and performed better on the BPST. Dysfunction on tests assessing executive abilities was the best predictor of avoidant coping, while physiological and psychological reactivity were the best predictors of planful coping. CONCLUSIONS: This study is the first to document differences between planners and avoiders with TBI. Understanding the determinants of coping following TBI will allow for more sophisticated and targeted rehabilitative intervention.

The future of cognitive neurorehabilitation.

Cognitive neurorehabilitation is rooted both in the cognitive function being treated and the neural substrates underlying that ability. Recent progress in understanding both brain (in particular brain plasticity) and the complexities of behaviour imply a promising future for cognitive neurorehabilitation. The manuscripts in this issue focuse on advances in the use of non-invasive brain stimulation (NIBS) as a tool for cognitive neurorehabilitation. This paper presents a broader context in which to understand the importance and potential of this specific approach. Achieving the promise requires theoretical and experimental rigour including selection of relevant outcome measures, and understanding of the complexities of individual patients. Success will depend on our ability to integrate knowledge and approaches.