A predictive coding framework of allostatic-interoceptive overload in frontotemporal dementia

Abstract

Recent allostatic-interoceptive explanations using predictive coding models propose that efficient regulation of the body's internal milieu is necessary to correctly anticipate environmental needs. We review this framework applied to understanding behavioral variant frontotemporal dementia (bvFTD) considering both allostatic overload and interoceptive deficits. First, we show how this framework could explain divergent deficits in bvFTD (cognitive impairments, behavioral maladjustment, brain atrophy, fronto-insular-temporal network atypicality, aberrant interoceptive electrophysiological activity, and autonomic disbalance). We develop a set of theory-driven predictions based on levels of allostatic interoception associated with bvFTD phenomenology and related physiopathological mechanisms. This approach may help further understand the disparate behavioral and physiopathological dysregulations of bvFTD, suggesting targeted interventions and strengthening clinical models of neurological and psychiatric disorders.

Keywords: allostatic interoception; allostatic overload; frontotemporal dementia; interoception; predictive coding.

Figure 1.

Predictive coding and allostatic interoception. (A) Predictive coding is a general algorithm that can be instantiated among different biological substrates and their hierarchies [120]. It has been widely applied to cortical brain activity (i.e., standard predictive coding), brain activity and proprioception (i.e., active inference), and brain activity and interoception (i.e., interoceptive inference). Three versions of predictive coding are schematically illustrated. In the first case, the minimization of prediction error is given by the updating of predictions to accommodate unexpected sensory signals. In the second case, the minimization is through performing actions that confirm predictions about sensory inputs. Finally, in the third case, the minimization is reached by performing actions to confirm predictions of interoceptive signals. (B) Allostasis refers to a general mechanism of bodily regulation by adaptation and changes. Allostasis can be instantiated at different levels of the body substrate. Three examples of interoceptive allostasis are illustrated. Left: greater oxygen requirement in the muscles during a fight or flight situation, leading to increased blood supply to the relevant muscles and the mobilization of resources needed to perform that redistribution (e.g., increasing cardiac input); Middle: reduction of heart rate during sleep to align with the reduced metabolic needs. Right: vasoconstriction (i.e., narrowing of blood vessels) when the body is facing low temperatures to conserve core temperature by reducing the blood flow to the skin capillaries.

Figure 2.

Levels of the allostatic–interoceptive system and its potential characterization in behavioral variant frontotemporal dementia (bvFTD). Multimodal allostatic load measurement can be used at different levels to characterize bvFTD symptomatology and physiopathology. The allostatic–interoceptive system (A) relies on the allostatic– interoceptive network (AIN), whose main hubs include the anterior mid-cingulate cortex (aMCC), pregenual anterior cingulate cortex (pACC), subgenual anterior cingulate cortex (sgACC), dorsal amygdala (dAmy), agranular insula (vaIns), dorsal mid-insula (dmIns), and dorsal posterior insula (dpIns). Specifically, the limbic cortices send prediction signals (unbroken magenta lines) and receive prediction error signals (dashed magenta lines) from the internal milieu, evoking psychological responses. Accordingly, multimodal measures of allostatic load can be used (B). At the cerebral level, the structure of the AIN hubs can be assessed by voxelbased morphometry (VBM) technique and its functional connectivity by resting-state functional magnetic resonance imaging (rsfMRI) technique. The cardiocerebral level can be evaluated by heartbeat-evoked potential (HEP). Moreover, the peripheral level can be assessed by cardiovascular, metabolic, inflammatory, stress hormone, and neurodegenerative biomarkers, constituting an allostatic load battery. Finally, the psychological level can be evaluated by the allostatic–interoceptive task and psychosocial measures such as the psychosocial index (PSI) and the diagnostic criteria for psychosomatic research (DCPR). Some multimodal impairments are expected in bvFTD patients (C). At the cerebral level, the AIN is selectively compromised in bvFTD, along with early structural and functional compromise of core AIN hubs. At the cardiocerebral level, less negative HEP during active tasks and more negative resting-state HEP (rsHEP) in resting state and noncardiac monitoring tasks are also expected. At the peripheral level, bvFTD may present altered biomarker parameters, leading to a high allostatic load index compared with healthy controls (HC). At the psychological level, bvFTD patients will present a dissonance among the objective and subjective arousal measures and abnormal responses to environmental demands. Figures in panels (B) and (C) are illustrational examples and do not represent actual data.

Figure 3.

The proposed model, summarized in the figure, expands previous allostatic–interoceptive models to bvFTD manifestations. (A) Prefrontal cortex (PFC), anterior mid-cingulate cortex (aMCC), pregenual cingulate cortex (pACC), subgenual anterior cingulate cortex (sgACC), agranular insula (vaIns), orbitofrontal cortex (OFC), and dorsal amygdala (Amy) are placed on top of the hierarchy. These regions are thought to modulate their activity by within-level interactions (arrows not shown) and generate predictions about the activity of other systems. In particular, they send visceromotor (yellow lines) and interoceptive predictions (dark lines) to the relay regions: the dorsal mid-insula (dmIns) and dorsal posterior insula (dpIns), thalamus (Thal), hypothalamus (HT). These relay regions integrate predictions from top regions and prediction errors from peripheral regions to generate their corresponding predictions and feedback. In this relay level, the parabrachial nucleus (PBN) and nucleus of the solitary tract (NTS) also receive predictions from dpIns, THAL, and HT. The types of predictions and errors correspond to visceromotor, neural interoceptive, and non-neural interoceptive communication. Finally, the periphery, formed by organs (heart, gut) but also autonomic, neuroendocrine, and immune systems, receives signals and communicates errors to relay regions (red lines), closing the loops through action. (B) A normal state of functioning of the organism is characterized by optimal matching among top-down predictions and sensory inputs, leading to an error minimization. In bvFTD, a predictive coding proposes a sui generis interoceptive deficits and elevated peripheral and immunological stress, leading to imprecise predictions overcharged by a feedback loop of inaccurate prediction errors, impairing error minimization. This would lead to an overconsumption of resources by the top regions to accommodate top-down predictions and sensory inputs, therefore impacting again the interoceptive system functionality. Similarly, the dysregulated responses to environmental stressors, one of the core bvFTD symptomatology, could be understood as a consequence of imprecise top-down predictions about the body’s peripheral level of energy predisposed to perform actions, therefore overreacting to seemingly inoffensive environmental stressors and underreacting to relevant ones. As actions would be inadequate, prediction errors would overcharge.