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Journal ArticleDOI

Pain and temperature processing in dementia: a clinical and neuroanatomical analysis

01 Nov 2015-Brain (Oxford University Press)-Vol. 138, Iss: 11, pp 3360-3372
TL;DR: Using a semi-structured caregiver questionnaire and MRI voxel-based morphometry in patients with frontotemporal degeneration or Alzheimer’s disease, Fletcher et al. show that symptoms are underpinned by atrophy in a distributed thalamo-temporo-insular network implicated in somatosensory processing.
Abstract: Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52-84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer's disease (n = 20, eight female, aged 53-74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients' brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer's disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer's disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest) and anterior temporal cortex (P < 0.001 uncorrected over whole brain) previously implicated in processing homeostatic signals. Pain and temperature symptoms accompanying C9orf72 mutations were specifically associated with posterior thalamic atrophy (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest). Together the findings suggest candidate cognitive and neuroanatomical bases for these salient but under-appreciated phenotypic features of the dementias, with wider implications for the homeostatic pathophysiology and clinical management of neurodegenerative diseases.

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Citations
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Journal ArticleDOI
TL;DR: In this article, the authors used group-independent component analysis (group-ICA) and extracted 53 maximally independent components (ICs) for the whole brain, then they used a sliding-window approach to estimate dFNC from the extracted 53 ICs, then group them into 3 different brain states using a clustering method.
Abstract: Background Alzheimer's disease (AD) is the most common age-related problem and progresses in different stages, including mild cognitive impairment (early stage), mild dementia (middle-stage), and severe dementia (late-stage). Recent studies showed changes in functional network connectivity obtained from resting-state functional magnetic resonance imaging (rs-fMRI) during the transition from healthy aging to AD. By assuming that the brain interaction is static during the scanning time, most prior studies are focused on static functional or functional network connectivity (sFNC). Dynamic functional network connectivity (dFNC) explores temporal patterns of functional connectivity and provides additional information to its static counterpart. Method We used longitudinal rs-fMRI from 1385 scans (from 910 subjects) at different stages of AD (from normal to very mild AD or vmAD). We used group-independent component analysis (group-ICA) and extracted 53 maximally independent components (ICs) for the whole brain. Next, we used a sliding-window approach to estimate dFNC from the extracted 53 ICs, then group them into 3 different brain states using a clustering method. Then, we estimated a hidden Markov model (HMM) and the occupancy rate (OCR) for each subject. Finally, we investigated the link between the clinical rate of each subject with state-specific FNC, OCR, and HMM. Results All states showed significant disruption during progression normal brain to vmAD one. Specifically, we found that subcortical network, auditory network, visual network, sensorimotor network, and cerebellar network connectivity decrease in vmAD compared with those of a healthy brain. We also found reorganized patterns (i.e., both increases and decreases) in the cognitive control network and default mode network connectivity by progression from normal to mild dementia. Similarly, we found a reorganized pattern of between-network connectivity when the brain transits from normal to mild dementia. However, the connectivity between visual and sensorimotor network connectivity decreases in vmAD compared with that of a healthy brain. Finally, we found a normal brain spends more time in a state with higher connectivity between visual and sensorimotor networks. Conclusion Our results showed the temporal and spatial pattern of whole-brain FNC differentiates AD form healthy control and suggested substantial disruptions across multiple dynamic states. In more detail, our results suggested that the sensory network is affected more than other brain network, and default mode network is one of the last brain networks get affected by AD In addition, abnormal patterns of whole-brain dFNC were identified in the early stage of AD, and some abnormalities were correlated with the clinical score.

30 citations

Journal ArticleDOI
TL;DR: The current knowledge about the clinical, genetic and neuroimaging features of FTD is discussed, with variable asymmetry of neuronal loss, widespread subcortical involvement and in many cases more posterior cortical atrophy.
Abstract: Frontotemporal dementia (FTD) is a heterogeneous group of disorders causing neurodegeneration within a network of areas centred on the frontal and temporal lobes. Clinically, patients present with behavioural symptoms (behavioural variant FTD) or language disturbance (primary progressive aphasia), although there is an overlap with motor neurone disease and atypical parkinsonian disorders. Whilst neuroimaging commonly reveals abnormalities in the frontal and temporal lobes, a closer review identifies a more complex picture with variable asymmetry of neuronal loss, widespread subcortical involvement and in many cases more posterior cortical atrophy. An autosomal-dominant genetic disorder is found in around a third of people with mutations in progranulin, C9orf72 and the microtubule-associated protein tau being the commonest causes. In the other two-thirds, the disorder is sporadic, although recent genome-wide association studies have started to identify genetic risk factors within this group. Much of this knowledge has been understood only in the past 10 years and so this review will discuss the current knowledge about the clinical, genetic and neuroimaging features of FTD.

30 citations

Journal ArticleDOI
16 Aug 2017-Cortex
TL;DR: This work presents a meta-modelling framework for estimating the neural pathways responsible for emotion and emotion regulation in a post-mortem setting and shows clear patterns of decline in aged patients with Alzheimer's disease.

29 citations

Journal ArticleDOI
TL;DR: Impaired emotional mimesis may be a core mechanism of disordered emotional signal understanding and reactivity in frontotemporal dementia, with implications for the development of novel physiological biomarkers of socio-emotional dysfunction in these diseases.
Abstract: Automatic motor mimicry is essential to the normal processing of perceived emotion, and disrupted automatic imitation might underpin socio-emotional deficits in neurodegenerative diseases, particularly the frontotemporal dementias. However, the pathophysiology of emotional reactivity in these diseases has not been elucidated. We studied facial electromyographic responses during emotion identification on viewing videos of dynamic facial expressions in 37 patients representing canonical frontotemporal dementia syndromes versus 21 healthy older individuals. Neuroanatomical associations of emotional expression identification accuracy and facial muscle reactivity were assessed using voxel-based morphometry. Controls showed characteristic profiles of automatic imitation, and this response predicted correct emotion identification. Automatic imitation was reduced in the behavioural and right temporal variant groups, while the normal coupling between imitation and correct identification was lost in the right temporal and semantic variant groups. Grey matter correlates of emotion identification and imitation were delineated within a distributed network including primary visual and motor, prefrontal, insular, anterior temporal and temporo-occipital junctional areas, with common involvement of supplementary motor cortex across syndromes. Impaired emotional mimesis may be a core mechanism of disordered emotional signal understanding and reactivity in frontotemporal dementia, with implications for the development of novel physiological biomarkers of socio-emotional dysfunction in these diseases.

28 citations

Journal ArticleDOI
TL;DR: In this article, the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups were investigated using parcellation methods on volumetric 3-T-T1-weighted MRI scans.

27 citations

References
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TL;DR: An automated labeling system for subdividing the human cerebral cortex into standard gyral-based neuroanatomical regions is both anatomically valid and reliable and may be useful for both morphometric and functional studies of the cerebral cortex.

9,940 citations


"Pain and temperature processing in ..." refers background in this paper

  • ...1 (Desikan et al., 2006; Jenkinson et al., 2012) to fit the group mean template brain image....

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Journal ArticleDOI
TL;DR: DARTEL has been applied to intersubject registration of 471 whole brain images, and the resulting deformations were evaluated in terms of how well they encode the shape information necessary to separate male and female subjects and to predict the ages of the subjects.

6,999 citations


"Pain and temperature processing in ..." refers methods in this paper

  • ...Preprocessing of patients’ brain magnetic resonance images for VBM was performed using New Segment (Ashburner and Friston, 2005) and the DARTEL (Ashburner, 2007) toolbox of SPM8 (www....

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  • ...A study-specific group mean template brain image was created by warping all native space whole-brain images to the final DARTEL template and calculating the average of the warped brain images....

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  • ...Preprocessing of patients’ brain magnetic resonance images for VBM was performed using New Segment (Ashburner and Friston, 2005) and the DARTEL (Ashburner, 2007) toolbox of SPM8 (www.fil.ion.ucl.ac.uk/spm) running under Matlab7....

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Journal ArticleDOI
TL;DR: Two distinct networks typically coactivated during functional MRI tasks are identified, anchored by dorsal anterior cingulate and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an “executive-control network” that links dorsolateral frontal and parietal neocortices.
Abstract: Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a "salience network," anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an "executive-control network" that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.

6,049 citations


"Pain and temperature processing in ..." refers background in this paper

  • ...More anterior insular regions are also targeted in PNFA, providing a candidate locus for altered homeostatic awareness in this syndrome (Seeley et al., 2009)....

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Journal ArticleDOI
TL;DR: New findings suggest a fundamental role for the AIC (and the von Economo neurons it contains) in awareness, and thus it needs to be considered as a potential neural correlate of consciousness.
Abstract: The anterior insular cortex (AIC) is implicated in a wide range of conditions and behaviours, from bowel distension and orgasm, to cigarette craving and maternal love, to decision making and sudden insight. Its function in the re-representation of interoception offers one possible basis for its involvement in all subjective feelings. New findings suggest a fundamental role for the AIC (and the von Economo neurons it contains) in awareness, and thus it needs to be considered as a potential neural correlate of consciousness.

5,279 citations


"Pain and temperature processing in ..." refers background or methods or result in this paper

  • ...Such noisy processing might involve degraded temporal scheduling of salient sensory and emotional signals, a key function attributed to anterior insula that is vulnerable in FTLD (Wiener and Coslett, 2008; Craig, 2009; Henley et al., 2014)....

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  • ...Together these networks have a core role in regulation of bodily homeostasis: current neurobiological formulations emphasize convergent processing of somatic and visceral pain and thermoregulatory signals as functionally interdependent aspects of interoception (Craig, 2002, 2009)....

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  • ...…labelled lines have been incorporated by current models that emphasize the intimate association of pain and thermal information and their integration as joint aspects of interoception, salient sensory phenomena that are potentially critical for signalling body homeostasis (Craig, 2002, 2009)....

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  • ...…neural networks that are engaged jointly by these diverse phenomena and reaffirms the primacy of the thalamo-insular linkage in regulating the interface between homeostatic and environmental contingencies, reward and punishment (Craig, 2002, 2009; Perry et al., 2014; Zhou and Seeley, 2014)....

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  • ...This region may be involved in generating subjective psychological states via projections to anterior insula, anterior cingulate, orbitofrontal and prefrontal cortices and in programming coherent autonomic effector responses (Craig, 2002, 2009; Grecucci et al., 2013; Zhou and Seeley, 2014)....

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Journal ArticleDOI
TL;DR: Functional anatomical work has detailed an afferent neural system in primates and in humans that represents all aspects of the physiological condition of the physical body that might provide a foundation for subjective feelings, emotion and self-awareness.
Abstract: As humans, we perceive feelings from our bodies that relate our state of well-being, our energy and stress levels, our mood and disposition. How do we have these feelings? What neural processes do they represent? Recent functional anatomical work has detailed an afferent neural system in primates and in humans that represents all aspects of the physiological condition of the physical body. This system constitutes a representation of 'the material me', and might provide a foundation for subjective feelings, emotion and self-awareness.

4,673 citations


"Pain and temperature processing in ..." refers background or methods or result in this paper

  • ...The present evidence suggests a model for synthesizing neurodegenerative disease effects on these cortical operations that is consistent both with data from normal neurophysiological and functional neuroimaging work and the effects of focal brain lesions (Craig, 2002, 2009; Borsook, 2012)....

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  • ...…interpretation, as under most circumstances thermal comfort or distress reflects the degree of perceived mismatch between one’s own body temperature and the environment; temperature sensibility might therefore be regarded as a probe of interoceptive signal processing par excellence (Craig, 2002)....

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  • ...Peripheral somatic and visceral sensory afferents conveying pain and thermal information relay via postero-lateral thalamic nuclei to somatosensory cortex (Brodmann area 3a) and dorsal posterior insula (Craig, 2002)....

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  • ...Temperature sensibility is mediated by a closely overlapping network (Craig, 2002; Moulton et al., 2012)....

    [...]

  • ...Together these networks have a core role in regulation of bodily homeostasis: current neurobiological formulations emphasize convergent processing of somatic and visceral pain and thermoregulatory signals as functionally interdependent aspects of interoception (Craig, 2002, 2009)....

    [...]

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