The Functions of Prospection – Variations in Health and Disease

Much of human life revolves around anticipating and planning for the future. It has become increasingly clear that this capacity for prospective cognition is a core adaptive function of the mind. Here, we review the role of prospection in two key functional domains: goal-directed behavior and flexible decision-making. We then survey and categorize variations in prospection, with a particular focus on functional impact in clinical psychological conditions and neurological disorders. Finally, we suggest avenues for future research into the functions of prospection and the manner in which these functions can shift toward maladaptive outcomes. In doing so, we consider the conceptualization and measurement of prospection, as well as novel approaches to its augmentation in healthy people and managing its alterations in a clinical context

Characterizing sexual behavior in frontotemporal dementia

Background: Frontotemporal dementia (FTD) is characterized by a number of prominent behavioral changes. While FTD has been associated with the presence of aberrant or unusual sexual behaviors in a proportion of patients, few studies have formally investigated changes in sexual function in this disease. Objective: We aimed to systematically quantify changes in sexual behavior, including current symptoms and changes from prior diagnoses, in behavioral-variant (bvFTD) and semantic dementia (SD), compared to Alzheimer’s disease (AD). Methods: Carers of 49 dementia patients (21 bvFTD, 11 SD, 17 AD) were interviewed using the Sexual Behavior and Intimacy Questionnaire (SIQ), a survey designed to assess changes in sexual function across multiple domains including initiating, level of affection, and aberrant or unusual sexual behavior. Results: BvFTD patients show prominent hyposexual behavior including decreased affection, initiation, and response to advances by partners, and decreased frequency of sexual relations, compared to AD and to SD patients. The greatest changes in sexual behavior compared to pre-diagnoses were found in the bvFTD group with a 90–100% decrease in initiation, response, and frequency of sexual relations. Notably, aberrant or unusual sexual behavior was reported in a minority of bvFTD and SD patients and occurred in patients who also showed hyposexual behavior toward their partner. Conclusion: Overall loss of affection, reduced initiation of sexual activity, and responsiveness is an overwhelming feature of bvFTD. In contrast, aberrant or unusual sexual behavior is observed in the minority of bvFTD patients. The underlying pathophysiology of these changes likely reflects structural and functional changes in frontoinsular and limbic regions including the hypothalamus

Neurocognitive mechanisms of theory of mind impairment in neurodegeneration: a transdiagnostic approach

Much of human interaction is predicated upon our innate capacity to infer the thoughts, beliefs, emotions, and perspectives of others, in short, to possess a “theory of mind” (ToM). While the term has evolved considerably since its inception, ToM encompasses our unique ability to apprehend the mental states of others, enabling us to anticipate and predict subsequent behavior. From a developmental perspective, ToM has been a topic of keen research interest, with numerous studies seeking to explicate the origins of this fundamental capacity and its disruption in developmental disorders such as autism. The study of ToM at the opposite end of the lifespan, however, is paradoxically new born, emerging as a topic of interest in its own right comparatively recently. Here, we consider the unique insights afforded by studying ToM capacity in neurodegenerative disorders. Arguing from a novel, transdiagnostic perspective, we consider how ToM vulnerability reflects the progressive degradation of neural circuits special- ized for an array of higher-order cognitive processes. This mechanistic approach enables us to consider the common and unique neurocognitive mechanisms that underpin ToM dysfunction across neurodegenerative disorders and for the first time examine its relation to behavioral disturbances across social, intimate, legal, and criminal settings. As such, we aim to provide a comprehensive overview of ToM research in neurodegeneration, the resultant challenges for family members, clinicians, and the legal profession, and future directions worthy of exploration

Neural Substrates of Semantic Prospection – Evidence from the Dementias

The ability to envisage personally relevant events at a future time point represents an incredibly sophisticated cognitive endeavor and one that appears to be intimately linked to episodic memory integrity. Far less is known regarding the neurocognitive mechanisms underpinning the capacity to envisage non-personal future occurrences, known as semantic future thinking. Moreover the degree of overlap between the neural substrates supporting episodic and semantic forms of prospection remains unclear. To this end, we sought to investigate the capacity for episodic and semantic future thinking in Alzheimer’s disease (n = 15) and disease-matched behavioral-variant frontotemporal dementia (n = 15), neurodegenerative disorders characterized by significant medial temporal lobe (MTL) and frontal pathology. Participants completed an assessment of past and future thinking across personal (episodic) and non-personal (semantic) domains, as part of a larger neuropsychological battery investigating episodic and semantic processing, and their performance was contrasted with 20 age- and education-matched healthy older Controls. Participants underwent whole-brain T1-weighted structural imaging and voxel-based morphometry analysis was conducted to determine the relationship between gray matter integrity and episodic and semantic future thinking. Relative to Controls, both patient groups displayed marked future thinking impairments, extending across episodic and semantic domains. Analyses of covariance revealed that while episodic future thinking deficits could be explained solely in terms of episodic memory proficiency, semantic prospection deficits reflected the interplay between episodic and semantic processing. Distinct neural correlates emerged for each form of future simulation with differential involvement of prefrontal, lateral temporal, and medial temporal regions. Notably, the hippocampus was implicated irrespective of future thinking domain, with the suggestion of lateralization effects depending on the type of information being simulated. Whereas episodic future thinking related to right hippocampal integrity, semantic future thinking was found to relate to left hippocampal integrity. Our findings support previous observations of significant MTL involvement for semantic forms of prospection and point to distinct neurocognitive mechanisms which must be functional to support future-oriented forms of thought across personal and non-personal contexts

Strategic value-directed learning and memory in Alzheimer's disease and behavioural-variant frontotemporal dementia

In healthy adults, the ability to prioritize learning of highly valued information is supported by executive functions and enhances subsequent memory retrieval for this information. In Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD), marked deficits are evident in learning and memory, presenting in the context of executive dysfunction. It is unclear whether these patients show a typical memory bias for higher valued stimuli. We administered a value-directed word-list learning task to AD (n = 10) and bvFTD (n = 21) patients and age-matched healthy controls (n = 22). Each word was assigned a low, medium or high point value, and participants were instructed to maximize the number of points earned across three learning trials. Participants’ memory for the words was assessed on a delayed recall trial, followed by a recognition test for the words and corresponding point values. Relative to controls, both patient groups showed poorer overall learning, delayed recall and recognition. Despite these impairments, patients with AD preferentially recalled high-value words on learning trials and showed significant value-directed enhancement of recognition memory for the words and points. Conversely, bvFTD patients did not prioritize recall of high-value words during learning trials, and this reduced selectivity was related to inhibitory dysfunction. Nonetheless, bvFTD patients showed value-directed enhancement of recognition memory for the point values, suggesting a mismatch between memory of high-value information and the ability to apply this in a motivationally salient context. Our findings demonstrate that value-directed enhancement of memory may persist to some degree in patients with dementia, despite pronounced deficits in learning and memory

Fair play: social norm compliance failures in behavioural variant frontotemporal dementia.

Adherence to social norms is compromised in a variety of neuropsychiatric conditions. Functional neuroimaging studies have investigated social norm compliance in healthy individuals, leading to the identification of a network of fronto-subcortical regions that underpins this ability. However, there is a lack of corroborative evidence from human lesion models investigating the structural anatomy of norm compliance across this fronto-subcortical network. To address this, we developed a neuroeconomic task to investigate social norm compliance in a neurodegenerative lesion model: behavioural variant frontotemporal dementia, a condition characterized by gross social dysfunction. The task assessed norm compliance across three behaviours that are well-studied in the neuroeconomics literature: fairness, prosocial and punishing behaviours. We administered our novel version of the Ultimatum Game in 22 patients with behavioural variant frontotemporal dementia and 22 age-matched controls, to assess how decision-making behaviour was modulated in response to (i) fairness of monetary offers; and (ii) social context of monetary offers designed to produce either prosocial or punishing behaviours. Voxel-based morphometry was used to characterize patterns of grey matter atrophy associated with task performance. Acceptance rates between patients and controls were equivalent when only fairness was manipulated. However, patients were impaired in modulating their decisions in response to social contextual information. Patients' performance in the punishment condition was consistent with a reduced tendency to engage in punishment; this was associated with decreased grey matter volume in the anterior cingulate, orbitofrontal cortex, left dorsolateral prefrontal cortex and right inferior frontal gyrus. In the prosocial condition, patients' performance suggested a reduced expression of prosocial behaviour, associated with decreased grey matter in the anterior insula, lateral orbitofrontal cortex, anterior cingulate and dorsal striatum. Acceptance rates in the Ultimatum Game were also significantly related to impairments in the everyday expression of empathic concern. In conclusion, we demonstrate that compliance to basic social norms (fairness) can be maintained in behavioural variant frontotemporal dementia; however, more complex normative behaviours (prosociality, punishment) that require integration of social contextual information are disrupted in association with atrophy in key fronto-striatal regions. These results suggest that the integration of social contextual information to guide normative behaviour is uniquely impaired in behavioural variant frontotemporal dementia, and may explain other common features of the condition including gullibility and impaired empathy. Our findings also converge with previous functional neuroimaging investigations in healthy individuals and provide the first description of the structural anatomy of social norm compliance in a neurodegenerative lesion model

Establishing two principal dimensions of cognitive variation in Logopenic Progressive Aphasia

Logopenic Progressive Aphasia (LPA) is a neurodegenerative syndrome characterised by sentence repetition and naming difficulties arising from left-lateralised temporoparietal atrophy. Clinical descriptions of LPA largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits, even on tasks with minimal language demands. Although non-linguistic cognitive deficits in LPA are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose individual-level variation in cognitive performance in 43 well-characterised LPA patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected ‘speech production and verbal memory’ deficits which typify LPA. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably ‘logopenic’ patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralised temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, LPA patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralised temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in LPA, suggesting the presence of a genuine co-occurring cognitive impairment that is independent of language function and disease severity.This work was supported in part by funding to Forefront, a collaborative research group specialized to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council (NHMRC) of Australia program grant (APP1037746) and the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Program (CE110001021). Siddharth Ramanan is supported by a Faculty of Science Ph.D. Research Scholarship from The University of Sydney. Olivier Piguet is supported by an NHMRC Senior Research Fellowship (APP1103258). Muireann Irish is supported by an ARC Future Fellowship (FT160100096) and an ARC Discovery Project (DP180101548). Matthew A. Lambon Ralph is supported by a UKRI-MRC Programme Grant (MR/R023883/1) and an ERC Advanced grant (GAP: 670428 - BRAIN2MIND_NEUROCOMP)

Anhedonia in Semantic Dementia-Exploring Right Hemispheric Contributions to the Loss of Pleasure.

Semantic dementia (SD) is a younger-onset neurodegenerative disease characterised by progressive deterioration of the semantic knowledge base in the context of predominantly left-lateralised anterior temporal lobe (ATL) atrophy. Mounting evidence indicates the emergence of florid socioemotional changes in SD as atrophy encroaches into right temporal regions. How lateralisation of temporal lobe pathology impacts the hedonic experience in SD remains largely unknown yet has important implications for understanding socioemotional and functional impairments in this syndrome. Here, we explored how lateralisation of temporal lobe atrophy impacts anhedonia severity on the Snaith-Hamilton Pleasure Scale in 28 SD patients presenting with variable right- (SD-R) and left-predominant (SD-L) profiles of temporal lobe atrophy compared to that of 30 participants with Alzheimer's disease and 30 healthy older Control participants. Relative to Controls, SD-R but not SD-L or Alzheimer's patients showed clinically significant anhedonia, representing a clear departure from premorbid levels. Overall, anhedonia was more strongly associated with functional impairment on the Frontotemporal Dementia Functional Rating Scale and motivational changes on the Cambridge Behavioural Inventory in SD than in Alzheimer's disease patients. Voxel-based morphometry analyses revealed that anhedonia severity correlated with reduced grey matter intensity in a restricted set of regions centred on right orbitofrontal and temporopolar cortices, bilateral posterior temporal cortices, as well as the anterior cingulate gyrus and parahippocampal gyrus, bilaterally. Finally, regression and mediation analysis indicated a unique role for right temporal lobe structures in modulating anhedonia in SD. Our findings suggest that degeneration of predominantly right-hemisphere structures deleteriously impacts the capacity to experience pleasure in SD. These findings offer important insights into hemispheric lateralisation of motivational disturbances in dementia and suggest that anhedonia may emerge at different timescales in the SD disease trajectory depending on the integrity of the right hemisphere.This study was supported in part by funding to ForeFront, a large collaborative research group dedicated to the study of neurodegenerative diseases, from the National Health and Medical Research Council (NHMRC) Program grant (#1132524) and Dementia Research Team Grant (#1095127), as well as the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders (CE11000102) and an NHMRC Project grant (#1121791). The authors acknowledge the technical assistance provided by the Sydney Informatics Hub, a Core Research Facility of the University of Sydney. M.I. is supported by an ARC Future Fellowship (FT160100096). A.E.W. is supported by an NHMRC Fellowship (#1110773). O.P. is supported by an NHMRC Senior Research Fellowship (GNT1103258). These funding sources were not involved in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the manuscript for publication

Assessment of Eating Behavior Disturbance and Associated Neural Networks in Frontotemporal Dementia.

IMPORTANCE: Abnormal eating behaviors are common in patients with frontotemporal dementia (FTD), yet their exact prevalence, severity, and underlying biological mechanisms are not understood. OBJECTIVE: To define the severity of abnormal eating behavior and sucrose preference and their neural correlates in patients with behavioral variant FTD (bvFTD) and semantic dementia. DESIGN, SETTING, AND PARTICIPANTS: Forty-nine patients with dementia (19 with bvFTD, 15 with semantic dementia, and 15 with Alzheimer disease) were recruited, and their eating behavior was compared with that of 25 healthy controls. The study was conducted from November 1, 2013, through May 31, 2015, and data analyzed from June 1 to August 31, 2015. MAIN OUTCOMES AND MEASURES: Patients participated in an ad libitum breakfast test meal, and their total caloric intake and food preferences were measured. Changes in eating behavior were also measured using the Appetite and Eating Habits Questionnaire (APEHQ) and the Cambridge Behavioral Inventory (CBI). Sucrose preference was tested by measuring liking ratings of 3 desserts of varying sucrose content (A: 26%, B: 39%, C: 60%). Voxel-based morphometry analysis of whole-brain 3-T high-resolution brain magnetic resonance imaging was used to determine the gray matter density changes across groups and their relations to eating behaviors. RESULTS: Mean (SD) ages of patients in all 4 groups ranged from 62 (8.3) to 66 (8.4) years. At the ad libitum breakfast test meal, all patients with bvFTD had increased total caloric intake (mean, 1344 calories) compared with the Alzheimer disease (mean, 710 calories), semantic dementia (mean, 573 calories), and control groups (mean, 603 calories) (P < .001). Patients with bvFTD and semantic dementia had a strong sucrose preference compared with the other groups. Increased caloric intake correlated with atrophy in discrete neural networks that differed between patients with bvFTD and semantic dementia but included the cingulate cortices, thalami, and cerebellum in patients with bvFTD, with the addition of the orbitofrontal cortices and nucleus accumbens in patients with semantic dementia. A distributed network of neural correlates was associated with sucrose preference in patients with FTD. CONCLUSIONS AND RELEVANCE: Marked hyperphagia is restricted to bvFTD, present in all patients with this diagnosis, and supports its diagnostic value. Differing neural networks control eating behavior in patients with bvFTD and semantic dementia and are likely responsible for the differences seen, with a similar network controlling sucrose preference. These networks share structures that control cognitive-reward, autonomic, neuroendocrine, and visual modulation of eating behavior. Delineating the neural networks involved in mediating these changes in eating behavior may enable treatment of these features in patients with complex medical needs and aid in our understanding of structures that control eating behavior in patients with FTD and healthy individuals.This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (#1037746 to MK and JH) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021 to OP and JH) and other grants/sources (NHMRC project grant #1003139). We are grateful to the research participants involved with the ForeFront research studies. RA is a Royal Australasian College of Physicians PhD scholar and MND Australia PhD scholar. MI is an ARC Discovery Early Career Researcher Award Fellow Ahmed et al. (#DE130100463). OP is an NHMRC Career Development Research Fellow (#1022684). ISF is supported by the Wellcome Trust, Medical Research Council, European Research Council, NIHR Cambridge Biomedical Research Centre and The Bernard Wolfe Endowment.This is the author accepted manuscript. The final version is available from American Medical Association at http://dx.doi.org/10.1001/jamaneurol.2015.4478

Preservation of episodic memory in semantic dementia:The importance of regions beyond the medial temporal lobes

Episodic memory impairment represents one of the hallmark clinical features of patients with Alzheimer's disease (AD) attributable to the degeneration of medial temporal and parietal regions of the brain. In contrast, a somewhat paradoxical profile of relatively intact episodic memory, particularly for non-verbal material, is observed in semantic dementia (SD), despite marked atrophy of the hippocampus. This retrospective study investigated the neural substrates of episodic memory retrieval in 20 patients with a diagnosis of SD and 21 disease-matched cases of AD and compared their performance to that of 35 age- and education-matched healthy older Controls. Participants completed the Rey Complex Figure and the memory subscale of the Addenbrooke's Cognitive Examination-Revised as indices of visual and verbal episodic recall, respectively. Relative to Controls, AD patients showed compromised memory performance on both visual and verbal memory tasks. In contrast, memory deficits in SD were modality-specific occurring exclusively on the verbal task. Controlling for semantic processing ameliorated these deficits in SD, while memory impairments persisted in AD. Voxel-based morphometry analyses revealed significant overlap in the neural correlates of verbal episodic memory in AD and SD with predominantly anteromedial regions, including the bilateral hippocampus, strongly implicated. Controlling for semantic processing negated this effect in SD, however, a distributed network of frontal, medial temporal, and parietal regions was implicated in AD. Our study corroborates the view that episodic memory deficits in SD arise very largely as a consequence of the conceptual loading of traditional tasks. We propose that the functional integrity of frontal and parietal regions enables new learning to occur in SD in the face of significant hippocampal and anteromedial temporal lobe pathology, underscoring the inherent complexity of the episodic memory circuitry