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: A clinical approach to the progressive aphasias is presented, based on the experience of these disorders and directed at non-specialists, and a prospect for future progress is concluded, emphasising generic information processing deficits and novel pathophysiological biomarkers.
Abstract: The primary progressive aphasias are a heterogeneous group of focal 'language-led' dementias that pose substantial challenges for diagnosis and management Here we present a clinical approach to the progressive aphasias, based on our experience of these disorders and directed at non-specialists We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including 'clinical pearls' that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic 'roadmap' After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers
159 citations
TL;DR: This review aims to clarify the often confusing terminology of FTD, and outline the various clinical features and diagnostic criteria of sporadic and familial FTD syndromes.
Abstract: The term frontotemporal dementia (FTD) describes a clinically, genetically and pathologically diverse group of neurodegenerative disorders. Symptoms of FTD can present in individuals in their 20s through to their 90s, but the mean age at onset is in the sixth decade. The most common presentation is with a change in personality and impaired social conduct (behavioural variant FTD). Less frequently patients present with language problems (primary progressive aphasia). Both of these groups of patients can develop motor features consistent with either motor neuron disease (usually the amyotrophic lateral sclerosis variant) or parkinsonism (most commonly a progressive supranuclear palsy or corticobasal syndrome). In about a third of cases FTD is familial, with mutations in the progranulin, microtubule-associated protein tau and chromosome 9 open reading frame 72 genes being the major causes. Mutations in a number of other genes including TANK-binding kinase 1 are rare causes of familial FTD. This review aims to clarify the often confusing terminology of FTD, and outline the various clinical features and diagnostic criteria of sporadic and familial FTD syndromes. It will also discuss the current major challenges in FTD research and clinical practice, and potential areas for future research. This review clarifies the terminology of frontotemporal dementia (FTD) and summarizes the various clinical features and most recent diagnostic criteria of sporadic and familial FTD syndromes. It also discusses the current major challenges in FTD research and clinical practice, and highlights potential areas for future research.
113 citations
TL;DR: It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic aggregates, which ultimately overwhelm capacity to function.
Abstract: Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter-relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.
113 citations
TL;DR: Given the multifactorial nature of pain in patients with ALS, different treatments have been suggested, ranging from non-steroidal anti-inflammatory drugs, drugs for neuropathic pain, opioids, and cannabinoids, to physical therapy strategies and preventive assistive devices.
Abstract: Pain is a largely neglected symptom in patients with amyotrophic lateral sclerosis (ALS) although it is reported by most of these patients. It occurs at all stages of the disease and can be an onset symptom preceding motor dysfunction. Pain is correlated with a deterioration in patients' quality of life and increased prevalence of depression. In the later stages of ALS, pain can be severe enough to require increased use of sedative and analgesic drugs, and is among the events that predict clinical deterioration and death. The site of pain depends on the pain type or underlying mechanism (eg, painful cramps, nociceptive pain, or neuropathic pain). Given the multifactorial nature of pain in patients with ALS, different treatments have been suggested, ranging from non-steroidal anti-inflammatory drugs, drugs for neuropathic pain, opioids, and cannabinoids, to physical therapy strategies and preventive assistive devices. Further understanding of the pathophysiology is crucial to drive assessment in clinical trials of therapeutic strategies targeted at specific mechanisms and studies of individualised therapies.
80 citations
Cites background from "Pain and temperature processing in ..."
...Using MRI voxel-based morphometry analysis pain and temperature symptoms were associated to a right-lateralized network including anterior temporal cortex, posterior thalamus and insula, indicating an altered processing of somatosensory signals.(69) Such failure to interpret pain and temperature variations can put patients at risk of injuries....
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TL;DR: A critical appraisal of common methods to access the behavioral and psychological symptoms as well as the cognitive alterations presented in the diagnostic criteria for Behavioral variant frontotemporal dementia is aimed at.
Abstract: Behavioral variant frontotemporal dementia (bvFTD) is the second leading cognitive disorder caused by neurodegeneration in patients under 65 years of age. Characterized by frontal, insular, and/or temporal brain atrophy, patients present with heterogeneous constellations of behavioral and psychological symptoms among which progressive changes in social conduct, lack of empathy, apathy, disinhibited behaviors, and cognitive impairments are frequently observed. Since the histopathology of the disease is heterogeneous and identified genetic mutations only account for ~30% of cases, there are no reliable biomarkers for the diagnosis of bvFTD available in clinical routine as yet. Early detection of bvFTD thus relies on correct application of clinical diagnostic criteria. Their evaluation however, requires expertise and in-depth assessments of cognitive functions, history taking, clinical observations as well as caregiver reports on behavioral and psychological symptoms and their respective changes. With this review, we aim for a critical appraisal of common methods to access the behavioral and psychological symptoms as well as the cognitive alterations presented in the diagnostic criteria for bvFTD. We highlight both, practical difficulties as well as current controversies regarding an overlap of symptoms and particularly cognitive impairments with other neurodegenerative and primary psychiatric diseases. We then review more recent developments and evidence on cognitive, behavioral and psychological symptoms of bvFTD beyond the diagnostic criteria which may prospectively enhance the early detection and differential diagnosis in clinical routine. In particular, evidence on specific impairments in social and emotional processing, praxis abilities as well as interoceptive processing in bvFTD is summarized and potential links with behavior and classic cognitive domains are discussed. We finally outline both, future opportunities and major challenges with regard to the role of clinical neuropsychology in detecting bvFTD and related neurocognitive disorders.
66 citations
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TL;DR: The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality-selective processing nodes.
Abstract: The neural organization of semantic memory remains much debated. A 'distributed-only' view contends that semantic knowledge is represented within spatially distant, modality-selective primary and association cortices. Observations in semantic variant primary progressive aphasia have inspired an alternative model featuring the anterior temporal lobe as an amodal hub that supports semantic knowledge by linking distributed modality-selective regions. Direct evidence has been lacking, however, to support intrinsic functional interactions between an anterior temporal lobe hub and upstream sensory regions in humans. Here, we examined the neural networks supporting semantic knowledge by performing a multimodal brain imaging study in healthy subjects and patients with semantic variant primary progressive aphasia. In healthy subjects, the anterior temporal lobe showed intrinsic connectivity to an array of modality-selective primary and association cortices. Patients showed focal anterior temporal lobe degeneration but also reduced physiological integrity throughout distributed modality-selective regions connected with the anterior temporal lobe in healthy controls. Physiological deficits outside the anterior temporal lobe correlated with scores on semantic tasks and with anterior temporal subregion atrophy, following domain-specific and connectivity-based predictions. The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality-selective processing nodes.
181 citations
"Pain and temperature processing in ..." refers background in this paper
...…previous autobiographical experiences and stored conceptual (including social normative) knowledge (Rankin et al., 2006; Zahn et al., 2009; Aminoff et al., 2013; Irish et al., 2014) and by engaging a distributed anterior fronto-temporal appraisal network (Guo et al., 2013; Zhou and Seeley, 2014)....
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..., 2014) and by engaging a distributed anterior fronto-temporal appraisal network (Guo et al., 2013; Zhou and Seeley, 2014)....
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TL;DR: It is argued that these apparently diverse clinical phenotypes of AD variant syndromes reflect the differential involvement of a common core temporoparietofrontal network that is vulnerable to AD.
Abstract: Variant syndromes of Alzheimer disease (AD), led by deficits that extend beyond memory dysfunction, are of considerable clinical and neurobiological importance. Such syndromes present major challenges for both diagnosis and monitoring of disease, and serve to illustrate the apparent paradox of a clinically diverse group of disorders underpinned by a common histopathological substrate. This Review focuses on the most common variant AD phenotypes: posterior cortical atrophy, logopenic variant primary progressive aphasia and frontal variant AD. The neuroanatomical, molecular and pathological correlates of these phenotypes are highlighted, and the heterogeneous clinical presentations of the syndromes are discussed in the context of the emerging network paradigm of neurodegenerative disease. We argue that these apparently diverse clinical phenotypes reflect the differential involvement of a common core temporoparietofrontal network that is vulnerable to AD. According to this interpretation, the network signatures corresponding to AD variant syndromes are produced by genetic and other modulating factors that have yet to be fully characterized. The clinical and neurobiological implications of this network paradigm in the quest for disease-modifying treatments are also explored.
179 citations
"Pain and temperature processing in ..." refers background in this paper
...…according to the colour bar. and prominent and may be underpinned by disintegration of a large-scale cortico-thalamo-cerebellar brain network (Downey et al., 2012; Mahoney et al., 2012; Snowden et al., 2012, 2013; Takada and Sha, 2012; Whitwell et al., 2012; Lee et al., 2014; Rohrer et al., 2015)....
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TL;DR: The cytoarchitectonic characteristics of VMpo and its relationship with immunoreactivity for calbindin, substance P and calcitonin gene-related peptide (CGRP) in the human thalamus are analysed and they suggest that the lamina I spinothalamic tract fibres and vagal-solitary-parabrachial afferents form closely related, but separate, termination fields that can be considered to represent different aspects of enteroceptive information regarding
Abstract: Previous studies in the macaque monkey have identified a thalamic nucleus, the posterior portion of the ventral medial nucleus (VMpo), as a dedicated lamina I spinothalamocortical relay for pain and temperature sensation. The dense plexus of calbindin-immunoreactive fibres that characterizes VMpo in primates enables its homologue to be identified in the human thalamus by immunohistochemical labelling for calbindin. We have now analysed in detail the cytoarchitectonic characteristics of VMpo and its relationship with immunoreactivity for calbindin, substance P and calcitonin gene-related peptide (CGRP) in the human thalamus. The area in the posterolateral thalamus in which dense calbindin-immunoreactive fibre terminations are present coincides nearly completely with a distinct region that contains small to medium-sized cells with round or oval shapes that are aggregated in clusters separated by cell sparse areas. This region, which we identify as VMpo, is located posteromedial to the ventral posterior lateral (VPL) and ventral posterior medial (VPM) nuclei, ventral to the anterior pulvinar and centre median nuclei, lateral to the limitans and parafascicular nuclei and dorsal to the medial geniculate nucleus. Calbindin-immunoreactive fibres enter VMpo from the spinal lemniscus and form large patches of dense terminal-like staining over clusters of VMpo neurons. A few of these clusters also display terminal-like substance P labelling. Small bursts of CGRP staining are intercalated between the calbindin-labelled clusters, but there is little or no overlap between these two markers. CGRP immunoreactivity is also present over small, non-clustered neurons in the calbindin-negative area that separates VMpo from the VPL and VPM nuclei, which we denote as the posterior nucleus (Po). These observations provide a concise description of VMpo in the human thalamus. Further, they suggest that the lamina I spinothalamic tract fibres (represented by calbindin and probably also substance P immunoreactivity) and vagal-solitary-parabrachial afferents (represented by CGRP immunoreactivity) form closely related, but separate, termination fields that can be considered to represent different aspects of enteroceptive information regarding the physiological status of the tissues and organs of the body. The location of VMpo and the adjacent Po fits with clinical descriptions of the thalamic area from which pain, temperature and visceral sensations can be evoked by microstimulation, and where nociceptive and thermoreceptive neurons have been recorded in humans. It also corresponds to the area in which infarcts cause analgesia and thermoanaesthesia and can lead to the paradoxical development of central pain.
176 citations
"Pain and temperature processing in ..." refers background in this paper
...…in contrast with the wellcharacterized central pain syndromes attending focal lesions of thalamocortical circuitry (Schmahmann and Leifer, 1992; Blomqvist et al., 2000; Borsook, 2012), the phenomenology of pain and temperature processing and their neuroanatomical bases have not been studied in…...
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...Focal lesions of posterior thalamus and posterior insula are well known to produce central pain syndromes and microstimulation of these regions may produce pain and thermal sensations (Blomqvist et al., 2000; Mazzola et al., 2009, 2012; Sprenger et al., 2012)....
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...These include pulvinar, which may regulate cortical ‘set’ for interpreting painful stimuli (Shipp, 2003); and the posterior portion of the ventral medial thalamic nucleus, which is likely to serve as a dedicated spinothalamocortical relay for pain and temperature sensations and may play a fundamental role in signalling physiological body states (Blomqvist et al., 2000)....
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...However, in contrast with the wellcharacterized central pain syndromes attending focal lesions of thalamocortical circuitry (Schmahmann and Leifer, 1992; Blomqvist et al., 2000; Borsook, 2012), the phenomenology of pain and temperature processing and their neuroanatomical bases have not been studied in detail in FTLD....
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...It would be intriguing if this clinical phenotype had a specific microanatomical marker (Blomqvist et al., 2000)....
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TL;DR: The data suggest that, in spite of large and often bilateral receptive fields, pain representation shows some degree of somatotopic organization in the human insula.
Abstract: The question whether pain encoding in the human insula shows some somatotopic organization is still pending. We studied 142 patients undergoing depth stereotactic EEG (SEEG) exploration of the insular cortex for pre-surgical evaluation of epilepsy. 472 insular electrical stimulations were delivered, of which only 49 (10.5%) elicited a painful sensation in 38 patients (27%). Most sites where low intensity electric stimulation produced pain, without after-discharge or concomitant visually detectable change in EEG activity outside the insula, were located in the posterior two thirds of the insula. Pain was located in a body area restricted to face, upper limb or lower limb for 27 stimulations (55%) and affected more than one of these regions for all others. The insular cortex being oriented parallel to the medial sagittal plane we found no significant difference between body segment representations in the medio-lateral axis. Conversely a somatotopic organization of sites where stimulation produced pain was observed along the rostro-caudal and vertical axis of the insula, showing a face representation rostral to those of upper and lower limbs, with an upper limb representation located above that of the lower limb. These data suggest that, in spite of large and often bilateral receptive fields, pain representation shows some degree of somatotopic organization in the human insula.
174 citations
"Pain and temperature processing in ..." refers background in this paper
...…et al., 2000, 2002, 2009; Critchley et al., 2000, 2011; Brooks et al., 2005; Critchley, 2005; Henderson et al., 2007; Seeley et al., 2007a, b, 2009; Corbetta et al., 2008; Sridharan et al., 2008; Bjornsdotter et al., 2009; Mazzola et al., 2009, 2012; Menon and Uddin, 2010; Beissner et al., 2013)....
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...…responses (anterior cingulate, orbitofrontal and prefrontal cortices) (Greenspan and Winfield, 1992; Peyron et al., 2000; Singer et al., 2004; Brooks et al., 2005; Höistad and Barbas, 2008; Craig, 2009; Mazzola et al., 2009, 2012; Isnard et al., 2011; Moulton et al., 2012; Meerwijk et al., 2013)....
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...Focal lesions of posterior thalamus and posterior insula are well known to produce central pain syndromes and microstimulation of these regions may produce pain and thermal sensations (Blomqvist et al., 2000; Mazzola et al., 2009, 2012; Sprenger et al., 2012)....
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TL;DR: This study reveals that the insula is organized somatotopically with respect to muscle and cutaneous pain and that this organization is further separated according to the tissue in which the pain originates.
Abstract: The insula is involved in processing noxious information. It is consistently activated by acute noxious stimuli, can elicit pain on stimulation, and lesions encompassing the insula can alter pain perception. Anatomical tracing, electrophysiological and functional brain imaging investigations have suggested that the insula is somatotopically organized with respect to noxious cutaneous inputs. It has also recently been revealed that the anterior insula displays differential activation during cutaneous compared with muscle pain. Given this difference, it is important to determine if an insula somatotopy also exists for muscle pain. Using high-resolution functional magnetic resonance imaging (fMRI) we compared insula activation patterns in 23 subjects during muscle and cutaneous pain induced in the right leg and forearm. Group and frequency analyses revealed somatotopically organized signal increases in the posterior contralateral (left) and ipsilateral (right) anterior insula. Within the posterior contralateral insula, signal increases during both cutaneous and muscle forearm pain were located lateral and anterior to those evoked by leg pain, whereas in the ipsilateral anterior insula the pattern was reversed. Furthermore, within the ipsilateral anterior insula, muscle pain activated a region anterior to that activated by cutaneous pain. This somatotopic organization may be crucial for pain localization or other aspects of the pain experience that differ depending on both stimulation site and type of tissue activated. This study reveals that the insula is organized somatopically with respect to muscle and cutaneous pain and that this organization is further separated according to the tissue in which the pain originates.
172 citations
"Pain and temperature processing in ..." refers background or result in this paper
...In line with these findings and with previous studies in the healthy brain (Peyron et al., 2000; Craig, 2002; Singer et al., 2004; Henderson et al., 2007; Herde et al., 2007; Isnard et al., 2011; Borsook, 2012; Moulton et al., 2012), a VBM group analysis of patients’ brain MRIs delineated a distributed network of brain regions where atrophy was associated with altered responsiveness to pain or temperature....
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...The thalamo-insular network plays a broader role in integrating external and interoceptive sensory signals to generate a coherent body schema that defines bodily integrity and agency in relation to the environment (Lenz et al., 1993; Davis et al., 1999; Banzett et al., 2000; Craig et al., 2000, 2002, 2009; Critchley et al., 2000, 2011; Brooks et al., 2005; Critchley, 2005; Henderson et al., 2007; Seeley et al., 2007a, b, 2009; Corbetta et al., 2008; Sridharan et al., 2008; Bjornsdotter et al., 2009; Mazzola et al., 2009, 2012; Menon and Uddin, 2010; Beissner et al., 2013)....
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...In line with these findings and with previous studies in the healthy brain (Peyron et al., 2000; Craig, 2002; Singer et al., 2004; Henderson et al., 2007; Herde et al., 2007; Isnard et al., 2011; Borsook, 2012; Moulton et al., 2012), a VBM group analysis of patients’ brain MRIs delineated a…...
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...…1993; Davis et al., 1999; Banzett et al., 2000; Craig et al., 2000, 2002, 2009; Critchley et al., 2000, 2011; Brooks et al., 2005; Critchley, 2005; Henderson et al., 2007; Seeley et al., 2007a, b, 2009; Corbetta et al., 2008; Sridharan et al., 2008; Bjornsdotter et al., 2009; Mazzola et al.,…...
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