Altered Behavioral and Autonomic Pain Responses in Alzheimer’s Disease Are Associated with Dysfunctional Affective, Self-Reflective and Salience Network Resting-State Connectivity

Abstract

While pain behaviors are increased in Alzheimer’s disease (AD) patients compared to healthy seniors (HS) across multiple disease stages, autonomic responses are reduced with advancing AD. To better understand the neural mechanisms underlying these phenomena, we undertook a controlled cross-sectional study examining behavioral (Pain Assessment in Advanced Dementia, PAINAD scores) and autonomic (heart rate, HR) pain responses in 24 HS and 20 AD subjects using acute pressure stimuli. Resting-state fMRI was utilized to investigate how group connectivity differences were related to altered pain responses. Pain behaviors (slope of PAINAD score change and mean PAINAD score) were increased in patients vs. controls. Autonomic measures (HR change intercept and mean HR change) were reduced in severe vs. mildly affected AD patients. Group functional connectivity differences associated with greater pain behavior reactivity in patients included: connectivity within a temporal limbic network (TLN) and between the TLN and ventromedial prefrontal cortex (vmPFC); between default mode network (DMN) subcomponents; between the DMN and ventral salience network (vSN). Reduced HR responses within the AD group were associated with connectivity changes within the DMN and vSN—specifically the precuneus and vmPFC. Discriminant classification indicated HR-related connectivity within the vSN to the vmPFC best distinguished AD severity. Thus, altered behavioral and autonomic pain responses in AD reflects dysfunction of networks and structures subserving affective, self-reflective, salience and autonomic regulation.

Dysautonomia in Alzheimer's Disease

“…For instance, in mild cognitive impairment, the basal nucleus of Meynert (the main source of cholinergic innervation of the cortex) undergoes decreased functional connectivity to the left insula and claustrum (which integrate information from various brain regions through their reciprocal projections to neocortex, limbic, and paralimbic regions) as well as neuronal loss with subsequent volume reduction as a result of β-amyloid deposition, neurofibrillary tangles formation, and impaired trophic support [ 23 , 24 ]. However, enhanced connectivity between different structures has also been described, possibly as a mechanism of functional reallocation, to compensate for cognitive decline [ 11 ]. One example is the increased connectivity between temporal limbic network and a cluster in the ventromedial prefrontal cortex in patients with behavioral over-responsiveness to pain, possibly extending to other negative emotional traits [ 11 ].…”

“…Over the past 30 years, evidence that ANS dysfunction develops in patients with AD and worsens with advanced disease has emerged [ 11 ]. Moreover, it might occur before the onset of the clinical symptoms of dementia [ 12 ].…”

“…In AD, in addition to the impaired autonomic homeostasis of physical efforts, inappropriate autonomic responses are also elicited by cognitive challenge and strong emotions, pointing to a defective connection between mental status and autonomic reply [ 4 , 9 ]. Moreover, altered autonomic acute pain responses (i.e., coherent adaptive responses to noxious stimuli, such as sympathetic activation with increased heart rate) signal impaired pain processing, possibly due to disconnection between behavioral and autonomic responses [ 11 ]. Compared to controls, patients with AD have increased pain behaviors and reactivity with reduced autonomic measures [ 11 ].…”

“…Moreover, altered autonomic acute pain responses (i.e., coherent adaptive responses to noxious stimuli, such as sympathetic activation with increased heart rate) signal impaired pain processing, possibly due to disconnection between behavioral and autonomic responses [ 11 ]. Compared to controls, patients with AD have increased pain behaviors and reactivity with reduced autonomic measures [ 11 ].…”

A Technical Note on the PainChek™ System: A Web Portal and Mobile Medical Device for Assessing Pain in People With Dementia

“…Facial expressions are also one of the strongest indicators of pain particularly in people with cognitive impairment or dementia (Kunz et al, 2007 , 2009 ). There is a significant increase of pain behaviors in AD compared to healthy control (Lautenbacher et al, 2013 ; Beach et al, 2017 ). Horgas et al ( 2009 ) indicated that the resultant numerical scores from summating pain behaviors are closely linked to the self-report of pain.…”