1 Nature Reviews Neurology 2012 Vol: 8(3):152-161. DOI: 10.1038/nrneurol.2012.11

Self-projection and the default network in frontotemporal dementia

Converging evidence suggests that when individuals are left to think to themselves, a so-called default network of the brain is engaged, allowing the individual to daydream, reflect on their past, imagine possible future scenarios, and consider the viewpoints of others. These flexible self-relevant mental explorations enable the anticipation and evaluation of events before they occur, and are essential for successful social interactions. Such self-projective efforts are particularly vulnerable to disruption in frontotemporal dementia (FTD), a neurodegenerative disorder involving damage to the frontal and temporal lobes of the brain. In this Review, we explore how the progressive degeneration of the neural networks in two subtypes of FTD—the behavioral variant and semantic dementia—affects key structures of the default network and putative self-projective functions. We examine the available evidence from studies of autobiographical memory, episodic future thinking, theory of mind, moral reasoning, and economic decision-making in these neurodegenerative diseases. Finally, we propose that the mapping of default-network functions onto discrete subsystems of the default network may need revision in light of neuropsychological and clinical evidence from studies in patients with FTD.

Mentions
Figures
Figure 1: The default network.Neuroanatomical substrates of the default network comprise the MTL and dmPFC subsystems, which converge on the midline core. The MTL subsystem (highlighted in blue) encompasses the hippocampal formation, parahippocampal cortex, retrosplenial cortex, ventromedial prefrontal cortex, and posterior inferior parietal lobule, whereas the dmPFC subsystem (highlighted in red) comprises the dorsomedial prefrontal cortex, temporoparietal junction, lateral temporal cortex, and temporal pole. The midline core (highlighted in green) refers to the anterior medial prefrontal cortex, and the posterior cingulate cortex. Regional anatomical boundaries are approximate. Abbreviations: dmPFC, dorsomedial prefrontal cortex; MTL, medial temporal lobe. Figure 2: Characteristic patterns of atrophy in bvFTD and semantic dementia.Patients with bvFTD show classic bilateral atrophy in mesial and orbital frontal regions, extending to the temporal pole and hippocampal formation as disease progresses (blue). In semantic dementia, the typical pattern of atrophy is lateralized (generally left>right hemisphere), chiefly targeting the anterior temporal lobes and temporal pole, including the hippocampal formation and amygdala, and spreading to ventromedial prefrontal cortical regions as the disease progresses (yellow). Regional anatomical boundaries are approximate. Abbreviation: bvFTD, behavioral variant frontotemporal dementia.
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References
  1. Raichle, M. E. et al. A default mode of brain function. Proc. Natl Acad. Sci. USA 98, 676-682 , .
    • . . . The discovery of a default mode of intrinsic brain function1 has led to the delineation of the default network—a neuroanatomically defined brain system that seems to preferentially activate when an individual is not focused on the external environment (Box 1).2, 3 Increased brain activation has been observed consistently in a set of brain regions, including prefrontal and temporal regions and posterior cingulate and parietal cortices,2, 4 when individuals are left to think to themselves.5 Activation of this network seems to be largely independent of cognitive processes,6, 7 yet many common and diverse introspective activities recruit the same frontal and medial temporoparietal structures of the default network . . .
    • . . . The term 'default' has been used interchangeably to refer to a mode of intrinsic brain activity1 as well as an anatomically defined brain system.4 For consistency in this Review, we use the term to refer to the latter of these definitions, focusing on the neuroanatomical structures that have been commonly implicated across resting-state functional connectivity studies and functional neuroimaging studies. . . .
  2. Buckner, R. L., Andrews-Hanna, J. R. & Schacter, D. L. The brain's default network: anatomy, function, and relevance to disease. Ann. NY Acad. Sci. 1124, 1-38 , .
    • . . . The discovery of a default mode of intrinsic brain function1 has led to the delineation of the default network—a neuroanatomically defined brain system that seems to preferentially activate when an individual is not focused on the external environment (Box 1).2, 3 Increased brain activation has been observed consistently in a set of brain regions, including prefrontal and temporal regions and posterior cingulate and parietal cortices,2, 4 when individuals are left to think to themselves.5 Activation of this network seems to be largely independent of cognitive processes,6, 7 yet many common and diverse introspective activities recruit the same frontal and medial temporoparietal structures of the default network . . .
    • . . . Results from anatomical and functional connectivity studies suggest that the default network is organized into distinct subsystems (Figure 1), which converge on a midline core comprising the posterior cingulate and anteromedial prefrontal cortex (PFC).2, 4, 13 The medial temporal lobe (MTL) subsystem includes the hippocampal formation, the parahippocampal, retrosplenial and ventromedial PFCs, and the posterior parietal lobule . . .
    • . . . The ability to imagine oneself in the future is an adaptive behavior, as the mental simulation of possible future outcomes helps an individual to maximize positive outcomes and avoid negative ones.12 Moral reasoning relies on the integration of several self-projective cognitive processes that use social semantic knowledge represented in the anterior temporal cortex,109 and motivational and emotional states associated with activation of cortical–limbic circuits.114 Indeed, resolution of moral dilemmas is the type of situation in which alternative events must be simulated.2, 109 Importantly, certain forms of moral decision-making have been shown to activate default-network regions, such as the PFC and anterior temporal regions.109, 114 Moral reasoning is, unsurprisingly, substantially compromised in bvFTD.42, 115 Such socially relevant decision-making is more impaired in bvFTD than in semantic dementia, and the extent of impairment in bvFTD may reflect compromised theory of mind and reduced cognitive flexibility,41 as well as a lack of empathy (as rated by caregivers).107 . . .
  3. Zhang, D. & Raichle, M. E. Disease and the brain's dark energy. Nat. Rev. Neurol. 6, 15-28 , .
    • . . . The discovery of a default mode of intrinsic brain function1 has led to the delineation of the default network—a neuroanatomically defined brain system that seems to preferentially activate when an individual is not focused on the external environment (Box 1).2, 3 Increased brain activation has been observed consistently in a set of brain regions, including prefrontal and temporal regions and posterior cingulate and parietal cortices,2, 4 when individuals are left to think to themselves.5 Activation of this network seems to be largely independent of cognitive processes,6, 7 yet many common and diverse introspective activities recruit the same frontal and medial temporoparietal structures of the default network . . .
  4. Andrews-Hanna, J. R., Reidler, J. S., Sepulcre, J., Poulin, R. & Buckner, R. L. Functional-anatomic fractionation of the brain's default network. Neuron 65, 550-562 , .
    • . . . The discovery of a default mode of intrinsic brain function1 has led to the delineation of the default network—a neuroanatomically defined brain system that seems to preferentially activate when an individual is not focused on the external environment (Box 1).2, 3 Increased brain activation has been observed consistently in a set of brain regions, including prefrontal and temporal regions and posterior cingulate and parietal cortices,2, 4 when individuals are left to think to themselves.5 Activation of this network seems to be largely independent of cognitive processes,6, 7 yet many common and diverse introspective activities recruit the same frontal and medial temporoparietal structures of the default network . . .
    • . . . The term 'default' has been used interchangeably to refer to a mode of intrinsic brain activity1 as well as an anatomically defined brain system.4 For consistency in this Review, we use the term to refer to the latter of these definitions, focusing on the neuroanatomical structures that have been commonly implicated across resting-state functional connectivity studies and functional neuroimaging studies. . . .
    • . . . Results from anatomical and functional connectivity studies suggest that the default network is organized into distinct subsystems (Figure 1), which converge on a midline core comprising the posterior cingulate and anteromedial prefrontal cortex (PFC).2, 4, 13 The medial temporal lobe (MTL) subsystem includes the hippocampal formation, the parahippocampal, retrosplenial and ventromedial PFCs, and the posterior parietal lobule . . .
    • . . . Our hypothesis that disrupted episodic future thinking arises owing to frontal lobe dysfunction in bvFTD conflicts to some extent with the current concept of the MTL default-network subsystem, which has been posited to underlie retrieval of autobiographical memories and the capacity for episodic future thinking.4, 13 The ascribing of future thinking, as a memory-based constructive endeavor, to the MTL system could reflect the focus of research in this field, which to date has been almost exclusively on the hippocampus . . .
  5. Andrews-Hanna, J. R., Reidler, J. S., Huang, C. & Buckner, R. L. Evidence for the default network's role in spontaneous cognition. J. Neurophysiol. 104, 322-335 , .
    • . . . The discovery of a default mode of intrinsic brain function1 has led to the delineation of the default network—a neuroanatomically defined brain system that seems to preferentially activate when an individual is not focused on the external environment (Box 1).2, 3 Increased brain activation has been observed consistently in a set of brain regions, including prefrontal and temporal regions and posterior cingulate and parietal cortices,2, 4 when individuals are left to think to themselves.5 Activation of this network seems to be largely independent of cognitive processes,6, 7 yet many common and diverse introspective activities recruit the same frontal and medial temporoparietal structures of the default network . . .
  6. Raichle, M. E. & Snyder, A. Z. A default mode of brain function: a brief history of an evolving idea. NeuroImage 37, 1083-1090 , .
    • . . . The discovery of a default mode of intrinsic brain function1 has led to the delineation of the default network—a neuroanatomically defined brain system that seems to preferentially activate when an individual is not focused on the external environment (Box 1).2, 3 Increased brain activation has been observed consistently in a set of brain regions, including prefrontal and temporal regions and posterior cingulate and parietal cortices,2, 4 when individuals are left to think to themselves.5 Activation of this network seems to be largely independent of cognitive processes,6, 7 yet many common and diverse introspective activities recruit the same frontal and medial temporoparietal structures of the default network . . .
  7. Raichle, M. E. & Gusnard, D. A. Appraising the brain's energy budget. Proc. Natl Acad. Sci. USA 99, 10237-10239 , .
    • . . . The discovery of a default mode of intrinsic brain function1 has led to the delineation of the default network—a neuroanatomically defined brain system that seems to preferentially activate when an individual is not focused on the external environment (Box 1).2, 3 Increased brain activation has been observed consistently in a set of brain regions, including prefrontal and temporal regions and posterior cingulate and parietal cortices,2, 4 when individuals are left to think to themselves.5 Activation of this network seems to be largely independent of cognitive processes,6, 7 yet many common and diverse introspective activities recruit the same frontal and medial temporoparietal structures of the default network . . .
  8. Buckner, R. L. & Carroll, D. C. Self-projection and the brain. Trends Cogn. Sci. 11, 49-57 , .
  9. Buckner, R. L. et al. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J. Neurosci. 29, 1860-1873 , .
    • . . . Recent advances in measuring resting-state functional connectivity have revealed differential functional network alterations that are specific to Alzheimer disease9 (AD) and frontotemporal dementia (FTD).10, 11 How such alterations in structure and connectivity manifest clinically, however, remains to be fully explored . . .
    • . . . The pattern of hypometabolism in this disease typically involves posterior structures of the default network, suggesting that these areas may be particularly vulnerable to amyloid-β deposition.9, 15, 16 The characteristic MTL degeneration and resulting episodic-memory deficits in AD17 support the proposed self-projective functions of the MTL subsystem of the default network, particularly in performing tasks that require memory-based construction and simulation of alternative events.13 . . .
  10. Seeley, W. W. Selective functional, regional, and neuronal vulnerability in frontotemporal dementia. Curr. Opin. Neurol. 21, 701-707 , .
    • . . . Recent advances in measuring resting-state functional connectivity have revealed differential functional network alterations that are specific to Alzheimer disease9 (AD) and frontotemporal dementia (FTD).10, 11 How such alterations in structure and connectivity manifest clinically, however, remains to be fully explored . . .
    • . . . Patients with bvFTD present with progressive changes in social cognition, motivation and decision-making, which have a profound effect on their interpersonal conduct, and place considerable stress on family members.10, 23, 32 At a neural level, atrophy emerges first in the anterior cingulate and frontoinsular cortices, the dmPFC, and the frontal pole, striatum and thalamus (Table 1, Figure 2).33, 34, 35 As the disease progresses, pathology gradually spreads into adjacent frontal and temporal regions,36 with structures in the right hemisphere typically being more affected than those in the left hemisphere . . .
    • . . . The bvFTD subtype undoubtedly targets the social brain,10 resulting in the loss of complex social cognitive functions including theory of mind and moral reasoning, which can be subsumed largely under the putative functions of the dmPFC introspective subsystem . . .
  11. Seeley, W. W., Crawford, R. K., Zhou, J., Miller, B. L. & Greicius, M. D. Neurodegenerative diseases target large-scale human brain networks. Neuron 62, 42-52 , .
    • . . . Recent advances in measuring resting-state functional connectivity have revealed differential functional network alterations that are specific to Alzheimer disease9 (AD) and frontotemporal dementia (FTD).10, 11 How such alterations in structure and connectivity manifest clinically, however, remains to be fully explored . . .
    • . . . Converging evidence from resting-state functional connectivity studies corroborates the disruption of connectivity between the medial temporal, lateral temporoparietal, posterior cingulate and medial frontal cortices in AD.11, 16 The degeneration of these structures has been linked to the deficits in episodic memory15 and visuospatial imagery18 that typify the early stages of AD . . .
    • . . . The clinical presentation of patients with semantic dementia is dominated by the progressive decline in language skills that primarily involve naming of objects and comprehension of words, while phonology and syntax are preserved.26 The key cognitive deficits are, theoretically, attributable to degeneration of a central amodal semantic hub.45, 46 The neural basis of semantic dementia has been studied extensively in vivo using a range of quantitative methods, as well as at postmortem.47, 48 Crucial brain regions that are involved from an early stage are the anterior fusiform gyrus (containing the perirhinal cortex), the temporal pole, the amygdala and the rostral hippocampus.47, 48, 49, 50 Functional connectivity studies have pointed to a role for disruption of a network involving the temporal pole, the subgenual cingulate area, the ventral striatum and the amygdala in the pathogenesis of semantic dementia (Figure 2).11, 51 . . .
  12. Spreng, R. N., Mar, R. A. & Kim, A. S. The common neural basis of autobiographical memory, prospection, navigation, theory of mind, and the default mode: a quantitative meta-analysis. J. Cogn. Neurosci. 21, 489-510 , .
  13. Andrews-Hanna, J. R. The brain's default network and its adaptive role in internal mentation. Neuroscientist , .
  14. Pievani, M., de Haan, W., Wu, T., Seeley, W. W. & Frisoni, G. B. Functional network disruption in the degenerative dementias. Lancet Neurol. 10, 829-843 , .
    • . . . The shift in the focus of current research away from the function of localized brain structures to brain networks is relevant to neurodegenerative disorders, which affect interconnected brain regions.14 Research on the default network may help in understanding some of the cognitive manifestations of neurodegenerative diseases . . .
  15. Buckner, R. L. et al. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J. Neurosci. 25, 7709-7717 , .
    • . . . The pattern of hypometabolism in this disease typically involves posterior structures of the default network, suggesting that these areas may be particularly vulnerable to amyloid-β deposition.9, 15, 16 The characteristic MTL degeneration and resulting episodic-memory deficits in AD17 support the proposed self-projective functions of the MTL subsystem of the default network, particularly in performing tasks that require memory-based construction and simulation of alternative events.13 . . .
    • . . . Converging evidence from resting-state functional connectivity studies corroborates the disruption of connectivity between the medial temporal, lateral temporoparietal, posterior cingulate and medial frontal cortices in AD.11, 16 The degeneration of these structures has been linked to the deficits in episodic memory15 and visuospatial imagery18 that typify the early stages of AD . . .
  16. Zhou, J. et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease. Brain 133, 1352-1367 , .
    • . . . The pattern of hypometabolism in this disease typically involves posterior structures of the default network, suggesting that these areas may be particularly vulnerable to amyloid-β deposition.9, 15, 16 The characteristic MTL degeneration and resulting episodic-memory deficits in AD17 support the proposed self-projective functions of the MTL subsystem of the default network, particularly in performing tasks that require memory-based construction and simulation of alternative events.13 . . .
    • . . . Converging evidence from resting-state functional connectivity studies corroborates the disruption of connectivity between the medial temporal, lateral temporoparietal, posterior cingulate and medial frontal cortices in AD.11, 16 The degeneration of these structures has been linked to the deficits in episodic memory15 and visuospatial imagery18 that typify the early stages of AD . . .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
  17. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239-249 , .
    • . . . The pattern of hypometabolism in this disease typically involves posterior structures of the default network, suggesting that these areas may be particularly vulnerable to amyloid-β deposition.9, 15, 16 The characteristic MTL degeneration and resulting episodic-memory deficits in AD17 support the proposed self-projective functions of the MTL subsystem of the default network, particularly in performing tasks that require memory-based construction and simulation of alternative events.13 . . .
  18. Cavanna, A. E. & Trimble, M. R. The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129, 564-583 , .
    • . . . Converging evidence from resting-state functional connectivity studies corroborates the disruption of connectivity between the medial temporal, lateral temporoparietal, posterior cingulate and medial frontal cortices in AD.11, 16 The degeneration of these structures has been linked to the deficits in episodic memory15 and visuospatial imagery18 that typify the early stages of AD . . .
  19. Irish, M., Lawlor, B. A., O'Mara, S. M. & Coen, R. F. Impaired capacity for autonoetic reliving during autobiographical event recall in mild Alzheimer's disease. Cortex 47, 236-249 , .
    • . . . Mounting evidence demonstrates that patients with AD, as well as individuals in the prodromal phase of AD, have considerable impairment in their capacity for self-projection to their personal past, which precludes retrieval and reliving of past autobiographical events.19, 20 These impairments extend into an inability to project forwards in subjective time to imagine their personal future.21, 22 Socio-emotional functions, however, are often spared in the early stages of AD, in contrast to the profound impairments in behavior and interpersonal conduct that typically occur in FTD.23, 24 . . .
  20. Irish, M., Lawlor, B. A., O'Mara, S. M. & Coen, R. F. Exploring the recollective experience during autobiographical memory retrieval in amnestic mild cognitive impairment. J. Int. Neuropsychol. Soc. 16, 546-555 , .
    • . . . Mounting evidence demonstrates that patients with AD, as well as individuals in the prodromal phase of AD, have considerable impairment in their capacity for self-projection to their personal past, which precludes retrieval and reliving of past autobiographical events.19, 20 These impairments extend into an inability to project forwards in subjective time to imagine their personal future.21, 22 Socio-emotional functions, however, are often spared in the early stages of AD, in contrast to the profound impairments in behavior and interpersonal conduct that typically occur in FTD.23, 24 . . .
  21. Addis, D. R., Sacchetti, D. C., Ally, B. A., Budson, A. E. & Schacter, D. L. Episodic simulation of future events is impaired in mild Alzheimer's disease. Neuropsychologia 47, 2660-2671 , .
    • . . . Mounting evidence demonstrates that patients with AD, as well as individuals in the prodromal phase of AD, have considerable impairment in their capacity for self-projection to their personal past, which precludes retrieval and reliving of past autobiographical events.19, 20 These impairments extend into an inability to project forwards in subjective time to imagine their personal future.21, 22 Socio-emotional functions, however, are often spared in the early stages of AD, in contrast to the profound impairments in behavior and interpersonal conduct that typically occur in FTD.23, 24 . . .
    • . . . A key role in this process—not only in the retrieval of relevant details from episodic memory to be used in future constructions, but also in the integration of such details into a coherent event—has been ascribed to the hippocampus.78 Damage to the episodic memory system is proposed to compromise the ability to generate simulations of future events.79 Indeed, recent reports have confirmed that patients with mild AD display an impaired capacity both for remembering past autobiographical events and for imagining personal future events.21 This finding concords with growing evidence that patients with bilateral hippocampal damage and intact premorbid semantic memory,80 healthy elderly adults,81 and individuals with mild cognitive impairment22 all experience difficulties in imagining specific future episodes. . . .
  22. Gamboz, N. et al. Episodic future thinking in amnesic mild cognitive impairment. Neuropsychologia 48, 2091-2097 , .
    • . . . Mounting evidence demonstrates that patients with AD, as well as individuals in the prodromal phase of AD, have considerable impairment in their capacity for self-projection to their personal past, which precludes retrieval and reliving of past autobiographical events.19, 20 These impairments extend into an inability to project forwards in subjective time to imagine their personal future.21, 22 Socio-emotional functions, however, are often spared in the early stages of AD, in contrast to the profound impairments in behavior and interpersonal conduct that typically occur in FTD.23, 24 . . .
    • . . . A key role in this process—not only in the retrieval of relevant details from episodic memory to be used in future constructions, but also in the integration of such details into a coherent event—has been ascribed to the hippocampus.78 Damage to the episodic memory system is proposed to compromise the ability to generate simulations of future events.79 Indeed, recent reports have confirmed that patients with mild AD display an impaired capacity both for remembering past autobiographical events and for imagining personal future events.21 This finding concords with growing evidence that patients with bilateral hippocampal damage and intact premorbid semantic memory,80 healthy elderly adults,81 and individuals with mild cognitive impairment22 all experience difficulties in imagining specific future episodes. . . .
  23. Piguet, O., Hornberger, M., Mioshi, E. & Hodges, J. R. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol. 10, 162-172 , .
    • . . . Mounting evidence demonstrates that patients with AD, as well as individuals in the prodromal phase of AD, have considerable impairment in their capacity for self-projection to their personal past, which precludes retrieval and reliving of past autobiographical events.19, 20 These impairments extend into an inability to project forwards in subjective time to imagine their personal future.21, 22 Socio-emotional functions, however, are often spared in the early stages of AD, in contrast to the profound impairments in behavior and interpersonal conduct that typically occur in FTD.23, 24 . . .
    • . . . Patients with bvFTD present with progressive changes in social cognition, motivation and decision-making, which have a profound effect on their interpersonal conduct, and place considerable stress on family members.10, 23, 32 At a neural level, atrophy emerges first in the anterior cingulate and frontoinsular cortices, the dmPFC, and the frontal pole, striatum and thalamus (Table 1, Figure 2).33, 34, 35 As the disease progresses, pathology gradually spreads into adjacent frontal and temporal regions,36 with structures in the right hemisphere typically being more affected than those in the left hemisphere . . .
  24. Rascovsky, K. et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456-2477 , .
  25. Ratnavalli, E., Brayne, C., Dawson, K. & Hodges, J. The prevalence of frontotemporal dementia. Neurology 58, 1615-1621 , .
    • . . . Epidemiological studies suggest that FTD is the second most common cause of early-onset dementia, after AD.25 Unlike in AD, however, both the clinical profile and underlying pathology are heterogeneous in FTD . . .
  26. Hodges, J. R. & Patterson, K. Semantic dementia: a unique clinicopathological syndrome. Lancet Neurol. 6, 1004-1014 , .
    • . . . Primary progressive aphasia can be further subdivided according to the predominant pattern of language breakdown into progressive nonfluent aphasia (PNFA) and semantic dementia.26, 27, 28, 29 The PNFA variant has proved informative in exploring the neuroanatomy of speech production and grammar.30 More recently, a logopenic variant of FTD has been identified, which is predominantly associated with amyloid-β pathology.31 . . .
    • . . . The clinical presentation of patients with semantic dementia is dominated by the progressive decline in language skills that primarily involve naming of objects and comprehension of words, while phonology and syntax are preserved.26 The key cognitive deficits are, theoretically, attributable to degeneration of a central amodal semantic hub.45, 46 The neural basis of semantic dementia has been studied extensively in vivo using a range of quantitative methods, as well as at postmortem.47, 48 Crucial brain regions that are involved from an early stage are the anterior fusiform gyrus (containing the perirhinal cortex), the temporal pole, the amygdala and the rostral hippocampus.47, 48, 49, 50 Functional connectivity studies have pointed to a role for disruption of a network involving the temporal pole, the subgenual cingulate area, the ventral striatum and the amygdala in the pathogenesis of semantic dementia (Figure 2).11, 51 . . .
  27. Neary, D. et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51, 1546-1554 , .
    • . . . Primary progressive aphasia can be further subdivided according to the predominant pattern of language breakdown into progressive nonfluent aphasia (PNFA) and semantic dementia.26, 27, 28, 29 The PNFA variant has proved informative in exploring the neuroanatomy of speech production and grammar.30 More recently, a logopenic variant of FTD has been identified, which is predominantly associated with amyloid-β pathology.31 . . .
    • . . . Unsurprisingly, patients with bvFTD demonstrate profound impairments in social cognitive abilities and, indeed, these deficits are necessary for the diagnosis of bvFTD.24, 27 Study of the progressive decline of social cognition in this disease could potentially inform our understanding of other conditions such as autistic spectrum disorders, in which social communication difficulties are prominent.99 . . .
  28. Gorno-Tempini, M. L. et al. Classification of primary progressive aphasia and its variants. Neurology 76, 1006-1014 , .
    • . . . Primary progressive aphasia can be further subdivided according to the predominant pattern of language breakdown into progressive nonfluent aphasia (PNFA) and semantic dementia.26, 27, 28, 29 The PNFA variant has proved informative in exploring the neuroanatomy of speech production and grammar.30 More recently, a logopenic variant of FTD has been identified, which is predominantly associated with amyloid-β pathology.31 . . .
  29. Seeley, W. W., Zhou, J. & Kim, E. J. Frontotemporal dementia: what can the behavioural variant teach us about human brain organization? Neuroscientist , .
    • . . . Primary progressive aphasia can be further subdivided according to the predominant pattern of language breakdown into progressive nonfluent aphasia (PNFA) and semantic dementia.26, 27, 28, 29 The PNFA variant has proved informative in exploring the neuroanatomy of speech production and grammar.30 More recently, a logopenic variant of FTD has been identified, which is predominantly associated with amyloid-β pathology.31 . . .
  30. Knibb, J. A., Woollams, A. M., Hodges, J. R. & Patterson, K. Making sense of progressive non-fluent aphasia: an analysis of conversational speech. Brain 132, 2734-2746 , .
    • . . . Primary progressive aphasia can be further subdivided according to the predominant pattern of language breakdown into progressive nonfluent aphasia (PNFA) and semantic dementia.26, 27, 28, 29 The PNFA variant has proved informative in exploring the neuroanatomy of speech production and grammar.30 More recently, a logopenic variant of FTD has been identified, which is predominantly associated with amyloid-β pathology.31 . . .
  31. Leyton, C. E. et al. Subtypes of progressive aphasia: application of the International Consensus Criteria and validation using β-amyloid imaging. Brain 134, 3030-3043 , .
  32. Mioshi, E., Bristow, M., Cook, R. & Hodges, J. R. Factors underlying caregiver stress in frontotemporal dementia and Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 27, 76-81 , .
    • . . . Patients with bvFTD present with progressive changes in social cognition, motivation and decision-making, which have a profound effect on their interpersonal conduct, and place considerable stress on family members.10, 23, 32 At a neural level, atrophy emerges first in the anterior cingulate and frontoinsular cortices, the dmPFC, and the frontal pole, striatum and thalamus (Table 1, Figure 2).33, 34, 35 As the disease progresses, pathology gradually spreads into adjacent frontal and temporal regions,36 with structures in the right hemisphere typically being more affected than those in the left hemisphere . . .
  33. Seeley, W. W. et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch. Neurol. 65, 249-255 , .
    • . . . Patients with bvFTD present with progressive changes in social cognition, motivation and decision-making, which have a profound effect on their interpersonal conduct, and place considerable stress on family members.10, 23, 32 At a neural level, atrophy emerges first in the anterior cingulate and frontoinsular cortices, the dmPFC, and the frontal pole, striatum and thalamus (Table 1, Figure 2).33, 34, 35 As the disease progresses, pathology gradually spreads into adjacent frontal and temporal regions,36 with structures in the right hemisphere typically being more affected than those in the left hemisphere . . .
  34. Broe, M. et al. Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology 60, 1005-1011 , .
    • . . . Patients with bvFTD present with progressive changes in social cognition, motivation and decision-making, which have a profound effect on their interpersonal conduct, and place considerable stress on family members.10, 23, 32 At a neural level, atrophy emerges first in the anterior cingulate and frontoinsular cortices, the dmPFC, and the frontal pole, striatum and thalamus (Table 1, Figure 2).33, 34, 35 As the disease progresses, pathology gradually spreads into adjacent frontal and temporal regions,36 with structures in the right hemisphere typically being more affected than those in the left hemisphere . . .
    • . . . The medial PFC has been implicated in enabling individuals to shift their perspective beyond the immediate present to represent themselves across subjective time.8, 85 Patients with frontal lobe damage are known to demonstrate deficits in planning actions for tasks that require foresight.86 The ability to think about the self and to focus attention on one's inner experience is clearly important for the process of future thinking,87, 88 and is posited to rely on the dmPFC subsystem of the default network.13 Future thinking has not yet been explored in bvFTD, but considerable impairments to this function are probable, given the early dmPFC atrophy.34 The hypothesized impaired capacity to engage in future thinking is likely to be multifactorial, arising from disrupted memory monitoring and executive dysfunction,89 reduced ability for self-reflection,90 loss of motivation,91 and a diminished sense of autonoetic consciousness.58, 90 . . .
  35. Schroeter, M. L., Raczka, K., Neumann, J. & von Cramon, D. Y. Neural networks in frontotemporal dementia-a meta-analysis. Neurobiol. Aging 29, 418-426 , .
    • . . . Patients with bvFTD present with progressive changes in social cognition, motivation and decision-making, which have a profound effect on their interpersonal conduct, and place considerable stress on family members.10, 23, 32 At a neural level, atrophy emerges first in the anterior cingulate and frontoinsular cortices, the dmPFC, and the frontal pole, striatum and thalamus (Table 1, Figure 2).33, 34, 35 As the disease progresses, pathology gradually spreads into adjacent frontal and temporal regions,36 with structures in the right hemisphere typically being more affected than those in the left hemisphere . . .
  36. Rabinovici, G. D. et al. Distinct MRI atrophy patterns in autopsy-proven Alzheimer's disease and frontotemporal lobar degeneration. Am. J. Alzheimers Dis. Other Demen. 22, 474-488 , .
    • . . . Patients with bvFTD present with progressive changes in social cognition, motivation and decision-making, which have a profound effect on their interpersonal conduct, and place considerable stress on family members.10, 23, 32 At a neural level, atrophy emerges first in the anterior cingulate and frontoinsular cortices, the dmPFC, and the frontal pole, striatum and thalamus (Table 1, Figure 2).33, 34, 35 As the disease progresses, pathology gradually spreads into adjacent frontal and temporal regions,36 with structures in the right hemisphere typically being more affected than those in the left hemisphere . . .
  37. Seeley, W. W. et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J. Neurosci. 27, 2349-2356 , .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli. . . .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
  38. Seeley, W. W. et al. Divergent social functioning in behavioral variant frontotemporal dementia and Alzheimer disease: reciprocal networks and neuronal evolution. Alzheimer. Dis. Assoc. Disord. 21, S50-S57 , .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
  39. Gregory, C. et al. Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer's disease: theoretical and practical implications. Brain 125, 752-764 , .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
  40. Torralva, T. et al. The relationship between affective decision-making and theory of mind in the frontal variant of fronto-temporal dementia. Neuropsychologia 45, 342-349 , .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
    • . . . Economic decision-making tasks have been shown to recruit the medial PFC, anterior cingulate cortex, and limbic structures such as the thalamus, amygdala and insula.117 A selective role for the ventromedial PFC in perceiving and monitoring risks and potentially associated losses has been proposed, suggesting involvement of the MTL default-network subsystem in these cognitive functions.118, 119 The ventromedial PFC is particularly vulnerable to atrophy in bvFTD, even in the very early stages of disease.120 Studies using the Iowa gambling task in patients with bvFTD have revealed substantial impairments in interpreting and using feedback from the task to adjust future decisions.40 Such patients seem to be aware of their risky choices but consistently choose disadvantageously,120 pointing towards the possible role of disinhibition and other aspects of executive dysfunction that could be particularly important for decision-making in risky or ambiguous situations.117, 121 Interestingly, poor economic and moral decision-making following orbitofrontal damage may stem from an inability to self-project to consider or simulate the possible future outcomes of actions.122 Healthy individuals benefit from envisioning future scenarios to reduce the likelihood of impulsive discounting,123 whereas patients with damage to midline structures necessary for self-projection tend to value immediate rather than future gain . . .
  41. Lough, S. et al. Social reasoning, emotion and empathy in frontotemporal dementia. Neuropsychologia 44, 950-958 , .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
    • . . . The ability to imagine oneself in the future is an adaptive behavior, as the mental simulation of possible future outcomes helps an individual to maximize positive outcomes and avoid negative ones.12 Moral reasoning relies on the integration of several self-projective cognitive processes that use social semantic knowledge represented in the anterior temporal cortex,109 and motivational and emotional states associated with activation of cortical–limbic circuits.114 Indeed, resolution of moral dilemmas is the type of situation in which alternative events must be simulated.2, 109 Importantly, certain forms of moral decision-making have been shown to activate default-network regions, such as the PFC and anterior temporal regions.109, 114 Moral reasoning is, unsurprisingly, substantially compromised in bvFTD.42, 115 Such socially relevant decision-making is more impaired in bvFTD than in semantic dementia, and the extent of impairment in bvFTD may reflect compromised theory of mind and reduced cognitive flexibility,41 as well as a lack of empathy (as rated by caregivers).107 . . .
  42. Mendez, M. F. What frontotemporal dementia reveals about the neurobiological basis of morality. Med. Hypotheses 67, 411-418 , .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
    • . . . The ability to imagine oneself in the future is an adaptive behavior, as the mental simulation of possible future outcomes helps an individual to maximize positive outcomes and avoid negative ones.12 Moral reasoning relies on the integration of several self-projective cognitive processes that use social semantic knowledge represented in the anterior temporal cortex,109 and motivational and emotional states associated with activation of cortical–limbic circuits.114 Indeed, resolution of moral dilemmas is the type of situation in which alternative events must be simulated.2, 109 Importantly, certain forms of moral decision-making have been shown to activate default-network regions, such as the PFC and anterior temporal regions.109, 114 Moral reasoning is, unsurprisingly, substantially compromised in bvFTD.42, 115 Such socially relevant decision-making is more impaired in bvFTD than in semantic dementia, and the extent of impairment in bvFTD may reflect compromised theory of mind and reduced cognitive flexibility,41 as well as a lack of empathy (as rated by caregivers).107 . . .
  43. Rankin, K. P. et al. Detecting sarcasm from paralinguistic cues: anatomic and cognitive correlates in neurodegenerative disease. NeuroImage 47, 2005-2015 , .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
  44. Kumfor, F. et al. Are you really angry? The effect of intensity on facial emotion recognition in frontotemporal dementia. Soc. Neurosci. 6, 502-514 , .
    • . . . Functional connectivity studies have been important in elucidating the disruption of a largely anterior network in bvFTD, termed the salience network.16, 37 This network is thought to underpin neural activity in response to emotion-related internal and external stimuli.16, 37, 38 Changes in theory of mind,39, 40 moral reasoning,41, 42 and emotion processing43, 44 are well-documented in bvFTD . . .
    • . . . Perception of emotion has recently been shown to be compromised in semantic dementia to a level similar to that seen in bvFTD.44, 105 Patients with semantic dementia can display reduced empathy,106 although this finding has not been consistently demonstrated.107 . . .
  45. Patterson, K., Nestor, P. & Rogers, T. Where do you know what you know? The representation of semantic knowledge in the human brain. Nat. Rev. Neurosci. 8, 976-987 , .
    • . . . The clinical presentation of patients with semantic dementia is dominated by the progressive decline in language skills that primarily involve naming of objects and comprehension of words, while phonology and syntax are preserved.26 The key cognitive deficits are, theoretically, attributable to degeneration of a central amodal semantic hub.45, 46 The neural basis of semantic dementia has been studied extensively in vivo using a range of quantitative methods, as well as at postmortem.47, 48 Crucial brain regions that are involved from an early stage are the anterior fusiform gyrus (containing the perirhinal cortex), the temporal pole, the amygdala and the rostral hippocampus.47, 48, 49, 50 Functional connectivity studies have pointed to a role for disruption of a network involving the temporal pole, the subgenual cingulate area, the ventral striatum and the amygdala in the pathogenesis of semantic dementia (Figure 2).11, 51 . . .
  46. Rogers, T. T. et al. Structure and deterioration of semantic memory: a neuropsychological and computational investigation. Psychol. Rev. 111, 205-235 , .
    • . . . The clinical presentation of patients with semantic dementia is dominated by the progressive decline in language skills that primarily involve naming of objects and comprehension of words, while phonology and syntax are preserved.26 The key cognitive deficits are, theoretically, attributable to degeneration of a central amodal semantic hub.45, 46 The neural basis of semantic dementia has been studied extensively in vivo using a range of quantitative methods, as well as at postmortem.47, 48 Crucial brain regions that are involved from an early stage are the anterior fusiform gyrus (containing the perirhinal cortex), the temporal pole, the amygdala and the rostral hippocampus.47, 48, 49, 50 Functional connectivity studies have pointed to a role for disruption of a network involving the temporal pole, the subgenual cingulate area, the ventral striatum and the amygdala in the pathogenesis of semantic dementia (Figure 2).11, 51 . . .
  47. Davies, R. R., Graham, K. S., Xuereb, J. H., Williams, G. B. & Hodges, J. R. The human perirhinal cortex and semantic memory. Eur. J. Neurosci. 20, 2441-2446 , .
    • . . . The clinical presentation of patients with semantic dementia is dominated by the progressive decline in language skills that primarily involve naming of objects and comprehension of words, while phonology and syntax are preserved.26 The key cognitive deficits are, theoretically, attributable to degeneration of a central amodal semantic hub.45, 46 The neural basis of semantic dementia has been studied extensively in vivo using a range of quantitative methods, as well as at postmortem.47, 48 Crucial brain regions that are involved from an early stage are the anterior fusiform gyrus (containing the perirhinal cortex), the temporal pole, the amygdala and the rostral hippocampus.47, 48, 49, 50 Functional connectivity studies have pointed to a role for disruption of a network involving the temporal pole, the subgenual cingulate area, the ventral striatum and the amygdala in the pathogenesis of semantic dementia (Figure 2).11, 51 . . .
    • . . . The pattern of hippocampal degeneration, however, differs between the two diseases: in semantic dementia, the anterior (rostral) segment is the predominant region to be affected, whereas in AD the atrophy involves rostral and caudal portions of the hippocampus equally.47, 48, 49, 84 Crucially, the hippocampal atrophy in semantic dementia is accompanied by severe temporal lobe neocortical atrophy, which disrupts the semantic memory system.48 . . .
  48. Galton, C. et al. Differing patterns of temporal atrophy in Alzheimer's disease and semantic dementia. Neurology 57, 216-225 , .
  49. Chan, D. et al. Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease. Ann. Neurol. 49, 433-442 , .
    • . . . The clinical presentation of patients with semantic dementia is dominated by the progressive decline in language skills that primarily involve naming of objects and comprehension of words, while phonology and syntax are preserved.26 The key cognitive deficits are, theoretically, attributable to degeneration of a central amodal semantic hub.45, 46 The neural basis of semantic dementia has been studied extensively in vivo using a range of quantitative methods, as well as at postmortem.47, 48 Crucial brain regions that are involved from an early stage are the anterior fusiform gyrus (containing the perirhinal cortex), the temporal pole, the amygdala and the rostral hippocampus.47, 48, 49, 50 Functional connectivity studies have pointed to a role for disruption of a network involving the temporal pole, the subgenual cingulate area, the ventral striatum and the amygdala in the pathogenesis of semantic dementia (Figure 2).11, 51 . . .
    • . . . The pattern of hippocampal degeneration, however, differs between the two diseases: in semantic dementia, the anterior (rostral) segment is the predominant region to be affected, whereas in AD the atrophy involves rostral and caudal portions of the hippocampus equally.47, 48, 49, 84 Crucially, the hippocampal atrophy in semantic dementia is accompanied by severe temporal lobe neocortical atrophy, which disrupts the semantic memory system.48 . . .
  50. Mion, M. et al. What the left and right anterior fusiform gyri tell us about semantic memory. Brain 133, 3256-3268 , .
    • . . . The clinical presentation of patients with semantic dementia is dominated by the progressive decline in language skills that primarily involve naming of objects and comprehension of words, while phonology and syntax are preserved.26 The key cognitive deficits are, theoretically, attributable to degeneration of a central amodal semantic hub.45, 46 The neural basis of semantic dementia has been studied extensively in vivo using a range of quantitative methods, as well as at postmortem.47, 48 Crucial brain regions that are involved from an early stage are the anterior fusiform gyrus (containing the perirhinal cortex), the temporal pole, the amygdala and the rostral hippocampus.47, 48, 49, 50 Functional connectivity studies have pointed to a role for disruption of a network involving the temporal pole, the subgenual cingulate area, the ventral striatum and the amygdala in the pathogenesis of semantic dementia (Figure 2).11, 51 . . .
  51. Brambati, S. M. et al. Atrophy progression in semantic dementia with asymmetric temporal involvement: a tensor-based morphometry study. Neurobiol. Aging 30, 103-111 , .
  52. Binder, J. R. et al. Conceptual processing during the conscious resting state. A functional MRI study. J. Cogn. Neurosci. 11, 80-95 , .
    • . . . The neural systems specialized for the storage and retrieval of semantic knowledge show considerable overlap with brain regions that show activation when an individual is not engaged by the immediate external environment.52, 53, 54 This finding has led to the proposal that semantic processing constitutes a large component of brain activity when individuals are left to think to themselves and engage in internal mentation or introspection.52 If this scenario holds true, the progressive and crossmodal loss of semantic knowledge, as occurs in semantic dementia, may adversely affect cognitive functions that are posited to recruit structures of the default network. . . .
    • . . . A striking overlap exists between the neural network of the semantic system that is thought to underpin much of the default-mode introspective activity in individuals when left to think to themselves52 and a large-scale network involved in the retrieval of autobiographical memories.66, 67 The study of autobiographical memory in semantic dementia is of particular interest in this context, by enabling the importance of semantic processing for self-projection to the past to be investigated . . .
  53. Binder, J. R., Desai, R. H., Graves, W. W. & Conant, L. L. Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies. Cereb. Cortex 19, 2767-2796 , .
    • . . . The neural systems specialized for the storage and retrieval of semantic knowledge show considerable overlap with brain regions that show activation when an individual is not engaged by the immediate external environment.52, 53, 54 This finding has led to the proposal that semantic processing constitutes a large component of brain activity when individuals are left to think to themselves and engage in internal mentation or introspection.52 If this scenario holds true, the progressive and crossmodal loss of semantic knowledge, as occurs in semantic dementia, may adversely affect cognitive functions that are posited to recruit structures of the default network. . . .
  54. Greicius, M. D., Krasnow, B., Reiss, A. L. & Menon, V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc. Natl Acad. Sci. USA 100, 253-258 , .
    • . . . The neural systems specialized for the storage and retrieval of semantic knowledge show considerable overlap with brain regions that show activation when an individual is not engaged by the immediate external environment.52, 53, 54 This finding has led to the proposal that semantic processing constitutes a large component of brain activity when individuals are left to think to themselves and engage in internal mentation or introspection.52 If this scenario holds true, the progressive and crossmodal loss of semantic knowledge, as occurs in semantic dementia, may adversely affect cognitive functions that are posited to recruit structures of the default network. . . .
  55. Conway, M. A., Singer, J. A. & Tagini, A. The self and autobiographical memory: correspondence and coherence. Soc. Cogn. 22, 491-529 , .
    • . . . Autobiographical memory refers to the shifting of perspective from the present to past personal events, thereby allowing an individual to maintain a sense of self and continuity across subjective time.55 Studies of autobiographical memory in people with FTD have shown that the profile of memory retrieval across the lifespan depends on the disease subtype . . .
  56. Irish, M. et al. Profiles of recent autobiographical memory retrieval in semantic dementia, behavioural-variant frontotemporal dementia, and Alzheimer's disease. Neuropsychologia 49, 2694-2702 , .
    • . . . Most studies of autobiographical memory retrieval in bvFTD have revealed severe and global deficits in this cognitive function, irrespective of the specific memory task or life epoch under consideration.56, 57, 58 Retrieval of specific autobiographical memories in the early stages of the disease process is affected to the same extent in cases of bvFTD as in patients with AD who are matched for disease severity.56 The consequences of the regional atrophy pattern of bvFTD are generally thought to be impairments in introspective and socio-emotional functions . . .
    • . . . This pattern of memory loss is referred to as a reverse temporal gradient or, more correctly, a step function,56, 68, 69, 70, 71 but has not always been reported.72, 73 The pathology that affects the anterior temporal lobe in semantic dementia probably disrupts the integration of semantic and sensory information into a coherent spatial context to form a mental scene,63 which is essential for the retrieval of past events and the imagining of future experiences.63, 74 . . .
    • . . . Alternatively, given that episodic retrieval from the past is crucial for the ability to simulate possible future events,75 the relative preservation of recent autobiographical memory in this disease56, 58, 71 could imply a spared capacity for future thinking . . .
    • . . . The first hypothesis is based on the proposal that the capacity to infer the intentions of others relies on the ability to consciously recollect past occurrences via autobiographical memory.8, 12 Accordingly, patients with semantic dementia would be expected to pass standard tests of theory of mind, given their largely preserved retrieval of recent memories.56 The second hypothesis is based on reports in two patients with severe amnesia following traumatic brain injury, who showed intact theory of mind ability, possibly reflecting their largely intact semantic and general knowledge abilities.108 According to this hypothesis, the progressive semantic breakdown that characterizes semantic dementia might be expected to disrupt the semantic underpinnings of social cognition, such as knowledge of rules and behaviors in various social situations. . . .
  57. Matuszewski, V. et al. Retrieval mechanisms for autobiographical memories: insights from the frontal variant of frontotemporal dementia. Neuropsychologia 44, 2386-2397 , .
    • . . . Most studies of autobiographical memory retrieval in bvFTD have revealed severe and global deficits in this cognitive function, irrespective of the specific memory task or life epoch under consideration.56, 57, 58 Retrieval of specific autobiographical memories in the early stages of the disease process is affected to the same extent in cases of bvFTD as in patients with AD who are matched for disease severity.56 The consequences of the regional atrophy pattern of bvFTD are generally thought to be impairments in introspective and socio-emotional functions . . .
    • . . . Such disruption reflects the importance of executive functions mediated by anterior brain regions—including searching, verification and monitoring of information—in successful retrieval of autobiographical memory.57, 59 . . .
    • . . . With disease progression and advancing atrophy into another component of the default network, the lateral temporal cortex, the integrity of the autobiographical memory system in these patients is probably also affected by compromise of semantic and constructive processes,57, 63 which are known to be essential for the retrieval of such memories.57, 63, 64, 65 . . .
  58. Piolino, P. et al. Autobiographical memory and autonoetic consciousness: triple dissociation in neurodegenerative diseases. Brain 126, 2203-2219 , .
    • . . . Most studies of autobiographical memory retrieval in bvFTD have revealed severe and global deficits in this cognitive function, irrespective of the specific memory task or life epoch under consideration.56, 57, 58 Retrieval of specific autobiographical memories in the early stages of the disease process is affected to the same extent in cases of bvFTD as in patients with AD who are matched for disease severity.56 The consequences of the regional atrophy pattern of bvFTD are generally thought to be impairments in introspective and socio-emotional functions . . .
    • . . . Alternatively, given that episodic retrieval from the past is crucial for the ability to simulate possible future events,75 the relative preservation of recent autobiographical memory in this disease56, 58, 71 could imply a spared capacity for future thinking . . .
    • . . . The medial PFC has been implicated in enabling individuals to shift their perspective beyond the immediate present to represent themselves across subjective time.8, 85 Patients with frontal lobe damage are known to demonstrate deficits in planning actions for tasks that require foresight.86 The ability to think about the self and to focus attention on one's inner experience is clearly important for the process of future thinking,87, 88 and is posited to rely on the dmPFC subsystem of the default network.13 Future thinking has not yet been explored in bvFTD, but considerable impairments to this function are probable, given the early dmPFC atrophy.34 The hypothesized impaired capacity to engage in future thinking is likely to be multifactorial, arising from disrupted memory monitoring and executive dysfunction,89 reduced ability for self-reflection,90 loss of motivation,91 and a diminished sense of autonoetic consciousness.58, 90 . . .
  59. Piolino, P. et al. In search of autobiographical memories: a PET study in the frontal variant of frontotemporal dementia. Neuropsychologia 45, 2730-2743 , .
  60. Williamson, C. et al. Standardised measurement of self-awareness deficits in FTD and AD. J. Neurol. Neurosurg. Psychiatry 81, 140-145 , .
    • . . . The contribution of the PFC to autobiographical memory, particularly in relation to the self-reflective impairments in bvFTD,60 remains poorly understood.61 Recent evidence of early atrophy in other components of the default network—namely, the hippocampus and parahippocampal gyrus—in patients with bvFTD62 suggests that MTL degeneration, in addition to PFC damage, might contribute to disruption of autobiographical memory in this patient group . . .
  61. McKinnon, M. et al. Autobiographical memory and patterns of brain atrophy in fronto-temporal lobar degeneration. J. Cogn. Neurosci. 20, 1839-1853 , .
    • . . . The contribution of the PFC to autobiographical memory, particularly in relation to the self-reflective impairments in bvFTD,60 remains poorly understood.61 Recent evidence of early atrophy in other components of the default network—namely, the hippocampus and parahippocampal gyrus—in patients with bvFTD62 suggests that MTL degeneration, in addition to PFC damage, might contribute to disruption of autobiographical memory in this patient group . . .
  62. Whitwell, J. L. et al. Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study. Brain 132, 2932-2946 , .
    • . . . The contribution of the PFC to autobiographical memory, particularly in relation to the self-reflective impairments in bvFTD,60 remains poorly understood.61 Recent evidence of early atrophy in other components of the default network—namely, the hippocampus and parahippocampal gyrus—in patients with bvFTD62 suggests that MTL degeneration, in addition to PFC damage, might contribute to disruption of autobiographical memory in this patient group . . .
    • . . . However, investigating disruption of the neural hubs (anterior medial PFC and posterior cingulate cortex) in FTD syndromes will also be useful, given that these midline core regions robustly activate during retrieval of real autobiographical memories but not those of fictitious experiences,127, 128 and are consistently implicated in self-referential introspective abilities.13, 129 Furthermore, given that atrophy of the anterior medial PFC is common in bvFTD,62 whereas the posterior cingulate is one of the earliest regions of disruption in AD,84 relative performance on tasks that do or do not require self-relevant introspection might be expected to differ between dementia subtypes . . .
  63. Hassabis, D. & Maguire, E. A. Deconstructing episodic memory with construction. Trends Cogn. Sci. 11, 299-306 , .
    • . . . With disease progression and advancing atrophy into another component of the default network, the lateral temporal cortex, the integrity of the autobiographical memory system in these patients is probably also affected by compromise of semantic and constructive processes,57, 63 which are known to be essential for the retrieval of such memories. . . .
    • . . . With disease progression and advancing atrophy into another component of the default network, the lateral temporal cortex, the integrity of the autobiographical memory system in these patients is probably also affected by compromise of semantic and constructive processes,57, 63 which are known to be essential for the retrieval of such memories.57, 63, 64, 65 . . .
    • . . . This pattern of memory loss is referred to as a reverse temporal gradient or, more correctly, a step function,56, 68, 69, 70, 71 but has not always been reported.72, 73 The pathology that affects the anterior temporal lobe in semantic dementia probably disrupts the integration of semantic and sensory information into a coherent spatial context to form a mental scene,63 which is essential for the retrieval of past events and the imagining of future experiences.63, 74 . . .
    • . . . Even if past episodic details can be retrieved by patients with semantic dementia, we anticipate that the marked hippocampal atrophy in this patient group48 will impair the subsequent recombination of these details into a specific78 and spatially coherent63 novel simulation. . . .
  64. Gilboa, A. Autobiographical and episodic memory-one and the same? Evidence from prefrontal activation in neuroimaging studies. Neuropsychologia 42, 1336-1349 , .
    • . . . With disease progression and advancing atrophy into another component of the default network, the lateral temporal cortex, the integrity of the autobiographical memory system in these patients is probably also affected by compromise of semantic and constructive processes,57, 63 which are known to be essential for the retrieval of such memories.57, 63, 64, 65 . . .
  65. Greenberg, D. L. & Verfaellie, M. Interdependence of episodic and semantic memory: evidence from neuropsychology. J. Int. Neuropsychol. Soc. 16, 748-753 , .
  66. Maguire, E. A. Neuroimaging studies of autobiographical event memory. Philos. Trans. R. Soc. Lond. B Biol. Sci. 356, 1441-1451 , .
    • . . . A striking overlap exists between the neural network of the semantic system that is thought to underpin much of the default-mode introspective activity in individuals when left to think to themselves52 and a large-scale network involved in the retrieval of autobiographical memories.66, 67 The study of autobiographical memory in semantic dementia is of particular interest in this context, by enabling the importance of semantic processing for self-projection to the past to be investigated . . .
  67. Svoboda, E., McKinnon, M. C. & Levine, B. The functional neuroanatomy of autobiographical memory: a meta-analysis. Neuropsychologia 44, 2189-2208 , .
    • . . . A striking overlap exists between the neural network of the semantic system that is thought to underpin much of the default-mode introspective activity in individuals when left to think to themselves52 and a large-scale network involved in the retrieval of autobiographical memories.66, 67 The study of autobiographical memory in semantic dementia is of particular interest in this context, by enabling the importance of semantic processing for self-projection to the past to be investigated . . .
  68. Nestor, P. J., Graham, K. S., Bozeat, S., Simons, J. S. & Hodges, J. R. Memory consolidation and the hippocampus: further evidence from studies of autobiographical memory in semantic dementia and frontal variant frontotemporal dementia. Neuropsychologia 40, 633-654 , .
    • . . . This pattern of memory loss is referred to as a reverse temporal gradient or, more correctly, a step function,56, 68, 69, 70, 71 but has not always been reported.72, 73 The pathology that affects the anterior temporal lobe in semantic dementia probably disrupts the integration of semantic and sensory information into a coherent spatial context to form a mental scene,63 which is essential for the retrieval of past events and the imagining of future experiences.63, 74 . . .
  69. Graham, K. & Hodges, J. Differentiating the roles of the hippocampal complex and the neocortex in long-term memory storage: evidence from the study of semantic dementia and Alzheimer's disease. Neuropsychology 11, 77-89 , .
    • . . . This pattern of memory loss is referred to as a reverse temporal gradient or, more correctly, a step function,56, 68, 69, 70, 71 but has not always been reported.72, 73 The pathology that affects the anterior temporal lobe in semantic dementia probably disrupts the integration of semantic and sensory information into a coherent spatial context to form a mental scene,63 which is essential for the retrieval of past events and the imagining of future experiences.63, 74 . . .
  70. Hou, C., Miller, B. & Kramer, J. Patterns of autobiographical memory loss in dementia. Int. J. Geriatr. Psychiatry 20, 809-815 , .
    • . . . This pattern of memory loss is referred to as a reverse temporal gradient or, more correctly, a step function,56, 68, 69, 70, 71 but has not always been reported.72, 73 The pathology that affects the anterior temporal lobe in semantic dementia probably disrupts the integration of semantic and sensory information into a coherent spatial context to form a mental scene,63 which is essential for the retrieval of past events and the imagining of future experiences.63, 74 . . .
  71. Matuszewski, V. et al. Patterns of autobiographical memory impairment according to disease severity in semantic dementia. Cortex 45, 456-472 , .
    • . . . This pattern of memory loss is referred to as a reverse temporal gradient or, more correctly, a step function,56, 68, 69, 70, 71 but has not always been reported.72, 73 The pathology that affects the anterior temporal lobe in semantic dementia probably disrupts the integration of semantic and sensory information into a coherent spatial context to form a mental scene,63 which is essential for the retrieval of past events and the imagining of future experiences.63, 74 . . .
    • . . . As in bvFTD, disease severity affects autobiographical memory retrieval in semantic dementia: as the disease progresses, recent autobiographical memories can also become disrupted.71 Importantly, despite pronounced atrophy of key regions in the dmPFC subsystem (the temporal pole and lateral temporal cortex) and the MTL subsystem (the hippocampus) of the default network, possible compensatory mechanisms involving the ventromedial and ventrolateral PFC, the right temporal neocortex and the precuneus seem to facilitate the retrieval of autobiographical memory in semantic dementia.72 . . .
    • . . . Alternatively, given that episodic retrieval from the past is crucial for the ability to simulate possible future events,75 the relative preservation of recent autobiographical memory in this disease56, 58, 71 could imply a spared capacity for future thinking . . .
  72. Maguire, E. A., Kumaran, D., Hassabis, D. & Kopelman, M. D. Autobiographical memory in semantic dementia: a longitudinal fMRI study. Neuropsychologia 48, 123-136 , .
  73. McKinnon, M., Black, S., Miller, B., Moscovitch, M. & Levine, B. Autobiographical memory in semantic dementia: implications for theories of limbic-neocortical interaction in remote memory. Neuropsychologia 44, 2421-2429 , .
    • . . . This pattern of memory loss is referred to as a reverse temporal gradient or, more correctly, a step function,56, 68, 69, 70, 71 but has not always been reported.72, 73 The pathology that affects the anterior temporal lobe in semantic dementia probably disrupts the integration of semantic and sensory information into a coherent spatial context to form a mental scene,63 which is essential for the retrieval of past events and the imagining of future experiences.63, 74 . . .
  74. Schacter, D., Addis, D. & Buckner, R. Remembering the past to imagine the future: the prospective brain. Nat. Rev. Neurosci. 8, 657-661 , .
  75. Addis, D. R., Wong, A. T. & Schacter, D. L. Remembering the past and imagining the future: common and distinct neural substrates during event construction and elaboration. Neuropsychologia 45, 1363-1377 , .
    • . . . An adaptive feature of the episodic memory system lies in enabling the simulation of future occurrences,74 pointing towards a possible common set of processes mediating the ability to remember the past and imagine the future.75 The neural architecture that is consistently implicated in future simulation includes MTL structures76 and medial frontal regions77 of the default network . . .
    • . . . Alternatively, given that episodic retrieval from the past is crucial for the ability to simulate possible future events,75 the relative preservation of recent autobiographical memory in this disease56, 58, 71 could imply a spared capacity for future thinking . . .
  76. Schacter, D. L. & Addis, D. R. On the nature of medial temporal lobe contributions to the constructive simulation of future events. Philos. Trans. R. Soc. Lond. B Biol. Sci. 364, 1245-1253 , .
    • . . . An adaptive feature of the episodic memory system lies in enabling the simulation of future occurrences,74 pointing towards a possible common set of processes mediating the ability to remember the past and imagine the future.75 The neural architecture that is consistently implicated in future simulation includes MTL structures76 and medial frontal regions77 of the default network . . .
  77. Wheeler, M. A., Stuss, D. T. & Tulving, E. T. Toward a theory of episodic memory: the frontal lobes and autonoetic consciousness. Psychol. Bull. 121, 331-354 , .
    • . . . An adaptive feature of the episodic memory system lies in enabling the simulation of future occurrences,74 pointing towards a possible common set of processes mediating the ability to remember the past and imagine the future.75 The neural architecture that is consistently implicated in future simulation includes MTL structures76 and medial frontal regions77 of the default network . . .
  78. Addis, D. R., Cheng, T., Roberts, R. P. & Schacter, D. L. Hippocampal contributions to the episodic simulation of specific and general future events. Hippocampus 21, 1045-1052 , .
    • . . . A key role in this process—not only in the retrieval of relevant details from episodic memory to be used in future constructions, but also in the integration of such details into a coherent event—has been ascribed to the hippocampus.78 Damage to the episodic memory system is proposed to compromise the ability to generate simulations of future events.79 Indeed, recent reports have confirmed that patients with mild AD display an impaired capacity both for remembering past autobiographical events and for imagining personal future events.21 This finding concords with growing evidence that patients with bilateral hippocampal damage and intact premorbid semantic memory,80 healthy elderly adults,81 and individuals with mild cognitive impairment22 all experience difficulties in imagining specific future episodes. . . .
    • . . . Even if past episodic details can be retrieved by patients with semantic dementia, we anticipate that the marked hippocampal atrophy in this patient group48 will impair the subsequent recombination of these details into a specific78 and spatially coherent63 novel simulation. . . .
  79. Schacter, D. & Addis, D. On the constructive episodic simulation of past and future events. Behav. Brain Sci. 30, 331-332 , .
    • . . . A key role in this process—not only in the retrieval of relevant details from episodic memory to be used in future constructions, but also in the integration of such details into a coherent event—has been ascribed to the hippocampus.78 Damage to the episodic memory system is proposed to compromise the ability to generate simulations of future events.79 Indeed, recent reports have confirmed that patients with mild AD display an impaired capacity both for remembering past autobiographical events and for imagining personal future events.21 This finding concords with growing evidence that patients with bilateral hippocampal damage and intact premorbid semantic memory,80 healthy elderly adults,81 and individuals with mild cognitive impairment22 all experience difficulties in imagining specific future episodes. . . .
  80. Hassabis, D., Kumaran, D., Vann, S. & Maguire, E. Patients with hippocampal amnesia cannot imagine new experiences. Proc. Natl Acad. Sci. USA 104, 1726-1731 , .
    • . . . A key role in this process—not only in the retrieval of relevant details from episodic memory to be used in future constructions, but also in the integration of such details into a coherent event—has been ascribed to the hippocampus.78 Damage to the episodic memory system is proposed to compromise the ability to generate simulations of future events.79 Indeed, recent reports have confirmed that patients with mild AD display an impaired capacity both for remembering past autobiographical events and for imagining personal future events.21 This finding concords with growing evidence that patients with bilateral hippocampal damage and intact premorbid semantic memory,80 healthy elderly adults,81 and individuals with mild cognitive impairment22 all experience difficulties in imagining specific future episodes. . . .
  81. Addis, D. R., Wong, A. T. & Schacter, D. L. Age-related changes in the episodic simulation of future events. Psychol. Sci. 19, 33-41 , .
    • . . . A key role in this process—not only in the retrieval of relevant details from episodic memory to be used in future constructions, but also in the integration of such details into a coherent event—has been ascribed to the hippocampus.78 Damage to the episodic memory system is proposed to compromise the ability to generate simulations of future events.79 Indeed, recent reports have confirmed that patients with mild AD display an impaired capacity both for remembering past autobiographical events and for imagining personal future events.21 This finding concords with growing evidence that patients with bilateral hippocampal damage and intact premorbid semantic memory,80 healthy elderly adults,81 and individuals with mild cognitive impairment22 all experience difficulties in imagining specific future episodes. . . .
  82. Maguire, E. A., Vargha-Khadem, F. & Hassabis, D. Imagining fictitious and future experiences: evidence from developmental amnesia. Neuropsychologia 48, 3187-3192 , .
    • . . . Recent studies have suggested that in patients with developmental amnesia due to hippocampal damage, semantic information might facilitate the construction of imagined experiences.82, 83 . . .
  83. Hurley, N. C., Maguire, E. A. & Vargha-Khadem, F. Patient HC with developmental amnesia can construct future scenarios. Neuropsychologia 49, 3620-3628 , .
  84. Nestor, P. J., Fryer, T. D. & Hodges, J. R. Declarative memory impairments in Alzheimer's disease and semantic dementia. NeuroImage 30, 1010-1020 , .
    • . . . The pattern of hippocampal degeneration, however, differs between the two diseases: in semantic dementia, the anterior (rostral) segment is the predominant region to be affected, whereas in AD the atrophy involves rostral and caudal portions of the hippocampus equally.47, 48, 49, 84 Crucially, the hippocampal atrophy in semantic dementia is accompanied by severe temporal lobe neocortical atrophy, which disrupts the semantic memory system.48 . . .
    • . . . However, investigating disruption of the neural hubs (anterior medial PFC and posterior cingulate cortex) in FTD syndromes will also be useful, given that these midline core regions robustly activate during retrieval of real autobiographical memories but not those of fictitious experiences,127, 128 and are consistently implicated in self-referential introspective abilities.13, 129 Furthermore, given that atrophy of the anterior medial PFC is common in bvFTD,62 whereas the posterior cingulate is one of the earliest regions of disruption in AD,84 relative performance on tasks that do or do not require self-relevant introspection might be expected to differ between dementia subtypes . . .
  85. Tulving, E. T. Memory and consciousness. Can. Psychol. 26, 1-12 , .
    • . . . The medial PFC has been implicated in enabling individuals to shift their perspective beyond the immediate present to represent themselves across subjective time.8, 85 Patients with frontal lobe damage are known to demonstrate deficits in planning actions for tasks that require foresight.86 The ability to think about the self and to focus attention on one's inner experience is clearly important for the process of future thinking,87, 88 and is posited to rely on the dmPFC subsystem of the default network.13 Future thinking has not yet been explored in bvFTD, but considerable impairments to this function are probable, given the early dmPFC atrophy.34 The hypothesized impaired capacity to engage in future thinking is likely to be multifactorial, arising from disrupted memory monitoring and executive dysfunction,89 reduced ability for self-reflection,90 loss of motivation,91 and a diminished sense of autonoetic consciousness.58, 90 . . .
  86. Shallice, T. Specific impairments of planning. Philos. Trans. R. Soc. Lond. B Biol. Sci. 298, 199-209 , .
    • . . . The medial PFC has been implicated in enabling individuals to shift their perspective beyond the immediate present to represent themselves across subjective time.8, 85 Patients with frontal lobe damage are known to demonstrate deficits in planning actions for tasks that require foresight.86 The ability to think about the self and to focus attention on one's inner experience is clearly important for the process of future thinking,87, 88 and is posited to rely on the dmPFC subsystem of the default network.13 Future thinking has not yet been explored in bvFTD, but considerable impairments to this function are probable, given the early dmPFC atrophy.34 The hypothesized impaired capacity to engage in future thinking is likely to be multifactorial, arising from disrupted memory monitoring and executive dysfunction,89 reduced ability for self-reflection,90 loss of motivation,91 and a diminished sense of autonoetic consciousness.58, 90 . . .
  87. Rathbone, C. J., Conway, M. A. & Moulin, C. J. Remembering and imagining: the role of the self. Conscious. Cogn. 20, 1175-1182 , .
    • . . . The medial PFC has been implicated in enabling individuals to shift their perspective beyond the immediate present to represent themselves across subjective time.8, 85 Patients with frontal lobe damage are known to demonstrate deficits in planning actions for tasks that require foresight.86 The ability to think about the self and to focus attention on one's inner experience is clearly important for the process of future thinking,87, 88 and is posited to rely on the dmPFC subsystem of the default network.13 Future thinking has not yet been explored in bvFTD, but considerable impairments to this function are probable, given the early dmPFC atrophy.34 The hypothesized impaired capacity to engage in future thinking is likely to be multifactorial, arising from disrupted memory monitoring and executive dysfunction,89 reduced ability for self-reflection,90 loss of motivation,91 and a diminished sense of autonoetic consciousness.58, 90 . . .
  88. D'Argembeau, A., Ortoleva, C., Jumentier, S. & Van der Linden, M. Component processes underlying future thinking. Mem. Cognit. 38, 809-819 , .
    • . . . The medial PFC has been implicated in enabling individuals to shift their perspective beyond the immediate present to represent themselves across subjective time.8, 85 Patients with frontal lobe damage are known to demonstrate deficits in planning actions for tasks that require foresight.86 The ability to think about the self and to focus attention on one's inner experience is clearly important for the process of future thinking,87, 88 and is posited to rely on the dmPFC subsystem of the default network.13 Future thinking has not yet been explored in bvFTD, but considerable impairments to this function are probable, given the early dmPFC atrophy.34 The hypothesized impaired capacity to engage in future thinking is likely to be multifactorial, arising from disrupted memory monitoring and executive dysfunction,89 reduced ability for self-reflection,90 loss of motivation,91 and a diminished sense of autonoetic consciousness.58, 90 . . .
  89. Souchay, C., Isingrini, M., Pillon, B. & Gil, R. Metamemory accuracy in Alzheimer's disease and frontotemporal lobe dementia. Neurocase 9, 482-492 , .
    • . . . The medial PFC has been implicated in enabling individuals to shift their perspective beyond the immediate present to represent themselves across subjective time.8, 85 Patients with frontal lobe damage are known to demonstrate deficits in planning actions for tasks that require foresight.86 The ability to think about the self and to focus attention on one's inner experience is clearly important for the process of future thinking,87, 88 and is posited to rely on the dmPFC subsystem of the default network.13 Future thinking has not yet been explored in bvFTD, but considerable impairments to this function are probable, given the early dmPFC atrophy.34 The hypothesized impaired capacity to engage in future thinking is likely to be multifactorial, arising from disrupted memory monitoring and executive dysfunction,89 reduced ability for self-reflection,90 loss of motivation,91 and a diminished sense of autonoetic consciousness.58, 90 . . .
  90. Bastin, C. et al. Frontal and posterior cingulate metabolic impairment in the behavioral variant of frontotemporal dementia with impaired autonoetic consciousness. Hum. Brain Mapp. , .
  91. Zamboni, G., Huey, E. D., Krueger, F., Nichelli, P. F. & Grafman, J. Apathy and disinhibition in frontotemporal dementia: insights into their neural correlates. Neurology 71, 736-742 , .
    • . . . The medial PFC has been implicated in enabling individuals to shift their perspective beyond the immediate present to represent themselves across subjective time.8, 85 Patients with frontal lobe damage are known to demonstrate deficits in planning actions for tasks that require foresight.86 The ability to think about the self and to focus attention on one's inner experience is clearly important for the process of future thinking,87, 88 and is posited to rely on the dmPFC subsystem of the default network.13 Future thinking has not yet been explored in bvFTD, but considerable impairments to this function are probable, given the early dmPFC atrophy.34 The hypothesized impaired capacity to engage in future thinking is likely to be multifactorial, arising from disrupted memory monitoring and executive dysfunction,89 reduced ability for self-reflection,90 loss of motivation,91 and a diminished sense of autonoetic consciousness.58, 90 . . .
  92. Addis, D. R. & Schacter, D. L. Constructive episodic simulation: temporal distance and detail of past and future events modulate hippocampal engagement. Hippocampus 18, 227-237 , .
    • . . . Converging evidence, however, points towards the importance of the frontopolar complex in facilitating future simulation.92, 93 . . .
  93. Okuda, J. et al. Thinking of the future and past: the roles of the frontal pole and the medial temporal lobes. NeuroImage 19, 1369-1380 , .
  94. Gallagher, H. & Frith, C. Functional imaging of 'theory of mind'. Trends Cogn. Sci. 7, 77-83 , .
    • . . . Within the default network, the dmPFC subsystem seems to be preferentially activated during tasks that require the simulation of others' perspectives via theory of mind.8, 94 For this process, the medial PFC and right temporoparietal junction are differentially involved in understanding the intentions of others and in representing their mental states, respectively.95, 96, 97 Additionally, the right anterior temporal lobe seems to be necessary for the representation of context-independent social concepts, such as politeness or respect.98 . . .
  95. Saxe, R. & Wexler, A. Making sense of another mind: the role of the right temporo-parietal junction. Neuropsychologia 43, 1391-1399 , .
    • . . . Within the default network, the dmPFC subsystem seems to be preferentially activated during tasks that require the simulation of others' perspectives via theory of mind.8, 94 For this process, the medial PFC and right temporoparietal junction are differentially involved in understanding the intentions of others and in representing their mental states, respectively.95, 96, 97 Additionally, the right anterior temporal lobe seems to be necessary for the representation of context-independent social concepts, such as politeness or respect.98 . . .
  96. Becchio, C., Adenzato, M. & Bara, B. G. How the brain understands intention: different neural circuits identify the componential features of motor and prior intentions. Conscious. Cogn. 15, 64-74 , .
    • . . . Within the default network, the dmPFC subsystem seems to be preferentially activated during tasks that require the simulation of others' perspectives via theory of mind.8, 94 For this process, the medial PFC and right temporoparietal junction are differentially involved in understanding the intentions of others and in representing their mental states, respectively.95, 96, 97 Additionally, the right anterior temporal lobe seems to be necessary for the representation of context-independent social concepts, such as politeness or respect.98 . . .
  97. Ciaramidaro, A. et al. The intentional network: how the brain reads varieties of intentions. Neuropsychologia 45, 3105-3113 , .
    • . . . Within the default network, the dmPFC subsystem seems to be preferentially activated during tasks that require the simulation of others' perspectives via theory of mind.8, 94 For this process, the medial PFC and right temporoparietal junction are differentially involved in understanding the intentions of others and in representing their mental states, respectively.95, 96, 97 Additionally, the right anterior temporal lobe seems to be necessary for the representation of context-independent social concepts, such as politeness or respect.98 . . .
  98. Zahn, R. et al. Social conceptual impairments in frontotemporal lobar degeneration with right anterior temporal hypometabolism. Brain 132, 604-616 , .
  99. Pelphrey, K., Adolphs, R. & Morris, J. P. Neuroanatomical substrates of social cognition dysfunction in autism. Ment. Retard. Dev. Disabil. Res. Rev. 10, 259-271 , .
  100. Kipps, C. M. & Hodges, J. R. Theory of mind in frontotemporal dementia. Soc. Neurosci. 1, 235-244 , .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
  101. Kipps, C. M., Nestor, P. J., Acosta-Cabronero, J., Arnold, R. & Hodges, J. R. Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing. Brain 132, 592-603 , .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
  102. Eslinger, P. J. et al. Oops! Resolving social dilemmas in frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 78, 457-460 , .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
  103. Adenzato, M., Cavallo, M. & Enrici, I. Theory of mind ability in the behavioural variant of frontotemporal dementia: an analysis of the neural, cognitive, and social levels. Neuropsychologia 48, 2-12 , .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
  104. Bird, C. M., Castelli, F., Malik, O., Frith, U. & Husain, M. The impact of extensive medial frontal lobe damage on 'Theory of Mind' and cognition. Brain 127, 914-928 , .
    • . . . The ability to infer the mental state of others is considerably compromised in bvFTD,39, 40, 41, 100 extending across multiple domains of social cognition including deduction of intent from the eyes,39 recognition of sarcasm,43, 101 detection of social transgressions,41 displaying of empathy,41 and moral reasoning.42 Impairments in executive function affect theory of mind performance in bvFTD,102 particularly in patients at advanced stages of the disease.103 Importantly, however, deficits in theory of mind cannot be ascribed solely to the disruption of these frontally mediated cognitive processes,40, 103, 104 as theory of mind requires the ability not only to self-project to consider the internal state of another,8 but also to apply past recollection to social problem-solving . . .
  105. Miller, L. A. et al. One size does not fit all: face emotion processing impairments are mediated by different cognitive deficits in frontotemporal dementia and Alzheimer's disease. Behav. Neurol. 25, 53-60 , .
    • . . . Perception of emotion has recently been shown to be compromised in semantic dementia to a level similar to that seen in bvFTD.44, 105 Patients with semantic dementia can display reduced empathy,106 although this finding has not been consistently demonstrated.107 . . .
  106. Rankin, K. P. et al. Structural anatomy of empathy in neurodegenerative disease. Brain 129, 2945-2956 , .
    • . . . Perception of emotion has recently been shown to be compromised in semantic dementia to a level similar to that seen in bvFTD.44, 105 Patients with semantic dementia can display reduced empathy,106 although this finding has not been consistently demonstrated.107 . . .
  107. Eslinger, P. J., Moore, P., Anderson, C. & Grossman, M. Social cognition, executive functioning, and neuroimaging correlates of empathic deficits in frontotemporal dementia. J. Neuropsychiatry Clin. Neurosci. 23, 74-82 , .
  108. Rosenbaum, R. S., Stuss, D. T., Levine, B. & Tulving, E. Theory of mind is independent of episodic memory. Science 318, 1257 , .
    • . . . The first hypothesis is based on the proposal that the capacity to infer the intentions of others relies on the ability to consciously recollect past occurrences via autobiographical memory.8, 12 Accordingly, patients with semantic dementia would be expected to pass standard tests of theory of mind, given their largely preserved retrieval of recent memories.56 The second hypothesis is based on reports in two patients with severe amnesia following traumatic brain injury, who showed intact theory of mind ability, possibly reflecting their largely intact semantic and general knowledge abilities.108 According to this hypothesis, the progressive semantic breakdown that characterizes semantic dementia might be expected to disrupt the semantic underpinnings of social cognition, such as knowledge of rules and behaviors in various social situations. . . .
  109. Moll, J., Zahn, R., de Oliveira-Souza, R., Krueger, F. & Grafman, J. The neural basis of human moral cognition. Nat. Rev. Neurosci. 6, 799-809 , .
    • . . . The anterior temporal lobes seem to be important for the abstract conceptual representations of social knowledge that are necessary for social interactions and everyday adaptive social behavior.109, 110 The generalized semantic deficits seen in semantic dementia, however, are likely to produce substantial difficulties in comprehension of complex theory of mind tasks, which may not simply reflect impaired loss of word meaning . . .
    • . . . The ability to imagine oneself in the future is an adaptive behavior, as the mental simulation of possible future outcomes helps an individual to maximize positive outcomes and avoid negative ones.12 Moral reasoning relies on the integration of several self-projective cognitive processes that use social semantic knowledge represented in the anterior temporal cortex,109 and motivational and emotional states associated with activation of cortical–limbic circuits.114 Indeed, resolution of moral dilemmas is the type of situation in which alternative events must be simulated.2, 109 Importantly, certain forms of moral decision-making have been shown to activate default-network regions, such as the PFC and anterior temporal regions.109, 114 Moral reasoning is, unsurprisingly, substantially compromised in bvFTD.42, 115 Such socially relevant decision-making is more impaired in bvFTD than in semantic dementia, and the extent of impairment in bvFTD may reflect compromised theory of mind and reduced cognitive flexibility,41 as well as a lack of empathy (as rated by caregivers).107 . . .
  110. Zahn, R. et al. Social concepts are represented in the superior anterior temporal cortex. Proc. Natl Acad. Sci. USA 104, 6430-6435 , .
    • . . . The anterior temporal lobes seem to be important for the abstract conceptual representations of social knowledge that are necessary for social interactions and everyday adaptive social behavior.109, 110 The generalized semantic deficits seen in semantic dementia, however, are likely to produce substantial difficulties in comprehension of complex theory of mind tasks, which may not simply reflect impaired loss of word meaning . . .
  111. Castelli, F., Happe, F., Frith, U. & Frith, C. Movement and mind: a functional imaging study of perception and interpretation of complex intentional movement patterns. NeuroImage 12, 314-325 , .
    • . . . Interestingly, the anterior temporal lobes seem to have a role in the interpretation of nonverbal theory of mind, as shown by functional MRI studies that involve interpreting simple animations of geometric shape interactions that evoke the attribution of intentions.111, 112, 113 . . .
  112. Martin, A. & Weisberg, J. Neural foundations for understanding social and mechanical concepts. Cogn. Neuropsychol. 20, 575-587 , .
    • . . . Interestingly, the anterior temporal lobes seem to have a role in the interpretation of nonverbal theory of mind, as shown by functional MRI studies that involve interpreting simple animations of geometric shape interactions that evoke the attribution of intentions.111, 112, 113 . . .
  113. Ohnishi, T. et al. The neural network for the mirror system and mentalizing in normally developed children: an fMRI study. Neuroreport 15, 1483-1487 , .
  114. Sommer, M. et al. How should I decide? The neural correlates of everyday moral reasoning. Neuropsychologia 48, 2018-2026 , .
    • . . . The ability to imagine oneself in the future is an adaptive behavior, as the mental simulation of possible future outcomes helps an individual to maximize positive outcomes and avoid negative ones.12 Moral reasoning relies on the integration of several self-projective cognitive processes that use social semantic knowledge represented in the anterior temporal cortex,109 and motivational and emotional states associated with activation of cortical–limbic circuits.114 Indeed, resolution of moral dilemmas is the type of situation in which alternative events must be simulated.2, 109 Importantly, certain forms of moral decision-making have been shown to activate default-network regions, such as the PFC and anterior temporal regions.109, 114 Moral reasoning is, unsurprisingly, substantially compromised in bvFTD.42, 115 Such socially relevant decision-making is more impaired in bvFTD than in semantic dementia, and the extent of impairment in bvFTD may reflect compromised theory of mind and reduced cognitive flexibility,41 as well as a lack of empathy (as rated by caregivers).107 . . .
  115. Gleichgerrcht, E., Torralva, T., Roca, M., Pose, M. & Manes, F. The role of social cognition in moral judgment in frontotemporal dementia. Soc. Neurosci. 6, 113-122 , .
    • . . . The ability to imagine oneself in the future is an adaptive behavior, as the mental simulation of possible future outcomes helps an individual to maximize positive outcomes and avoid negative ones.12 Moral reasoning relies on the integration of several self-projective cognitive processes that use social semantic knowledge represented in the anterior temporal cortex,109 and motivational and emotional states associated with activation of cortical–limbic circuits.114 Indeed, resolution of moral dilemmas is the type of situation in which alternative events must be simulated.2, 109 Importantly, certain forms of moral decision-making have been shown to activate default-network regions, such as the PFC and anterior temporal regions.109, 114 Moral reasoning is, unsurprisingly, substantially compromised in bvFTD.42, 115 Such socially relevant decision-making is more impaired in bvFTD than in semantic dementia, and the extent of impairment in bvFTD may reflect compromised theory of mind and reduced cognitive flexibility,41 as well as a lack of empathy (as rated by caregivers).107 . . .
  116. Thompson, S. A., Patterson, K. & Hodges, J. R. Left/right asymmetry of atrophy in semantic dementia: behavioral-cognitive implications. Neurology 61, 1196-1203 , .
  117. Gleichgerrcht, E., Ibanez, A., Roca, M., Torralva, T. & Manes, F. Decision-making cognition in neurodegenerative diseases. Nat. Rev. Neurol. 6, 611-623 , .
    • . . . Economic decision-making tasks have been shown to recruit the medial PFC, anterior cingulate cortex, and limbic structures such as the thalamus, amygdala and insula.117 A selective role for the ventromedial PFC in perceiving and monitoring risks and potentially associated losses has been proposed, suggesting involvement of the MTL default-network subsystem in these cognitive functions.118, 119 The ventromedial PFC is particularly vulnerable to atrophy in bvFTD, even in the very early stages of disease.120 Studies using the Iowa gambling task in patients with bvFTD have revealed substantial impairments in interpreting and using feedback from the task to adjust future decisions.40 Such patients seem to be aware of their risky choices but consistently choose disadvantageously,120 pointing towards the possible role of disinhibition and other aspects of executive dysfunction that could be particularly important for decision-making in risky or ambiguous situations.117, 121 Interestingly, poor economic and moral decision-making following orbitofrontal damage may stem from an inability to self-project to consider or simulate the possible future outcomes of actions.122 Healthy individuals benefit from envisioning future scenarios to reduce the likelihood of impulsive discounting,123 whereas patients with damage to midline structures necessary for self-projection tend to value immediate rather than future gain . . .
  118. Liu, X. et al. Functional dissociation in frontal and striatal areas for processing of positive and negative reward information. J. Neurosci. 27, 4587-4597 , .
    • . . . Economic decision-making tasks have been shown to recruit the medial PFC, anterior cingulate cortex, and limbic structures such as the thalamus, amygdala and insula.117 A selective role for the ventromedial PFC in perceiving and monitoring risks and potentially associated losses has been proposed, suggesting involvement of the MTL default-network subsystem in these cognitive functions.118, 119 The ventromedial PFC is particularly vulnerable to atrophy in bvFTD, even in the very early stages of disease.120 Studies using the Iowa gambling task in patients with bvFTD have revealed substantial impairments in interpreting and using feedback from the task to adjust future decisions.40 Such patients seem to be aware of their risky choices but consistently choose disadvantageously,120 pointing towards the possible role of disinhibition and other aspects of executive dysfunction that could be particularly important for decision-making in risky or ambiguous situations.117, 121 Interestingly, poor economic and moral decision-making following orbitofrontal damage may stem from an inability to self-project to consider or simulate the possible future outcomes of actions.122 Healthy individuals benefit from envisioning future scenarios to reduce the likelihood of impulsive discounting,123 whereas patients with damage to midline structures necessary for self-projection tend to value immediate rather than future gain . . .
  119. O'Doherty, J. P., Buchanan, T. W., Seymour, B. & Dolan, R. J. Predictive neural coding of reward preference involves dissociable responses in human ventral midbrain and ventral striatum. Neuron 49, 157-166 , .
    • . . . Economic decision-making tasks have been shown to recruit the medial PFC, anterior cingulate cortex, and limbic structures such as the thalamus, amygdala and insula.117 A selective role for the ventromedial PFC in perceiving and monitoring risks and potentially associated losses has been proposed, suggesting involvement of the MTL default-network subsystem in these cognitive functions.118, 119 The ventromedial PFC is particularly vulnerable to atrophy in bvFTD, even in the very early stages of disease.120 Studies using the Iowa gambling task in patients with bvFTD have revealed substantial impairments in interpreting and using feedback from the task to adjust future decisions.40 Such patients seem to be aware of their risky choices but consistently choose disadvantageously,120 pointing towards the possible role of disinhibition and other aspects of executive dysfunction that could be particularly important for decision-making in risky or ambiguous situations.117, 121 Interestingly, poor economic and moral decision-making following orbitofrontal damage may stem from an inability to self-project to consider or simulate the possible future outcomes of actions.122 Healthy individuals benefit from envisioning future scenarios to reduce the likelihood of impulsive discounting,123 whereas patients with damage to midline structures necessary for self-projection tend to value immediate rather than future gain . . .
  120. Rahman, S., Sahakian, B. J., Hodges, J. R., Rogers, R. D. & Robbins, T. W. Specific cognitive deficits in mild frontal variant frontotemporal dementia. Brain 122, 1469-1493 , .
    • . . . Economic decision-making tasks have been shown to recruit the medial PFC, anterior cingulate cortex, and limbic structures such as the thalamus, amygdala and insula.117 A selective role for the ventromedial PFC in perceiving and monitoring risks and potentially associated losses has been proposed, suggesting involvement of the MTL default-network subsystem in these cognitive functions.118, 119 The ventromedial PFC is particularly vulnerable to atrophy in bvFTD, even in the very early stages of disease.120 Studies using the Iowa gambling task in patients with bvFTD have revealed substantial impairments in interpreting and using feedback from the task to adjust future decisions.40 Such patients seem to be aware of their risky choices but consistently choose disadvantageously,120 pointing towards the possible role of disinhibition and other aspects of executive dysfunction that could be particularly important for decision-making in risky or ambiguous situations.117, 121 Interestingly, poor economic and moral decision-making following orbitofrontal damage may stem from an inability to self-project to consider or simulate the possible future outcomes of actions.122 Healthy individuals benefit from envisioning future scenarios to reduce the likelihood of impulsive discounting,123 whereas patients with damage to midline structures necessary for self-projection tend to value immediate rather than future gain . . .
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    • . . . Economic decision-making tasks have been shown to recruit the medial PFC, anterior cingulate cortex, and limbic structures such as the thalamus, amygdala and insula.117 A selective role for the ventromedial PFC in perceiving and monitoring risks and potentially associated losses has been proposed, suggesting involvement of the MTL default-network subsystem in these cognitive functions.118, 119 The ventromedial PFC is particularly vulnerable to atrophy in bvFTD, even in the very early stages of disease.120 Studies using the Iowa gambling task in patients with bvFTD have revealed substantial impairments in interpreting and using feedback from the task to adjust future decisions.40 Such patients seem to be aware of their risky choices but consistently choose disadvantageously,120 pointing towards the possible role of disinhibition and other aspects of executive dysfunction that could be particularly important for decision-making in risky or ambiguous situations.117, 121 Interestingly, poor economic and moral decision-making following orbitofrontal damage may stem from an inability to self-project to consider or simulate the possible future outcomes of actions.122 Healthy individuals benefit from envisioning future scenarios to reduce the likelihood of impulsive discounting,123 whereas patients with damage to midline structures necessary for self-projection tend to value immediate rather than future gain . . .
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    • . . . Economic decision-making tasks have been shown to recruit the medial PFC, anterior cingulate cortex, and limbic structures such as the thalamus, amygdala and insula.117 A selective role for the ventromedial PFC in perceiving and monitoring risks and potentially associated losses has been proposed, suggesting involvement of the MTL default-network subsystem in these cognitive functions.118, 119 The ventromedial PFC is particularly vulnerable to atrophy in bvFTD, even in the very early stages of disease.120 Studies using the Iowa gambling task in patients with bvFTD have revealed substantial impairments in interpreting and using feedback from the task to adjust future decisions.40 Such patients seem to be aware of their risky choices but consistently choose disadvantageously,120 pointing towards the possible role of disinhibition and other aspects of executive dysfunction that could be particularly important for decision-making in risky or ambiguous situations.117, 121 Interestingly, poor economic and moral decision-making following orbitofrontal damage may stem from an inability to self-project to consider or simulate the possible future outcomes of actions.122 Healthy individuals benefit from envisioning future scenarios to reduce the likelihood of impulsive discounting,123 whereas patients with damage to midline structures necessary for self-projection tend to value immediate rather than future gain . . .
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    • . . . Economic decision-making tasks have been shown to recruit the medial PFC, anterior cingulate cortex, and limbic structures such as the thalamus, amygdala and insula.117 A selective role for the ventromedial PFC in perceiving and monitoring risks and potentially associated losses has been proposed, suggesting involvement of the MTL default-network subsystem in these cognitive functions.118, 119 The ventromedial PFC is particularly vulnerable to atrophy in bvFTD, even in the very early stages of disease.120 Studies using the Iowa gambling task in patients with bvFTD have revealed substantial impairments in interpreting and using feedback from the task to adjust future decisions.40 Such patients seem to be aware of their risky choices but consistently choose disadvantageously,120 pointing towards the possible role of disinhibition and other aspects of executive dysfunction that could be particularly important for decision-making in risky or ambiguous situations.117, 121 Interestingly, poor economic and moral decision-making following orbitofrontal damage may stem from an inability to self-project to consider or simulate the possible future outcomes of actions.122 Healthy individuals benefit from envisioning future scenarios to reduce the likelihood of impulsive discounting,123 whereas patients with damage to midline structures necessary for self-projection tend to value immediate rather than future gain . . .
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    • . . . This 'myopia for the future'124 is consistent with the real-life difficulties of patients with bvFTD, who seem to be attracted by the benefits of immediate rewards.125 Accordingly, such patients can show seemingly disinhibited and bizarre behavior when making decisions, owing in part to their insensitivity to negative feedback and risky consequences.126 . . .
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    • . . . This 'myopia for the future'124 is consistent with the real-life difficulties of patients with bvFTD, who seem to be attracted by the benefits of immediate rewards.125 Accordingly, such patients can show seemingly disinhibited and bizarre behavior when making decisions, owing in part to their insensitivity to negative feedback and risky consequences.126 . . .
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    • . . . However, investigating disruption of the neural hubs (anterior medial PFC and posterior cingulate cortex) in FTD syndromes will also be useful, given that these midline core regions robustly activate during retrieval of real autobiographical memories but not those of fictitious experiences,127, 128 and are consistently implicated in self-referential introspective abilities.13, 129 Furthermore, given that atrophy of the anterior medial PFC is common in bvFTD,62 whereas the posterior cingulate is one of the earliest regions of disruption in AD,84 relative performance on tasks that do or do not require self-relevant introspection might be expected to differ between dementia subtypes . . .
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    • . . . However, investigating disruption of the neural hubs (anterior medial PFC and posterior cingulate cortex) in FTD syndromes will also be useful, given that these midline core regions robustly activate during retrieval of real autobiographical memories but not those of fictitious experiences,127, 128 and are consistently implicated in self-referential introspective abilities.13, 129 Furthermore, given that atrophy of the anterior medial PFC is common in bvFTD,62 whereas the posterior cingulate is one of the earliest regions of disruption in AD,84 relative performance on tasks that do or do not require self-relevant introspection might be expected to differ between dementia subtypes . . .
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