Subliminal (latent) processing of pain and its evolution to conscious awareness

Abstract

By unconscious or covert processing of pain we refer to nascent interactions that affect the eventual deliverance of pain awareness. Thus, internal processes (viz., repeated nociceptive events, inflammatory kindling, reorganization of brain networks, genetic) or external processes (viz., environment, socioeconomic levels, modulation of epigenetic status) contribute to enhancing or inhibiting the presentation of pain awareness. Here we put forward the notion that for many patients, ongoing sub-conscious changes in brain function are significant players in the eventual manifestation of chronic pain. In this review, we provide clinical examples of nascent or what we term pre-pain processes and the neurobiological mechanisms of how these changes may contribute to pain, but also potential opportunities to define the process for early therapeutic interventions.

Keywords: Awareness; Brain; Chronic pain; Cognition; Iceberg; Neural networks; Subconscious.

Fig. 1

The Iceberg Principle and Chronic Pain (see Text). State I: No Pain Behavior (Left). Under healthy conditions, the tip of the iceberg presents with an adaptive behavior based on underlying normal brain network interactions that may be dependent on environment, health status, genetic status, etc. State II: Subliminal “Pain” (Middle): A pain event (viz., injury, a disease, a genetic condition, etc.) produces a transition fromm State I to State II. Multiple processes may be at play following a perturbation that may be endogenous (e.g., depression) or exogenous (e.g., trauma). These may be categorized as: (a) Network malfunction; (b) Network Disarray; (c) Pain Connectome Development; and (d) Pain Connectome Formation. Thus, latent processes are ongoing. State III: Overt Pain Behavior (Right): A number of changes in brain systems including morphometric, chemical and functional metrics that lead to a brain state of chronic pain (Pain Connectome Definition). The behavior becomes overt (and usually progressively worse) at a particular time. An altered brain system evolves with new connections, changes in grey matter volume to produce a ‘lighter iceberg’ where now more is obvious above the waterline (i.e., overt behavior), while ongoing dysregulation may be ongoing. At this point, the brain may rekindle its original form with pain behavior resolving, or remain in the same status (i.e., pain behavior becoming stuck). State III may continue with no resolution or reverse partially (State IV) or completely through similar processes noted in State II. With symptomatic reversal, the brain state is not fully ‘cured’ (i.e., does not revert completely to State I), but remains sensitized to pain recrudescence (see Text). State IV, not shown here, is the process of reversal (see Fig. 2 and Text).

Fig. 2

A putative model for pain relapse based on similar neurobiological mechanisms involved in pain and in addiction (see text). 1: Insult/Injury/Disease: Disease state produces acute pain as a result of insult (e.g., chemical, toxic), injury (e.g., surgery, chemotherapy), or disease (e.g., genetic, Parkinson’s, stroke) affecting either the central nervous system (CNS) or peripheral nervous system (PNS) or both. 2: Neuroadaptations: The peripheral and central changes due to the initial insult/injury/disease may endure or cease. 3: Dysfunction in Brain Systems: Using the Basolateral Amygdala (BLA) as an example, nociceptive input may produce changes in brain regions, in this case leading to negative affective states and an increase in pain conditioning to heretofore neutral stimuli. 4: Psychosocial and Biological Exacerbators or Inhibitors: Various factors such as social stress, therapeutic interventions, etc. may exacerbate the processes occurring in brain systems. 5: Neural Networks: Efferent projections of the BLA driving the key emotional, cognitive and behavioral components contributing to the relapse process, namely distress and other negative affective states along with poor inhibitory control, anhedonia, impulsivity and compulsivity. Note that these changes may be increased (red) or decreased (blue) based on afferent drive. 6: Relapse: Pain may be a remitting and relapsing condition. Drivers that alter brain state may change this from subliminal pain (treated) to regain a symptomatic pain state.

Fig. 3

Evolution Pain – Temporal Integration of Unconscious Perception to Pain Perception. The changes progress (black arrows) through different States I-III and may reverse (dashed blue arrows) State IV in the subliminal condition (Blue Circle); see Text for details on State specific processes. A: Normal/Healthy Brain State: Brain circuits (viz., connectivity at rest, functional responsivity and structure) are normal and at rest show normal connectivity (including Default Mode Network). These circuits respond normally to physiological stimuli (e.g., nociceptive input) and then revert back to their homeostatic state. In healthy individuals, the overall strength and connectivity of brain regions is high and responsive in this state (State I). B: Subliminal Pain State: Following injury, disease or genetic processes that are involved in the eventual development of the pain phenotype, brain circuits become abnormal. Individuals with a premorbid state that enhances their susceptibility to pain (e.g., genetic, sex, emotional) are more likely to progress within Stage II (see (George et al., 2016). In the subliminal or subconscious state these processes escape conscious perception through no or little cortical involvement or through inhibitory processes. The pre-pain state (State III) may include the development of a progressive aversive state with changes in reward function. Such changes may depend on, for example, opioidergic tone (Borsook, 2017). This state may be the harbinger of the pain phenotype or the ‘pain-free’ state with treatment or natural devolution (State IV). Putative functional changes in pain modulation, concentration of inhibitory neurons, or tone of pain related reward-aversion or cognitive and emotional circuits contribute to the maintenance of diminished phenotypic expression. C: Conscious Perception: The conscious phenotype evolves principally through aberrant brain connectivity that now involves cortical regions. Multiple changes in the brain structure and function evolve and may be responsive to treatment (see (Puiu et al., 2016) or resistant to treatment and become entrenched (stuck).

Fig. 4

Set Point and Descending Modulation: The figure shows Biological and Physiological influences on the Brain State. When a underlying process that causes chronic pain is initiated, subconscious processes persist as a result of antecendant or evolving pacompensatory or robust (+) modulatory tone and brain processes including alterations in brain connectivity (blue brain) that are evolving toward the clinical expression of pain are inhibited. The size of the blue circles represents the level of enhanced modulatory tone. Conceptually patients may have no or minimal pain until they reach an inflection point (black circle). In the clinical sense modulatory tone fails (−) and the pain connectome now presents with the pain behavior/phenotype. The magnitude of failure may correlate with the relative level of pain. The transitions at the set points contribute to conscious vs. unconscious. (See text). (See text).