Pain and temperature processing in dementia: a clinical and neuroanatomical analysis
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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TL;DR: The neuropathology of these dementias extends to structures involved in emotional processing, including the basolateral limbic network (orbitofrontal cortex, anterior temporal lobe, amygdala, and thalamus), the insula, and ventromedial frontal lobe as mentioned in this paper.
Abstract: Degenerative dementias such as Alzheimer's disease and frontotemporal dementia result in distinct alterations in emotional processing, emotional experiences, and mood. The neuropathology of these dementias extends to structures involved in emotional processing, including the basolateral limbic network (orbitofrontal cortex, anterior temporal lobe, amygdala, and thalamus), the insula, and ventromedial frontal lobe. Depression is the most common emotion and mood disorder affecting patients with Alzheimer's disease. The onset of depression can be a prodromal sign of this dementia. Anxiety can also be present early in the course of Alzheimer's disease and especially among patients with early-onset forms of the disease. In contrast, patients with behavioral variant frontotemporal dementia demonstrate hypoemotionality, deficits in the recognition of emotion, and decreased psychophysiological reactivity to emotional stimuli. They typically have a disproportionate impairment in emotional and cognitive empathy. One other unique feature of behavioral variant frontotemporal dementia is the frequent occurrence of bipolar disorder. The management strategies for these alterations of emotion and mood in degenerative dementias primarily involve the judicious use of the psychiatric armamentarium of medications.
8 citations
TL;DR: In this article, the aberrant activation of striatal-enriched protein tyrosine phosphatase (STEP) signaling, which modulates proteins related to nociception transduction, was investigated.
Abstract: Alzheimer disease (AD) is the most common form of dementia, accounting for approximately 60% of cases. In addition to memory loss, changes in pain sensitivity are found in a substantial proportion of patients with AD. However, the mechanism of nociception deficits in AD is still unclear. Here, we hypothesize that the nociception abnormality in AD is due to the aberrant activation of striatal-enriched protein tyrosine phosphatase (STEP) signaling, which modulates proteins related to nociception transduction. Our results indicated that the transgenic mice carrying human amyloid precursor protein (APP) gene had lower sensitivity to mechanical and thermal stimulation than the wild-type group at the ages of 6, 9, and 12 months. These APP mice exhibited elevated STEP activity and decreased phosphorylation of proteins involved in nociception transduction in hippocampi. The pharmacological inhibition of STEP activity using TC-2153 further reversed nociception and cognitive deficits in the APP mice. Moreover, the phosphorylation of nociception-related proteins in the APP mice was also rescued after STEP inhibitor treatment, indicating the key role of STEP in nociception alteration. In summary, this study identifies a mechanism for the reduced nociceptive sensitivity in an AD mouse model that could serve as a therapeutic target to improve the quality of life for patients with AD.
7 citations
TL;DR: The findings in alexithymic patients and frontotemporal dementia syndromes support the model of impaired interoceptive accuracy as the mechanism of aLexithymia, possibly from dysfunction in the insulae.
Abstract: Alexithymia is pervasive among psychiatric patients, but its neurobiological mechanism is unclear Patients with alexithymia cannot "read emotions," a process involving interoception, or the perception of the body's internal state, primarily in the insulae The frontotemporal dementias are also associated with inability to correctly read emotions; hence, these dementias can provide a window into the mechanism of alexithymia Patients with behavioral variant frontotemporal dementia (bvFTD) have a weak emotional signal with impaired emotional recognition, hypoemotionality, and decreased physiological arousal bvFTD affects the insulae, and the weak emotional signal facilitates impaired interoceptive accuracy, resulting in an overreliance on cognitive appraisal rather than on internal sensations In contrast, patients with semantic dementia, another frontotemporal dementia syndrome, can have intact interoception, but they have disturbed cognitive appraisal of the meaning of their bodily sensations This "alexisomia" in semantic dementia can lead to misinterpreted somatic symptoms Together, the findings in alexithymic patients and frontotemporal dementia syndromes support the model of impaired interoceptive accuracy as the mechanism of alexithymia, possibly from dysfunction in the insulae
7 citations
TL;DR: In this paper, the authors searched PubMed and Scopus from 1/2000 to 12/2020 for human studies addressing the influence of ambient temperatures and human migration on Alzheimer's and non-Alzheimer's dementia, epilepsy, headache/migraine, multiple sclerosis, Parkinson's disease, stroke, and tick-borne encephalitis.
Abstract: Background Climate change, including global warming, will cause poorer global health and rising numbers of environmental refugees. As neurological disorders account for a major share of morbidity and mortality worldwide, global warming is also destined to alter neurological practice; however, to what extent and by which mechanisms is unknown. We aimed to collect information about the effects of ambient temperatures and human migration on the epidemiology and clinical manifestations of neurological disorders. Methods We searched PubMed and Scopus from 01/2000 to 12/2020 for human studies addressing the influence of ambient temperatures and human migration on Alzheimer's and non-Alzheimer's dementia, epilepsy, headache/migraine, multiple sclerosis, Parkinson's disease, stroke, and tick-borne encephalitis (a model disease for neuroinfections). The protocol was pre-registered with PROSPERO (2020 CRD42020147543). Results Ninety-three studies met inclusion criteria, 84 of which reported on ambient temperatures and nine on migration. Overall, most temperature studies suggested a relationship between increasing temperatures and higher mortality and/or morbidity, whereas results were more ambiguous for migration studies. However, we were unable to identify a single adequately designed study addressing how global warming and human migration will change neurological practice. Still, extracted data indicated multiple ways by which these aspects might alter neurological morbidity and mortality soon. Conclusion Significant heterogeneity exists across studies with respect to methodology, outcome measures, confounders and study design, including lack of data from low-income countries, but the evidence so far suggests that climate change will affect the practice of all major neurological disorders in the near future. Adequately designed studies to address this issue are urgently needed, requiring concerted efforts from the entire neurological community.
7 citations
TL;DR: The results demonstrate that subsets of PPA patients show novel or increased positive behaviours following dementia onset, and differences among subtypes may be helpful for improving diagnostic accuracy.
Abstract: Background/Aims: Although some patients with primary progressive aphasia (PPA) exhibit novel or improved skills after the onset of dementia, these changes have yet to be quantified. Therefore, this study systematically explored and identified the emergence of positive behaviours after dementia onset. Methods: This study included 48 carers of patients with PPA: 12 nonfluent/agrammatic PPA (nfvPPA), 22 semantic variant PPA (svPPA), and 14 logopenic variant PPA (lvPPA). The presence and frequency of positive behaviour changes after dementia onset were established using the Hypersensory and Social/Emotional Scale (HSS). Results: Scores on Sensitivity to Details, Visuospatial Activities, and Music Activities differed significantly among the groups. More specifically, svPPA was associated with increased visuospatial activity, but only in the mild stage of the disease; nfvPPA was associated with increased visuospatial activity and decreased music activity, while lvPPA exhibited the reverse profile. Conclusions: The results demonstrate that subsets of PPA patients show novel or increased positive behaviours following dementia onset, and differences among subtypes may be helpful for improving diagnostic accuracy. Additionally, harnessing these skills may improve the quality of life of both patients and carers.
6 citations
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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
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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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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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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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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)....
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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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