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.
Citations
More filters
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....
[...]
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
References
More filters
TL;DR: The high odds ratio at the ventral posterior nucleus-pulvinar border zone indicates that this area is crucial in the pathogenesis of thalamic pain and demonstrates the feasibility of identifying patients at risk of developing central post-stroke pain of Thalamic origin early afterThalamic insults.
Abstract: Central post-stroke pain of thalamic origin is an extremely distressing and often refractory disorder. There are no well-established predictors for pain development after thalamic stroke, and the role of different thalamic nuclei is unclear. Here, we used structural magnetic resonance imaging to identify the thalamic nuclei, specifically implicated in the generation of central post-stroke pain of thalamic origin. Lesions of 10 patients with central post-stroke pain of thalamic origin and 10 control patients with thalamic strokes without pain were identified as volumes of interest on magnetic resonance imaging data. Non-linear deformations were estimated to match each image with a high-resolution template and were applied to each volume of interest. By using a digital atlas of the thalamus, we elucidated the involvement of different nuclei with respect to each lesion. Patient and control volumes of interest were summed separately to identify unique areas of involvement. Voxelwise odds ratio maps were calculated to localize the anatomical site where lesions put patients at risk of developing central post-stroke pain of thalamic origin. In the patients with pain, mainly lateral and posterior thalamic nuclei were affected, whereas a more anterior-medial lesion pattern was evident in the controls. The lesions of 9 of 10 pain patients overlapped at the border of the ventral posterior nucleus and the pulvinar, coinciding with the ventrocaudalis portae nucleus. The lesions of this area showed an odds ratio of 81 in favour of developing thalamic pain. The high odds ratio at the ventral posterior nucleus-pulvinar border zone indicates that this area is crucial in the pathogenesis of thalamic pain and demonstrates the feasibility of identifying patients at risk of developing central post-stroke pain of thalamic origin early after thalamic insults. This provides a basis for pre-emptive treatment studies.
96 citations
"Pain and temperature processing in ..." refers background in this paper
...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)....
[...]
TL;DR: Only on itch, but not on heat pain, negative BOLD signals were found in the subgenual anterior cingulate cortex and the amygdala, and the latter results may be associated with the itch induced urge to scratch.
Abstract: Functional brain imaging studies on itch usually use histamine as a stimulus and, in consequence, have to cope with the highly variable time course of this particular itch sensation. In this study, we describe a novel method of histamine application. To provoke itch, a mixture of histamine and codeine was applied through intradermally positioned microdialysis fiber. The itch was terminated by lidocaine application through the same fiber. During one fMRI session, this procedure was repeated four times in four different microdialysis fibers, including one placebo control. Itch ratings of the subjects were correlated with blood-oxygen-level-dependent (BOLD) effects. In a subsequent experiment performed in the same fMRI session, heat pain was provoked in the right forearm with a Peltier thermode. During both experiments, activation clusters were found in brain areas that have been described previously to be frequently activated in response to painful stimuli. This includes prefrontal areas, supplementary motor areas (SMA), premotor cortex, anterior insula, anterior midcingulate cortex, S1, S2, thalamus, basal ganglia, and cerebellum. In general, itch stimulation entailed more activation clusters, in particular on the contralateral brain side. Only on itch, but not on heat pain, negative BOLD signals were found in the subgenual anterior cingulate cortex and the amygdala. The latter results may be associated with the itch induced urge to scratch. Amygdala deactivation may be related to the preparation of scratching by aiming to dissolve the otherwise aversive effects of the noxious scratch stimuli. These negative BOLD effects may also be attributed to the stressful character of itch stimulation.
95 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....
[...]
...…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…...
[...]
...…correlates of pain processing in the healthy brain comprise a distributed network with critical hubs in thalamus and insula and somatosensory, prefrontal, anterior temporal, limbic and subcortical connections (Peyron et al., 2000; Craig, 2002; Herde et al., 2007; Moulton et al., 2012)....
[...]
TL;DR: It is proposed that music constitutes a distinct domain of non-verbal knowledge but shares certain cognitive organizational features with other brain knowledge systems, including dissociable cognitive mechanisms process knowledge derived from physical sources and the knowledge of abstract musical entities.
Abstract: Despite much recent interest in the clinical neuroscience of music processing, the cognitive organization of music as a domain of non-verbal knowledge has been little studied. Here we addressed this issue systematically in two expert musicians with clinical diagnoses of semantic dementia and Alzheimer’s disease, in comparison with a control group of healthy expert musicians. In a series of neuropsychological experiments, we investigated associative knowledge of musical compositions (musical objects), musical emotions, musical instruments (musical sources) and music notation (musical symbols). These aspects of music knowledge were assessed in relation to musical perceptual abilities and extra-musical neuropsychological functions. The patient with semantic dementia showed relatively preserved recognition of musical compositions and musical symbols despite severely impaired recognition of musical emotions and musical instruments from sound. In contrast, the patient with Alzheimer’s disease showed impaired recognition of compositions, with somewhat better recognition of composer and musical era, and impaired comprehension of musical symbols, but normal recognition of musical emotions and musical instruments from sound. The findings suggest that music knowledge is fractionated, and superordinate musical knowledge is relatively more robust than knowledge of particular music. We propose that music constitutes a distinct domain of non-verbal knowledge but shares certain cognitive organizational features with other brain knowledge systems. Within the domain of music knowledge, dissociable cognitive mechanisms process knowledge derived from physical sources and the knowledge of abstract musical entities.
93 citations
"Pain and temperature processing in ..." refers background in this paper
...…inspection of individual magnetic resonance brain images and the relaxed VBM analysis, and chimes with previous evidence implicating this region in nonverbal sensory semantic (including pain and somatic) processing (Chan et al., 2009; Goll et al., 2010; Omar et al., 2010, 2013; Hsieh et al., 2011)....
[...]
TL;DR: Findings indicate that in some patients with behavioural variant frontotemporal dementia, low volume of subcortical reward-related structures is associated with increased pursuit of primary rewards, which may be a product of increased thalamocortical feedback.
Abstract: Behavioural variant frontotemporal dementia is characterized by abnormal responses to primary reward stimuli such as food, sex and intoxicants, suggesting abnormal functioning of brain circuitry mediating reward processing. The goal of this analysis was to determine whether abnormalities in reward-seeking behaviour in behavioural variant frontotemporal dementia are correlated with atrophy in regions known to mediate reward processing. Review of case histories in 103 patients with behavioural variant frontotemporal dementia identified overeating or increased sweet food preference in 80 (78%), new or increased alcohol or drug use in 27 (26%), and hypersexuality in 17 (17%). For each patient, a primary reward-seeking score of 0-3 was created with 1 point given for each target behaviour (increased seeking of food, drugs, or sex). Voxel-based morphometry performed in 91 patients with available imaging revealed that right ventral putamen and pallidum atrophy correlated with higher reward-seeking scores. Each of the reward-related behaviours involved partially overlapping right hemisphere reward circuit regions including putamen, globus pallidus, insula and thalamus. These findings indicate that in some patients with behavioural variant frontotemporal dementia, low volume of subcortical reward-related structures is associated with increased pursuit of primary rewards, which may be a product of increased thalamocortical feedback.
87 citations
"Pain and temperature processing in ..." refers background in this paper
...…of these diseases (Bathgate et al., 2001; Snowden et al., 2001; Pijnenburg et al., 2004; Jesso et al., 2011; Omar et al., 2011a, 2013; Rohrer et al., 2012; Fletcher et al., 2013; Downey et al., 2014; Landqvist Waldo et al., 2014; Perry et al., 2014; Woolley et al., 2014; Zhou and Seeley, 2014)....
[...]
...…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)....
[...]
...This work has demonstrated 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)....
[...]
...…2011a; Kumfor and Piguet, 2012; Zhou and Seeley, 2014) and may show obsessional attachment to particular stimuli such as sweet foods (Woolley et al., 2014) or music (Fletcher et al., 2013) suggesting a generic disturbance in processing reward and attributing hedonic valence (Perry et al., 2014)....
[...]
TL;DR: The results indicate that heat intensity is encoded by the somatosensory cortices, and that pain evaluation may either arise from multimodal evaluative processes, or is a distributed process.
Abstract: The discovery of cortical networks that participate in pain processing has led to the common generalization that blood oxygen level-dependent (BOLD) responses in these areas indicate the processing of pain. Physical stimuli have fundamental properties that elicit sensations distinguishable from pain, such as heat. We hypothesized that pain intensity coding may reflect the intensity coding of heat sensation during the presentation of thermal stimuli during fMRI. Six 3T fMRI heat scans were collected for 16 healthy subjects, corresponding to perceptual levels of “low innocuous heat,” “moderate innocuous heat,” “high innocuous heat,” “low painful heat,” “moderate painful heat,” and “high painful heat” delivered by a contact thermode to the face. Subjects rated pain and heat intensity separately after each scan. A general linear model analysis detected different patterns of brain activation for the different phases of the biphasic response to heat. During high painful heat, the early phase was associated with significant anterior insula and anterior cingulate cortex activation. Persistent responses were detected in the right dorsolateral prefrontal cortex and inferior parietal lobule. Only the late phase showed significant correlations with perceptual ratings. Significant heat intensity correlated activation was identified in contralateral primary and secondary somatosensory cortices, motor cortex, and superior temporal lobe. These areas were significantly more related to heat ratings than pain. These results indicate that heat intensity is encoded by the somatosensory cortices, and that pain evaluation may either arise from multimodal evaluative processes, or is a distributed process.
82 citations
"Pain and temperature processing in ..." refers background in this paper
...Temperature sensibility is mediated by a closely overlapping network (Craig, 2002; Moulton et al., 2012)....
[...]
...…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)....
[...]
...…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…...
[...]
...…correlates of pain processing in the healthy brain comprise a distributed network with critical hubs in thalamus and insula and somatosensory, prefrontal, anterior temporal, limbic and subcortical connections (Peyron et al., 2000; Craig, 2002; Herde et al., 2007; Moulton et al., 2012)....
[...]