I suggest RPs—as motor predictions—are biophysically realized via accumulation of recurrent neural activity in frontal-parietal action-oriented proprioceptive body maps (Figures 6–8), coupling with cingulate-insula salience networks, with patterns of enaction released when critical thresholds are surpassed in control hubs (e.g., pre-supplementary motor area) [354]. This threshold-crossing could be understood as an "ignition event" as described by global workspace theories [73,74,227,334], so constituting one (of multiple) means by which consciousness enters causal streams to leading to action. These periods of non-linear increases in activity may also correspond to periods where action-oriented body maps possess the highest degrees of integrated information, whose estimation could potentially correlate with measured strength of will [73]. Conscious intentions (as conjoined beliefs-desires) would contribute to ramping activity via the kinds of affectively-driven mental simulations described above [355,356] (Figure 5). This hypothesis of imaginative planning contributing to RPs is consistent with observed patterns of dopaminergic discharges, and also decreasing variance (and larger magnitude waveforms) leading up to volitional actions, indicative of value-based control processes [357,358].

Neurophenomenologically (Figures 7 and 8), the feeling of "urge" preceding action corresponds to (non-linear) positive feedback interactions between frontal action hierarchies [351], posterior body-space-affordance hierarchies [94], and insulo-cingular (interoceptively-grounded) salience hierarchies [162] (Figure 6). These feelings are more than mere epiphenomena, influencing attentional selection for affective states, thereby modulating effective connectivity between these control hierarchies [154,160] (Figure 5). The stream of consciousness would further contribute to action selection via the counterfactual processing (e.g., simulated movements) and imaginative planning enabled by the hippocampal system [139,214,216,359] (Figure 4), including with respect to "Type 1" planned or "Type 2" capricious RPs [360]. These systems also contribute to imagining/predicting the consequences of more complex (and potentially meaningful) decisions [348], which would involve greater hierarchical depth and multiple realizability via particular actions from a "contrastive causation" perspective [361]. At these higher levels of abstraction, maximal explanatory power would be found in terms of more coarse-grained descriptions such as personhood and self-consciousness [162,207,264,315], so providing further neurocomputational grounding for agency. Finally, the "isolated qualia" model described above could also be relevant for explaining gaps between estimated 'decision' times and measured RPs, in that capricious actions will be more likely to be associated with quale-states that are difficult to take up into coherently introspectable streams of experience, yet nonetheless involve meaningful driving of dynamics by person-relevant values.

**Figure 7.** (**a**) Experience deciding to stand in order to make tea (see Table 1 and Figures 2, 4 and 5). The individual alternates between (1) perceiving sitting with an empty cup, and (2) imagining actions related to achieving the desired goal of obtaining tea. As the individual imagines (or rehearses) possible actions, feelings of urge accumulate across multimodal body maps, which peak accompanying the overt enaction of standing. (**b**) Experience deciding to move one's hand in a Libet paradigm. The individual alternates between (1) perceiving one's hand and the clock and (2) imagining button-pressing. As possible actions are imagined/rehearsed, feelings of "urge" accumulate across multimodal body maps, which peak accompanying the overt action of button-pressing.

**Figure 8.** Readiness potential reflecting the accumulation of urge from simulated actions. (**a**) Neural processes accompanying decision to stand (see Figure 7a). (**b**) Neural processes accompanying decision to press a button in a Libet-type paradigm (see Figure 7b). Imaginative simulations (alpha oscillations, blue shading) are hippocampally orchestrated (Figure 4) via theta oscillations (yellow shading) and cross-frequency phased coupled nested gamma. Potential actions are selected based

on estimation of their relative expected value, with contrasting realized by coupled maps/graphs of the hippocampal system and vmPFC, with estimation and selection particularly influenced by the NAc and associated cortical systems. Lightly colored red hexagons indicate potential trajectories through (generalized) space, and dark red hexagons indicate chosen directions (either in imagination or reality). Imaginings cause increasing expectation (beta oscillations, red shading) for the value of potential actions, with corresponding accumulation of recurrent activity in body maps resulting in overt enaction once critical thresholds are surpassed. Abbreviations: Nac = nucleus accumbens; vmPFC = ventromedial prefrontal cortex; dmPFC = dorsomedial prefrontal cortex; SMA = supplementary motor area; Pre-SMA = presupplementary motor area; SEF = supplementary eye fields.

#### *5.4. Qualia Explained?*

Above we have considered prototypical qualitative aspects of experience, including pleasure, pain, and desire. Each of these "qualia" can be extremely rich in terms of their particular characteristics, underlying mechanisms, and functionalities, and the ways these vary across contexts. In what follows, I adopt a neurophenomenological approach [4,362–364] in beginning to explore how principles and mechanisms from FEP-AI can be used to cast light on how these aspects of our existence can be so fundamental, yet remain so mysterious.

#### 5.4.1. Emotions and Feelings

In attempting to analyze the nature of emotional experience, perhaps some of the continuing mystery is due to a lack of agreement on terminology. Damasio et al. [63,156,285,365], argue emotions can be ascribed to the value-oriented behavior of all living organisms, including single-celled organisms such as bacteria. However, Damasio reserves the word "feeling" for the conscious re-representation of emotions. Feldman-Barrett and LeDoux [179,284], in contrast, object to this more inclusive conceptualization of emotion, arguing instead that emotional language should be reserved for consciously-experienced affective states that are expressed and constructed through interpretive processes. LeDoux has even gone as far as to claim that emotions only arose via cultural evolution *after* the advent of language.

There are clear merits to both points of view. While less inclusive conceptualizations may avoid some confusions, they also miss opportunities to identify ways in which value and integrated informational dynamics are essential to all life [366,367]. I propose adopting an intermediate position, viewing emotions and feelings as respective action and perception components of action-perception cycles over large-scale changes in organismic modes. Relevant macroscale dynamics include diverse phenomena ranging from autonomic functions, to musculoskeletal body modifications [368], to nervous system alterations via neuromodulatory systems and effective connectivity from neural areas with high effective centrality (e.g., the amygdala complex). In addition to this cybernetic formulation of emotions as a kind of action, and feelings as a kind of perception, we may add an additional distinction as to the extent to which we are conscious of expressed emotions and sensed feelings. While potentially counter-intuitive, from this more inclusive point of view we may have both conscious and unconscious emotions, as well as conscious and unconscious feelings. This use of terminology would support many of the rationales for the positions described above, as well as many folk intuitions as expressed in normal linguistic use. If useful for communicative clarity and ethical considerations, additional distinctions can be made as to whether consciousness involves basic phenomenal awareness or is of a more complex access or autonoetic variety.

LeDoux [179,369] has argued that animals without complex language cannot be said to possess emotions, but merely have functional activity within "survival circuits". These claims are justified by language providing necessary syntactic structures for the construction of complex extended self-models; or as LeDoux states: "No self, no fear." This emphasis on the foundational importance of selfhood for conscious experience is largely compatible with the view presented here, and elsewhere [91]. Without extended selfprocesses, emotions and feelings will be qualitatively different than the kinds of emotions and feelings constructed by humans governed by (and governing) a symbolic order of

being. However, within this cybernetic formulation, functional activity of "survival circuits" could contribute to the generation of emotions as large-scale organismic modes, yet still not be consciously expressed or felt.

Hence, all evolved cybernetic systems could be said to have emotions and feelings, but only systems capable of coherent integrative world modeling would consciously experience those affects [73,74]. These conscious systems likely include all mammals and birds, and possibly reptiles or fish if pallial tissue [370,371] is sufficiently elaborated to model systemworld states with spatial, temporal, and causal coherence. Thus, we may take a middle way between the perspectives described above in viewing emotions and feelings as ubiquitous features of life, while simultaneously recognizing qualitative differences that emerge when these phenomena are associated with various kinds of consciousness. Both more and less inclusive conceptual stances are reasonable, but with respect to qualitatively different kinds of affective phenomena.

#### 5.4.2. What Is Value? Reward Prediction Errors and Self-Annihilating Free Energy Gradients

In FEP-AI, all living systems can be described as obeying a single objective of selfmodel-evidence maximization and prediction error minimization [372]. In this framework, organisms begin development by implicitly predicting the rectification of homeostatic (and later reproductive) prediction errors, so forming a foundation out of which all subsequent models grow. With experience, these modeling efforts come to apply to the modeling processes themselves and the experiences they generate, including models of what is likely to cause changes in prediction error. In this way, we come to predict ourselves minimizing prediction errors and experiencing associated mental states, including with respect to emotions and feelings. Through this associative chaining of memories from early organismic experiences, biological agents begin life being reinforced/punished as they continually attempt to engage in predictive homeostatic rectification (i.e., allostasis). However, organisms progressively learn sensorimotor contingencies for making these reward-related stimuli more/less likely to be available. Mechanistically, representations detecting these contingencies are themselves connected to midbrain value signals—e.g., orbitofrontal cortex accumbens shell ventral tegmental area dopamine [110]—so allowing cortical models to drive reinforcement/punishment and shape adaptive policies for enaction.

This account has parallels with work on meta-reinforcement learning [342], where systems are initially given primary reward functions from which more capable secondary reward functions may be acquired from experience. From an FEP-AI perspective, these secondary predictions would constitute higher-order beliefs about likely patterns of prediction error minimization. According to candidate trace models [373], dopamine is likely to strengthen whatever predictions were most likely to contribute to its release by being most active leading up to phasic increases, so providing a partial solution to the credit assignment problem. If phasic dopamine increases are proportional to the rate of change of prediction error rectification [76,374–377], then the more quickly something minimizes prediction error, the more it will come to be predicted.

In these ways, organisms come to predict states of initial increases in prediction error, so that these free energy gradients (experienced as desire, or "wanting") may be destroyed through enaction (experienced as pleasure, or "liking") [378,379]. The creation and destruction of these gradients of anticipatory and consummatory reward will then stimulate dopamine release proportional to magnitudes of free energy minimization, as well as temporal intervals over which prediction errors are reduced [380]. These experiences, in turn, update beliefs and desires, whose counterfactual nature provide further sources of free energy to motivate future behavior. These mechanisms will shape organisms to predict themselves not only in homeostatic and reproductive states, but also diverging from these desirable modes of being, to the degree that such discrepancies between goals and actualities are anticipated to be manageable. Thus, through experience, we come to predict ourselves encountering initially negatively valanced states, which may become positively

valanced when we annihilate these free energy gradients through either imagined or overt enaction, so establishing new goals/gradients to pursue/destroy in the future.

#### 5.4.3. Curiosity and Play/Joy

This prediction of prediction error minimization creates an interesting setup in which organisms end up being surprised when they do not find themselves riding down steep enough gradients of prediction error [76,374]. This is exactly what evolution would 'want' [17,381], since there is no limit to how evolutionarily fit an organism can be, and so organisms ought to always seek opportunities for realizing value in new ways. Driving of dopamine release by reward prediction errors may provide one means of realizing this evolutionary imperative for expansion in seeking opportunities for value realization. If the mechanisms underlying reinforcement and behavioral disinhibition are only activated for unexpectedly good outcomes, then organisms will always find themselves seeking to explore the limits of what they can attain. This exploratory impulse will be even stronger if accompanied by opportunities for refining models and satisfying curiosity-based desires, so realizing the intrinsic value of learning in addition to the extrinsic value of utility maximization [382–386].

Boredom, in contrast, represents a punishing process that functions in an inverse fashion to curiosity (and play). One mechanism for implementing this negative incentive could be found in predictive coding in terms of habituation. If organisms come to nearperfectly predict rewards—or consider associated stimuli to be not worth attending to then this familiarity will result in prediction errors only being generated at lower levels of cortical hierarchies, which lack access to richly connected networks enabling conscious awareness [73]. Prediction errors failing to reach deeper levels will result in reduced recognition of features associated with those potential rewards. Both with respect to implicit predictions and explicit expectations, previously rewarding events that do not fully register will be experienced as disappointing in contrast to expected value [387,388], so resulting in stimulus-devaluation and reduced probabilities for selecting associated policies. Almost paradoxically, by becoming less (pleasantly) surprised by (or more familiar with) rewarding stimuli, organisms end up becoming more (unpleasantly) surprised relative to anticipated rewards, since predicted rewards never manifest in experience. Some evidence for this model can be found in over-rehearsed pleasurable acts being overly automatic, habitual, and progressively losing their hedonic tone. Between these twin masters of curiosity and boredom, agents are shaped to always expand their repertoire of policies for value realization, with growth continuing to the extent that these efforts are expected to result in increasingly desirable outcomes [386].

Under FEP-AI, we ought to expect living organisms—by virtue of being successful at existing—to be equipped with (or constituted by) system-defining prior expectations (or preferences) in which they are optimizing models of themselves doing the kinds of things which would be required for survival, including foraging for information. These modeling imperatives require organisms to enact system-world configurations dependent on policies with consequences in the future, and to also depend on policies not yet deployed [389]. This means successfully persisting adaptive systems must not only minimize free energy, but also expected free energy in (definitionally counterfactual) futures. A successful active inferential agent will expect itself to be maximizing information gain (i.e., precision-weighted prediction errors), while also avoiding the accumulation of cybernetic entropy [59–61,390,391] with respect to existential threats to the system. Within FEP-AI, this dilemma of balancing stability/plasticity tradeoffs is (boundedly optimally) resolved by gradient descent over a singular objective functional of expected free energy.

The maximal rate of reduction in overall expected free energy will be found in situations where agents are able to simultaneously balance imperatives for maximizing the intrinsic value of information/exploration with the extrinsic value of realizing preferred world states. This situation may be referred to as play, or "PLAY" [386,392,393] —potentially subjectively accompanied by "flow" states [394]—which, in maximizing reward, represents attracting states for organisms that places them precisely where they ought to be to maximize learning and evolutionary fitness [395]. The balanced conditions of play attract agents to a zone of proximal development [396]—or "edge of the adjacent possible" [397,398], and also the "edge of chaos" [239]—where learning rate is optimal, creating neither overly nor underly challenging conditions for promoting increasingly skillful engagement with the world [399,400].

These considerations help explain why we would not expect agents to minimize surprise by sequestering themselves in low-complexity environments. This is an a priori unlikely outcome, since such conditions would increase prediction errors from homeostatic regulatory nuclei and systems with which they (allostatically) couple. Further, such agents would both experience boredom and deprivation with respect to curiosity and play. Although we should also keep in mind that this supposed "Dark Room problem" [401] may not be completely solved by active inferential systems, as people often do seek out reduced complexity environments, whether due to the kinds of pathological beliefs associated with anxiety and depression [363,402], or by getting stuck at local maxima of excessive exploitation relative to exploration in model optimization.

#### 5.4.4. Synesthetic Affects

In the account described above, all affect is ultimately associatively linked to the rectification of either homeostatic or reproductive error signals, for which interoceptive consequences may be some of the most reliable sources of information [75]. However, these signals from the body's internal milieu have poor spatial localizability and controllability. If spatiotemporal and causal contextualization are necessary for enabling coherent experience, then these constraints on sense-making could result in interoceptive information being attributed to non-interoceptive sources. The best available inference regarding these visceral (and vital) signals may be that they are both caused by and also inextricably part of the conditions with which they are associated. Theoretically, this could cause much of interoception to have a quasi-synesthetic quality, wherein poorly localizable signals become intimately entangled with (or 'infused' into) more easily modeled proprioceptive and exteroceptive phenomena (Figure 5). For example, we may both feel our body from within, while also projecting these feelings onto and into associated objects.

While it may seem odd to describe feelings as a kind of synesthesia, all perception may have at least some degree of synesthetic phenomenology by virtue of involving cross-modal blending [403–407]. Analogous (and likely overlapping) phenomena would include "oral referral" in which primarily olfactory percepts are mapped onto taste sensations [408]. Theoretically, synesthetic affects may provide a partial account of referred pain phenomena, in which damage to body parts are mistakenly attributed to another location [152,409]. To go out on a further speculative limb, the phenomenology of color perception may often be synesthetic in this way, with prototypical qualia such as the "redness of red" having its particular 'textures' due to interoceptive cross-mappings.

This *synesthetic-affects hypothesis* may have further support from descriptions of pleasure as a kind of "gloss" applied to objects of hedonic experience [378]. If accurate, this model could also explain part of why emotional experiences often have an ineffable quality when reported. That is, affects may heavily depend on information that is difficult to explicitly model, and for which modeling efforts usually involve a kind of anomalous inference that are personal feelings are inextricably—and essentially [410]—part of the conditions that evoke them.

Synesthetic affects may not only explain some of the ways that our feelings 'color' the world—for both good and ill—but also the phenomenology of will with respect to both motivation and effort (Figures 5–8). In this view, the feeling of willing corresponds to a hybrid percept in which interoceptive states are mapped onto the effector systems by which intentions are realized. Thus, in addition to helping to explain otherwise mysterious aspects of experience, these synesthesia-like processes would also have extensive functional consequences. Perhaps most fundamentally, this kind of synesthetic phenomenology may

help to establish senses of body ownership and minimal (embodied) selfhood upon which most aspects of mind ultimately depend. One line of evidence provided in support of these models is findings using augmented reality, in which superimposing interoceptive cardiac signals enhanced susceptibility to "rubber hand illusions" [411]. Intriguingly, such anomalous inferences are also moderated by tendencies for experiencing mirror-touch synesthesia and kinesthetic mirror illusions [197,412].

Predictive coding accounts of emotional active inference have been proposed in which prediction errors from interoceptive states can be minimized through either (a) changing autonomic conditions, or (b) changing related world states via mobilization of proprioceptive effector systems [75,413]. If synesthetic phenomenology increases the extent to which interoceptive states are tightly coupled with actions and perceived outcomes, then this conjunction would help establish affordance-informed salience mappings over perceptual contents, so facilitating action selection and planning [414]. As described above with respect to free energy flows across multimodal body maps and the generation of readiness potentials (Figures 5–8), these tight perceptual couplings could strengthen patterns of effective connectivity between interoceptive and proprioceptive modalities. Such linkages would be more than mere epiphenomena, but would enable greater control energy from networks whose dynamics are ultimately grounded in evolutionary fitness and experiential histories with organismic value.

The subjective sense of presence [243] for affective phenomena may substantially depend on relatively tight associations between emotions and outcomes, so contributing to synesthetic mappings between feelings and inferred causes. If these links are disconnected —e.g., via insensitivity to interoceptive sensations or inabilities to imagine the realization of valued goals—synesthetic infusions of interoceptive value into other percepts would be compromised. In terms of consequences for normative functioning, severing synesthetic bridges to interoception could be involved in clinical conditions like anhedonia, alexithymia, the negative symptoms of schizophrenia, and even Cotard's syndrome and Capgras illusions [154].

5.4.5. The Computational Neurophenomenology of Desires/Pains as Free Energy Gradients That Become Pleasure through Self-Annihilation

Dopaminergic neuromodulation is commonly understood as indicating desire-related states [415,416], and also plays important roles in FEP-AI [417–419]. Dopamine modulates activity for representations of value-relevant stimuli, including actions associated with realizing valued goals. While dopaminergic functionality is complex [420], elevated signaling levels may be interpreted as indicating confidence that current policies/capabilities are likely to realize desired outcomes with respect to sensed or imagined stimuli. Relevant stimulus-features include both external reward cues as well as multimodal representations of activities involved in seeking valued goals, including avoiding undesirable outcomes.

In the predictive processing accounts of goal-oriented behavior described above, when an agent predicts itself obtaining value, but has not yet realized these desired outcomes, generated prediction errors correspond to discrepancies between representations for goal attainment, relative to estimated present or imagined likely states. These discrepancies are suggested to derive from iterative contrasting of desired and estimated likely states, occurring at theta frequencies orchestrated by hippocampal-prefrontal coupling [139,142] (Figure 4). As these comparison operations proceed, discrepant features generate increased activity as prediction errors, so drawing attention to and seeding imaginings with the most important features that need to be handled either by updating internal models or changing the world [105].

Much of the phenomenology of desire may represent the prediction of value-attainment, activating associated somatic and interoceptive concomitants of consummation, which are subjectively (and synesthetically) felt in body maps in places most associated with value realization (Figure 5). If these sensations are accompanied by temporary net decreases in predicting homeostatic or reproductive value-realization [76,374]—potentially mediated by opioid signaling [379,421]—overall unpleasant interoceptive inference may accompany

these perceptions. In this way, the feeling of desire would be experienced as a kind of pain, with its particular characteristics depending on unique learning histories. However, painful desire can be transformed into pleasurable anticipation if we find ourselves predicting overall increases in value, so creating pleasurable contrasts with the discomfort of wanting. If the visceral concomitants of affective experiences become entangled with exteroceptive and proprioceptive percepts in the quasi-synesthetic fashion described above, then pleasure and pain (including desire) would be generated as interoceptive modes becoming infused into other modalities in particular ways based on historical associations.

To use a musical metaphor, in experiences of pain and unfulfilled desire, the overall melody is played in a more minor, or entropic [390,391] key/timbre. Alternatively, in experiences of pleasure and fulfilled desire—potentially including virtual fulfillment (i.e., pleasurable anticipation)—affective orchestras play melodies with greater consonance. One could view such soundtracks to the (fully immersive virtual reality) movies of experience as separate streams of information that help contextualize what is being seen on 'screens' over which we see stories unfold (Figure 6). However, it may be closer to experience to say that this metaphorical music enters into what we see and feel, imbuing (or synesthetically coloring) it with meanings. Indeed, we may be able to find most of the principles of affective phenomena to be well-reflected in our experiences of music [16,385,422], where we play with building and releasing tension, enjoying the rise and fall of more and less consonant (or less and more dissonant) melodies. In musical pleasure, we explore harmony and the contrast of disharmony, eventually expecting to return home to the wholeness of the tonic, but with abilities of our "experiencing selves" [423–425] to find satisfaction in the moment not necessarily being the reasons that our "remembering selves" find ourselves attracted to particular songs.

The affective melodies played by neural orchestras will be dominated by interoceptive modalities, the most ancient—both developmentally and evolutionarily speaking—and reliable indicators of homeostatic and reproductive potential [63,130,285,426,427]. Do we have relaxed and dynamic cardiac rhythms? Is our breathing easy or forced? Do we feel warm—but not too hot—or cold? Are our bowels irritated or copacetic? Do we feel full or empty inside? Do we feel like our body is whole and strong, ours to command where we will, if we wanted it? Or do we feel damaged and weak? This interoceptive information speaks to foundations of life and the cores of value out of which persons may grow.

#### 5.4.6. Desiring to Desire; Transforming Pain into Pleasure, and Back Again

How can we reconcile the experience of desire as a species of pain in light of the fact that we often desire to desire? While desiring may sometimes be desirable, it is not a pleasant thing to be in a state of unsatisfied hunger or thirst without believing this situation to be manageable. To be hungry or thirsty without cessation is to predict moving away from homeostasis and survival. Unless an organism can be confident that it will eventually rectify this situation, failing to satisfy such desires would indicate an existential threat to the system. Thus, we would expect desire unsatisfied to be experienced as a kind of pain. However, the pain of desire can then be transformed into pleasure—and back again (and so on)—by consummation, or the vivid imagination of attainment.

Can an agent ever come out ahead with this back and forth between pleasure and pain, either with respect its experiencing or remembering selves [424]? How can motivation be maintained if all pleasures will eventually be transformed back into kinds of pain through their absence? In addition to low-level mechanisms such as opioid signaling resulting in concomitant dopamine release [421], additional asymmetries between pleasurable and painful experiences may be found in predictive coding mechanisms. That is, more changeable patterns will be more likely to violate expectations—by virtue of being difficult to precisely track—and so experiencing/remembering will likely be dominated by transitions between pleasure and pain, especially if accompanied by precipitous or punctuated alterations [76,248,374,380,428]. If seeking without finding results in relatively gradual accumulation of desire, and if consummation tends to rectify situations more rapidly, then

experience and memory for successfully enacted goals will have an overall pleasurable (and reinforcing) quality. Additionally, by virtue of being substantially generated by an agent's own (potentially intentional) actions, the greater predictability of consummatory acts might allow attentional resources to be marshalled in ways that allow for more extended conscious processing of pleasurable experiences. Finally, some symmetry breaking with respect to pain and pleasure may come from the motoric nature of attention described above, in that the experience of attending to pleasurable experiences will be more likely to be reinforcing both in the (extended) moment as well as across time. [Note: The conditioning of top-down attention also suggests that some quasi-psychodynamic phenomena are to be expected as almost inevitable consequences of the laws of learning.] However, this pleasure is not something that natural selection 'wanted' us to have and hold onto, but to be continually "SEEKING" [392], thereby maximizing fitness.

#### 5.4.7. Why Conscious Feelings?

Consciously-experienced feelings may provide unified attractors for coordinating global organismic states [130,285]. While emotional shaping may occur without consciousness, these affects may be more likely to entrain the overall system when integrated into coherent fields of experience. Even if these feelings take the form of "isolated qualia" without conscious access (as described above), these self-stabilizing cores may still provide sources of greatly elevated control energy. However, this entraining power would be even greater when made consciously accessible in ways that afford planning and continuous adjustments of actions based on organismic value. This mapping of hedonic states onto consciously introspectable models of enaction also provides a partial means of handling the credit assignment problem, via conjoining value and actions in both experience and memory. If affects took place "in the dark" without feeling like anything, they would be unable to strongly influence events, nor be coherently integrated into explicit modeling and planning, including plans involving pursuing those feelings as ends in and of themselves, such as in the domains of play and art.

#### *5.5. Facing up to the Meta-Problem of Consciousness*

The hard problem of consciousness asks, how can it be that there is "something that it is like" to be a physical system [429,430]? The "meta-problem" of consciousness refers to the (potentially more tractable) challenge of addressing why opinions and intuitions vary greatly with respect to what could meaningfully answer this question [431]. As suggested elsewhere [73], one potential solution to the meta-problem may derive from the unavailability of bridging principles, which would cause prospects for explaining consciousness to seem either impossible (perhaps even in principle), or merely (extremely) difficult. An additional solution to the meta-problem may be found in the nature of explanations for various qualia: while perhaps intuitive after consideration, at first glance some of the models proposed above seem to directly contradict experience, such as desire constituting a species of pain, and vice versa [152]. Other explanations of aspects of experience may not necessarily contradict intuitions, yet may nonetheless seem irreducibly strange and so prima facie implausible, such as the model of synesthetic affects described above. However, if it is indeed the case that some of the most fundamental and familiar aspects of experience are difficult to recognize upon close inspection, then this is itself something in need of explanation.

Much of this seeming paradox of the unrecognizability of the most fundamental and familiar could be resolved if such aspects of experience are likely to become "phenomenally transparent" [49,432], and so resistant to introspection. Neurocomputationally, the contents of perception in any given moment are likely entailed by synchronous beta complexes with particular zones of integration [73,74], but with these local inferences requiring further integration into larger (alpha- and theta-synchronized) complexes for phenomenal and access consciousness. Such broader integration may not end up occurring if predictive coding mechanisms are so successful that they are capable of "explaining away" aspects

of experience before they can be consciously registered. That is, iterative Bayesian model selection unfolds over multiple (potentially nested) levels of hierarchical depth, and so if explaining away observations is largely successful via smaller beta complexes closer to the modalities, that information would never reach more richly connected cores/subnetworks enabling coherent world modeling and experienceable perception. Alternatively, such information could give rise to experience in the form of "isolated qualia," yet fail to achieve conscious accessibility due to the transient nature of these quale states. In these ways, that which is most fundamental and familiar would almost inevitably become nearly invisible to introspective access.

The meta-problem may be as conceptually rich as the Hard problem itself. Further promising approaches may involve paradoxes from functional "Strange loops" and selfreference [433], computational limits of recursion [434], and seeming paradoxes deriving from mechanisms by which egocentric perspective is established [181]. Finally, some solutions may be sociological in nature, potentially reflecting a legacy of "physics envy" in the mind sciences [435]. Not only have we lacked bridging principles and understanding of embodiment as the core of selfhood and experience, but scientific practice both implicitly and explicitly denigrated subjectivity after the decline of introspectionism and rise of behaviorism. Given this taboo on subjectivity—i.e., the very thing we would hope to explain with respect to consciousness—why should we have been surprised if we lacked satisfying understanding of the nature(s) of experience? Finally, some of the (Hard) problem may derive from frames in cognitive science that rendered all Cartesian framings of mental functioning taboo. That is, if quasi-Cartesian intuitions were actually semi-faithful representations of the nature(s) of mind and brain, then why should we be surprised if our scholarship—and its denigration of folk psychology [436]—failed to provide satisfying accounts of the nature(s) of our conscious agency?

#### **6. Conclusions**

*"The intentionality of all such talk of signals and commands reminds us that rationality is being taken for granted, and in this way shows us where a theory is incomplete. It is this feature that, to my mind, puts a premium on the yet unfinished task of devising a rigorous definition of intentionality, for if we can lay claim to a purely formal criterion of intentional discourse, we will have what amounts to a medium of exchange for assessing theories of behavior. Intentionality abstracts from the inessential details of the various forms intelligence-loans can take (e.g., signal-readers, volition-emitters, librarians in the corridors of memory, egos and superegos) and serves as a reliable means of detecting exactly where a theory is in the red relative to the task of explaining intelligence; wherever a theory relies on a formulation bearing the logical marks of intentionality, there a little man is concealed."*

#### —Daniel Dennett [1]

These explorations have attempted to repay as many "intelligence loans" as possible by creating an embodied backing for intentionality, so providing a common currency for understanding cognition. I have suggested that consciousness is generated from dynamic predictive cores, centered on embodied self-models, functioning as cybernetic controllers for agents embedded in environments within which they seek valued goals. To realize these values, agents engage in imaginative planning in which they chain inferences from desired outcomes back to present-estimated states, with enaction realized via multilevel actionoriented body maps. For these quasi-homunculi, intentional control is driven by beliefs and desires, understood as free energy gradients, which are annihilated when prediction errors are minimized through skillful enaction, so establishing new goals to pursue in the future. Through a variety of simulated actions, embodied self-models both influence and are influenced by high-level representations from interoceptive and exteroceptive inferential hierarchies, so providing bases for various forms of conscious access, metacognition, and self-knowledge. This deeply embodied architecture provides enactive bases for most mental operations discussed in cognitive science, including means by which conscious

mental states can causally influence attention, working memory, imagination, and action. In these ways and more, understanding the radically embodied foundations of conscious minds may vindicate much of folk psychological and traditional conceptions of selves containing both multiplicity and unity, and of will defined by both constraints and freedom.

**Funding:** This research received no external funding.

**Data Availability Statement:** This manuscript does not have associated data.

**Acknowledgments:** I am deeply grateful to all the people with whom I have explored these ideas over many years. I would like to especially thank Karl Friston for his feedback on a previous version of this manuscript in early 2018, for giving me an opportunity to present some of this material at a University College London Theoretical Neurobiology Meeting, and for his ongoing guidance and inspiration. I would also like to thank Andy Clark and Anil Seth for their pioneering work which informed these ideas, and for providing me with the opportunity to present to their research groups. I would like to thank Jakob Hohwy for his feedback on another incarnation of this manuscript, and for introducing the concept of "self-evidencing," which continues to shape my thinking on many levels. I would like to thank Aaron Schurger and Uri Maoz for teaching me about readiness potentials and Libet phenomena, and Walter Sinnott-Armstrong for introducing me to the idea of "contrastive causation." Any errors and/or stylistic, thematic, or communicative judgment lapses are all my own.

I would like to thank Rutger Goekoop for his work on goal hierarchies and control structures, and also for his friendship. I would like to thank Paul Badcock for his work on hierarchical mechanistic minds and for making connections between the Free Energy Principle and (generalized) evolution, which I believe to be essential for describing agentic causation. I would like to thank Inês Hipólito for teaching me the ways of radical enactivism, and also for her openness to my (unusual) cognitivism. I would like to thank Zahra Sheikhbahaee for everything she has taught me about machine learning and its relations to the Free Energy Principle and Active Inference framework. I would also like to extend deep thanks to Amelia Thomley for sharing her artistic talent with me in attempting to illustrate the nature(s) of experience. I look forward to future collaborations.

Finally, I would like to express my deep gratitude to Daniel Dennett for rescuing me from an extended and severe existential crisis over free will, for giving me invaluable thinking tools, and for providing me with strongly motivating reasons to explore these ideas. If it were not for his monumental impact on cognitive science and philosophy of mind, I probably would not have engaged in this "strange inversion of reasoning," attempting to describe how what might seem to be the most naïve interpretation of mental phenomena may be the key to understanding how conscious purposes could emerge from nature, wherein we find ourselves in a world in which the only meanings are those which we create for ourselves and each other.

**Conflicts of Interest:** The author declares no conflict of interest.

#### **References**


Contents

**Chapter 7 99** An Empirical Study on Environmental Sustainability in Melaka City *by Noor Mohammad*

Preface

As a simple interpretation, sustainability can be described as either a process or a state that can be maintained at a certain level for as long as it is wanted. The term is associated with that proposed by the Bruntland Commission as "Sustainable Development," which is defined as development that "meets the needs of the present without compromising the ability of future generations to meet their own needs." Thus, "sustainability" is the study of how natural systems function, remain diverse, and produce everything they need for the ecology to remain in balance. However, in addition to natural resources, we also need social and economic resources; sustainability is not just environmentalism. Maintaining sustainability in any economic system is very important, and even more so in the context of developing countries. This book presents some case studies and methodological issues with a focus on developing countries. Part 1 includes studies on conceptual frameworks related to sustainability as well as methodologies relevant to its investigation. Part 2 includes case studies dealing with sustainability applications. Chapter 1 is a description of the people-centered social totality approach, which was applied to low-income housing policy. Since sustainability has three pillars (economic, social, and environmental), use of a multi-criteria decision-making tool is very appropriate. Chapter 2 examines such a tool. Chapter 3 presents an integration of the water-food-energy nexus, since natural resources are used for more than one purpose in an economic system requiring their integration. Chapter 4 examines the use of natural resources in rural areas, using herbicides as a case study. Part 2 begins with Chapter 5, which describes the issue of governance. Chapter 6 describes some of the activities that might lead to sustainability, and finally, Chapter 7 provides a description of sustainability status. The editor hopes that contributions would be of some interest not only for professional in developing

> **Dr. Surendra N. Kulshreshtha** University of Saskatchewan,

> > Saskatoon, Canada

College of Agriculture and Bioresources,

Department of Agricultural and Resource Economics,

countries but also in developed countries.


**Meet the editor**

Dr. Gani Bajraktari graduated in Medicine at the University of Prishtina (Kosovo) in 1990 and completed his specialization in cardiology at the Second Clinic of Cardiology, University Clinical Center "Mother Teresa", Tirana (Albania), in 1997. He finished his postgraduate studies, defending the Master's thesis at Medical Faculty of Zagreb (Croatia) in 2000, in the field of stress-echo-

cardiography, whereas he defended his doctoral thesis in 2002, at Medical Faculty of the University of Prishtina. He finished his PhD studies at Semelweis University in Budapest (Hungary), defending the Ph.D. thesis in 2007. In two mandates (2001-2003 and 2007-2009) he was the director of Internal Medicine Clinic, University Clinical Centre of Kosova, Prishtina. He was elected as Professor of Internal Medicine - Cardiology at Medical Faculty in 2006, whereas in 2009, he was elected as Dean of Medical Faculty, University of Prishtina.His clinical and research interests include echocardiography, diastology, diabetes and heart failure. He published 30 articles in these fields. He is the author of three books. Dr. Bajraktari is a Fellow of European Society of Cardiology and a Fellow of American College of Cardiology.

Contents

**Preface IX**

Gani Bajraktari

Chapter 4 **Diastolic Heart Failure 49**

Chapter 3 **Epiaortic Ultrasound Assessment of**

Alistair Royse and Colin Royse

**Fact and Controversy 77**

**Function in Failing Hearts 97**  Fadi N. Salloum and Rakesh C. Kukreja

**Part 2 Echocardiography in Heart Failure 47**

**Part 1 Echocardiography in Valvular Heart Disease 1**

Gheorghe Cerin, Bogdan Adrian Popa and Marco Diena

Ryotaro Wake, Junichi Yoshikawa and Minoru Yoshiyama

**Angioplasty in Acute ST-Elevation Myocardial Infarction: A Trans-Thoracic Coronary Artery Doppler Study 59**  Dawod Sharif, Amal Sharif-Rasslan and Uri Rosenschein

Chapter 5 **Effects of Eptifibatide on the Microcirculation After Primary**

Chapter 6 **Pulmonary Venous Flow Pattern and Atrial Fibrillation:**

Chapter 7 **Phosphodiesterase-5 Inhibitors Improve Left Ventricular**

Toru Maruyama, Yousuke Kokawa, Hisataka Nakamura,

Mitsuhiro Fukata, Shioto Yasuda, Keita Odashiro and Koichi Akashi

Chapter 1 **The Degenerative Mitral Valve Regurgitation: From Geometrical Echocardiographic Concepts to Successful Surgical Repair 3**

Chapter 2 **Echocardiography in Severe Aortic Stenosis 25**

**the Thoracic Aorta in Cardiac Surgery 35**


Quality of Life in Patients with Skin Disease and Their Cohabitants

*Trinidad Montero-Vílchez, Manuel Sánchez-Díaz, Antonio Martínez-López and Salvador Arias-Santiago*

#### **Abstract**

Health evaluation implies assess multidimensional aspects of a person's development, such as physical, social, psychological, and emotional features. It is important to consider all these factors to apply a needs-oriented each patient approach. Chronic skin diseases have a great impact on quality of life, even more than other chronic conditions. For example, hidradenitis suppurativa is estimated to impair quality of life more than cardiovascular disease, lung disease or endocrine diseases. Multiple tools have been developed to measure health-related quality of life in patient, being the Dermatology Life Quality Index (DLQI) the most used. Psoriasis, hidradenitis suppurativa, acne, atopic dermatitis and hair disorders are those with the greatest impact on patients' quality of life. Moreover, chronic skin conditions impair not only patients' quality of life, but also cohabitants. Nevertheless, there is scarce information regarding the impact on their cohabitants. So, the objective of this chapter is to review the literature to assess the psychological and social effects of dermatological conditions both on patients and cohabitants.

**Keywords:** Acne, Alopecia, Atopic Dermatitis, Cohabitants, Hidradenitis Suppurativa, Psoriasis, Quality of Life

#### **1. Introduction**

Health evaluation implies assess multidimensional facets of a person's development, such as physical, social, psychological and emotional aspects [1]. It is important to consider all these factors to apply a needs-oriented each patient approach. Chronic skin diseases have a great impact on quality of life, even more than other chronic conditions like asthma, epilepsy or diabetes [2]. Psoriasis, hidradenitis suppurativa, acne, atopic dermatitis and hair disorders are those with the greatest impact on patients' quality of life [2–4].

Multiple tools have been developed to measure health-related quality of life in patient, being the validated Dermatology Life Quality Index (DLQI) the most used. It evaluates the impact of skin symptoms of dermatological conditions and their treatment on patient's lives. The 10-item questionnaire covers the following aspects of patients' quality of life: symptoms and feelings, daily activities, leisure, work or school, personal relationships, and treatment. Each question is scored from 0 to 3 (not at all/not relevant (0), a little [1], a lot [2], and very much [3]) and reflects the extent to which the person's life quality is adversely affected by the skin condition. The total score ranges from 0 to 30, and higher score reflects a greater impairment in patients' life [5]. The DLQI punctuation is interpreted 0–1 = no effect at all; 2–5 = small effect; 6–10 = moderate effect; 11–20 = very large effect; 21–30 = extremely large effect [6]. There are also other scales to assess anxiety, depression or sexual dysfunction that are also uses to evaluate different aspects of patients' quality of life [6, 7]. The validated Hospital Anxiety and Depression Scale (HADS) is used to evaluate the prevalence of anxiety and depression. It is divided into two scales of seven items each. Scores equal or higher than 8 on the subscales are indicative of anxiety or depression [8]. The validated International Index of Erectile Function (IIEF-5) and the Female Sexual Function Index (FSFI-6) questionnaires are used to evaluate sexual dysfunction in men and women, respectively.  Furthermore, to compare different diseases impact on quality of life or to compare several treatment improvements in patients' life, quality-adjusted life-year (QALYs) or global disability-adjusted life years (DALYs) are used [11, 12].

Chronic skin conditions impair not only patients' quality of life, but also cohabitants. In fact, it has been described caregiver burnout syndrome, expressing with stress, anxiety or depression what may impair people's life [13]. This means that the primary caregivers of a sick person are also affected by the disease. Although there is scarce information regarding the impact on cohabitants' quality of life, recently the Family Dermatology Life Quality Index (FDLQI) has been developed. It is a 10-item questionnaire that covers family member's perception of a certain specific impact on his/her quality of life over the last 1 month. Each item is scored on a fourpoint scale (0–3). The final scored is calculated by summing the scores of individual items and ranges from of 0 to 30. Higher total FDLQI scores indicate greater impairment of the family member's quality of life [14]. FDLQI could be interpreted similarly to DLQI: 0–1 = no effect at all; 2–5 = small effect; 6–10 = moderate effect; 11–20 = very large effect; 21–30 = extremely large effect.

The objective of this chapter is to review the literature to assess the psychological and social effects of dermatological conditions both on patients and cohabitants.

### **2. Material and methods**

Search strategy. A literature search was performed using Medline, Scopus and Embase from conception to November 2020. The following search terms were used: ((Dermatology) OR (Skin diseases) OR (Alopecia) OR (Psoriasis) OR (Hidradenitis Suppurativa) OR (Acne) OR (Acne Inversa) OR (Atopic Dermatitis)) AND (Quality of Life).

Inclusion and exclusion criteria. The search was limited to: (i) human data, (ii) articles regarding impairment in quality of life in patients and cohabitants, (iii) articles written in English or Spanish. All types of epidemiological studies (clinical trials, cohort studies, case–control studies and cross-sectional studies) were included and analyzed. Reviews, guidelines, protocols, and conference abstracts were excluded. Skin conditions were selected regarding their high prevalence, their severity and their high impairment in quality of life. Psoriasis, hidradenitis suppurativa, atopic dermatitis, acne and alopecia were included. Only studies using validate scales to assess impairment in quality of life were included.

Study selection. Two researchers (TMV and MSD) independently reviewed the titles and abstracts of the articles obtained in the first search to assess relevant studies. The full texts of all articles meeting the inclusion criteria were reviewed, and their bibliographic references were checked for additional sources. The

*Quality of Life in Patients with Skin Disease and Their Cohabitants DOI: http://dx.doi.org/10.5772/intechopen.97450*

articles considered relevant by both researchers were included in the analysis. Disagreements about inclusion or exclusion of articles were subjected to discussion until a consensus was reached. If not reached, resolution was achieved by discussion with a third researcher (SAS).

Variables. The variables assessed were number of participants and cohabitants, assent tools used to evaluate quality of life, risk factors associated with impairment in cohabitants' quality of life, general impairment in patients' quality of life.

Target audience. Clinicians and research are the main audience of this review. Doctors should be aware to consider patients and cohabitant impairment in quality of life when making treatment decisions. Moreover, research should include validate measure of patients and cohabitants quality of life in their investigations.

#### **2.1 Psoriasis**

Psoriasis is a chronic, recurrent, multi-systemic inflammatory disease that mainly affects the skin and the joints [15]. It is a multifactorial disease caused by a combination of immunological imbalance, genetic associations and environmental factors [16]. Its prevalence around the word has been estimated from between 0.51% and 11.43% [17], being more frequent in countries more distant from the equator [18]. In Europe, psoriasis prevalence is about 1.3% [19]. Furthermore, its incidence is increasing over the years [19, 20]. It has a bimodal age of onset (16 to 22 and 57 to 60 years) [21] and it affects both sexes similarly [18].

Psoriasis is considered a major global health problem [22]. Although, the skin manifestations are commonly the only recognized symptoms of psoriasis [20], this disease is associated with multiple comorbidities such as arthritis, cardiovascular disease, metabolic syndrome, depression, anxiety or inflammatory bowel disease [23–26]. All of them contribute to increase the morbimortality in these patients. In fact, similar to many chronic inflammatory diseases, the risk of early mortality in patients with psoriasis is increased, especially due to cardiovascular events [27]. Likewise, the risk of mortality from cardiovascular disease is higher in patients with more severe psoriasis [28]. Patients with psoriasis are also at increased risk of mental problems. Rates of anxiety, depression and even suicide are increased in these patients [29]. Psoriasis can also influence the interpersonal and sexual health of people with psoriasis [30]. Psoriasis therefore impacts on physical, emotional, and social patient's life [20]. Moreover, the economic burden of psoriasis is high, as in Europe the annual total cost per patient is between 6,000-12,000€ [31].

Furthermore, psoriasis has a great impact on cohabitants' life [6, 7, 32]. The presence of psoriasis impaired the quality of life in almost 90% of the cohabitants. FDLQI scores of cohabitants are associated with the DLQI scores of the patients. Moreover, an increased body surface area affected, and the genital and scalp location were associated with a higher FDLQI score while FDLQI scores were lower for cohabitants with higher professional/university education [6]. Disease severity and duration impact negatively on cohabitants' quality of life, anxiety and depression [6, 32].

Multiple treatments are effective for treating psoriasis, including topical medications, phototherapy, oral systemic medications, and biologics [33]. Mild psoriasis can be treated with topical corticosteroids or corticosteroids plus vitamin D analogues. Moderate psoriasis needs to be treated with systemic treatments, such as methotrexate, acitretin or cyclosporine, or phototherapy. If psoriasis is severe or treatment-resistant, biologics are indicated. There is a wide range of biologics therapies for treating psoriasis: TNFα (etanercept, adalimumab, infliximab,

certolizumab), IL12/23 inhibitors (ustekinumab), IL23 inhibitor (guselkumab, risankizumab, tildrakizumab), IL17 inhibitors (secukinumab, ixekizumab, brodalumab) [34]. The economic outcomes of these targeted treatments have been compared with non-targeted ones. The incremental benefits compared with no targeted treatment are, in descending order: ixekizumab 1.68 QALYs, brodalumab 1.64 QALYs, secukinumab 1.51 QALYs, ustekinumab 1.43 QALYs, infliximab 1.27 QALYs, adalimumab 1.15 QALYs, etanercept 0.97 QALYs, and apremilast 0.87 QALYs. Initial targeted treatment with IL-17 inhibitors seems to be the most effective treatment strategy for plaque psoriasis patients who have failed systemics [11].

#### **2.2 Hidradenitis suppurativa**

Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating inflammatory skin disease of the hair follicle that usually presents after puberty with painful, deep-seated inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions [35]. A prevalence rate of around 1% has been estimated [36], of 0.03–1% in Europe [37–39] and of 0.053% in the USA [40].

Its etiopathogenesis is still elusive and may be of pivotal importance in improving patients and relative's quality of life. Genetic susceptibility, smoking, obesity and hormonal disorders are major risk factors for the development of HS [41]. Moreover HS, has been associated with multiple physical comorbidities such as spondylarthritis, inflammatory bowel disease and increased cardiovascular risk [42, 43]. Moreover, HS impairs patients' mental health. It has been related to higher levels of depression, anxiety, worse quality of life, sexual dysfunction and a higher suicide risk [44–47]. HS also has consequences on social relationships and professional careers, as high rates of absenteeism and unemployment have been reported in HS patients [43]. For all these reasons, HS is a stigmatizing and disabling disease that greatly impairs physical, emotional, and social patient's life. Moreover, the economic burden of HS is high [48]. Direct medical costs due only to surgery are around £2,000 per patient per year in the UK [49]. Indirect costs, for expel associated with frequent and long-term absenteeism and disability, have also a great impact on the health system [50].

Moreover, HS has a great impact on cohabitants' life as they are involved in patients' caregiving [51–53]. A positive association between the Dermatology Life Quality Index (DLQI) and the Family Dermatology Life Quality Index (FDLQI) has been observed [52]. The most affected areas are emotional distress (depression, anxiety, embarrassment), social life and routine household expenditure [53]. In fact, patient's anxiety and depression and higher score for negative affectivity are associated with a lower quality of life in their cohabitants [52]. Disease severity also impairs both patients and cohabitants life due to skin symptoms (disease duration, pain, more involved locations), the need of continuous care and more unpleasant treatments and a higher economic expenditure [51]. In addition, a great impact is found in partners or husband/wife compared with parents, leading to a potential effect on the couple relationships [51]. In fact, patient sexual dysfunction greatly impairs cohabitant's quality of life [52]. On the other hand, higher educational level and an early diagnosis and treatment have a positive impact on patients and their partners' life [51–53].

HS therapy is often challenging and requires the combination of medical and surgical treatments [54, 55]. Medical treatment of mild disease consists in topical clindamycin 1% solution/gel twice a day for 12 weeks or, for a more widespread disease, tetracycline 500 mg daily for 4 months. If patient do not respond or for moderate-to-severe disease, clindamycin 300 mg with rifampicin 600 mg daily for *Quality of Life in Patients with Skin Disease and Their Cohabitants DOI: http://dx.doi.org/10.5772/intechopen.97450*

10 weeks would be considered [56]. Adalimumab, a monoclonal antibody against tumor necrosis factor-α, is the only biologic agent currently available for treating moderate to severe HS, but a primary or secondary lack of response has been observed in some patients [57]. New insights into the pathogenesis of HS reveal an inflammatory cytokine profile including elevated levels of (TNF)-α, interleukin (IL)-1ß, IL-17 or interferon (IFN)-γ and other biologic treatments such as bermekimab, bimekizumab, brodalumab, guselkumab, risankizumab or secukinumab are being tested in clinical trials [58]. There is scarce evidence regarding cost-effectiveness therapies in HS. It has been estimated that the incremental cost-effectiveness ratio for adalimumab versus standard care was around £30,000 per QALY gained [59]. Nevertheless, it cost-effectiveness was highly susceptible to the health states' utility values, the treatment discontinuation and the resource utilization [60].

#### **2.3 Acne**

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit that usually presents at adolescence with comedones (blackheads and whiteheads), papules, pustules, nodules, cysts and scars. The most affected areas corresponds to the highest density of pilosebaceous units (face, neck, upper chest, shoulders, and back) [61]. It is a prevalent condition that involves 85% of adolescents and 6–10% of the general population [62].

Acne is a multifactorial disease resulting from androgen-induced disturbed sebaceous gland activity associated with increased sebum production and alterations in sebum fatty acid composition, altered keratinisation, inflammation, *Propionibacterium acnes* colonization of hair follicles and dysfunction of the innate and adaptive immunity [63]. Genetic susceptibility, air pollution, aggressive skincare products, corticosteroids and hormonal products are risk factors to develop acne. The role of nutrition in acne pathogenesis is still controversial [64]. Acne is associated with physical disability due to painful skin lesions. Moreover, it usually affects visible areas, with risk of permanent scarring and aesthetic consequences. In fact, acne is associated with high rates of anxiety, depression and even suicide [65, 66]. People with acne are also more prone to have social phobia [67].

Acne not only impairs patients' life but also their cohabitants. More than 90% of people leaving with acne patients have impaired their quality of life. A positive correlation between FDLQI in cohabitants and DLQI in patients is observed. Furthermore, patients' level of depression and anxiety are also associated with their cohabitants' [68].

Acne treatment is based on disease severity, patient preference, site of involvement, age of the patient and tolerability. Topical therapies may be used as monotherapy, in combination with other topical agents or in combination with oral agents in both initial control and maintenance. The most employed topical products are benzoyl peroxide, salicylic acid, antibiotics, combination antibiotics with benzoyl peroxide, retinoids, retinoid with benzoyl peroxide, retinoid with antibiotic, azelaic acid, and sulfone agents. Systemic antibiotics are used in moderate to severe inflammatory acne and should be used in combination with a topical retinoid and benzoyl peroxide. Tetracycline, mainly doxycycline and minocycline, are the most effective antibiotics. Oral contraceptives can improve acne for many women, mainly in those with clinical or laboratory signs of hyperandrogenism. Oral isotretinoin is indicated for severe acne or moderate treatment-resistant acne [69]. The effectiveness and cost effectiveness of isotretinoin are well proven as its cost per QALY of £898 (\$US l3 74) is affordable [70]. Dermatologist treatment appears cost-effective related to producing additional QALYs at a cost of \$40,000 per QALY gained [71].

#### **2.4 Atopic dermatitis**

Atopic dermatitis (AD) is a common and chronic inflammatory skin disease. It is characterized by recurrent eczematous lesions and intense itch which develop in people of all ages and ethnicities. The prevalence of AD has been estimated around 12% in children and 7% in adults in United States [72]. It is considered the leading non-fatal health burden attributable to skin diseases [73]. The etiopathogenesis of AD is not completely understood. However, most studies agree that skin barrier dysfunction and immune dysregulation play a key role in the development of AD [74, 75]. Genetic polymorphisms in the filaggrin gene, which encode a major structural protein in the stratum corneum, upregulation of Th2 cytokines, such as IL-4 and IL-13, changes in the skin microbiome and altered lipid composition are thought to be responsible for the appearance of pruritus and skin lesions in patients suffering from AD [75–78].

AD is frequently associated with food allergy, asthma and rhinitis, which is also known as the "atopic march". This concept refers to the propensity for AD to begin early in life and be followed by the serial incidence of food allergy, asthma, and hay fever [79]. Other associated conditions include eosinophilic esophagitis [80], allergic contact dermatitis [81], cardiovascular disease [82] and infections [83, 84].

Skin lesions and severe symptomatology, including severe itch and skin pain, contribute to an impaired quality of life in patients suffering from AD. Psychosocial distress, stigma, sleep disturbance avoidance of social interaction are consequences of AD [85]. Significantly poorer dermatology-related quality of life scores have been found in patients with AD: higher DLQI [86] and Children's DLQI [87], greater Skindex affectation [88] and itch-related quality of life [89]. Different general quality of life scores are also affected in patients with AD [86, 87, 89]. Furthermore, the impact on quality of life is not restricted to the patient itself, but also affects to their cohabitants. It has been shown that parents of children with AD have lower qualityof-life scores [90–92] and that AD influences marital conflicts [93].  The involvement of visible areas and sensual areas leads to lower quality of life indexes and higher burden scores in patients with AD [94].

Given its high burden, AD have been associated with high QALY loss, even higher than autoimmune disorders, diabetes, food allergy and heart disease in both males and female [96]. Moreover, six-dimensional health state short form (SF-6D) score, an utility score which ranges from 0 (worst health) to 1 (best health) was estimated to 0.63 in severe AD. This was lower than SF-6D in high blood pressure (0.63), diabetes (0.65) and similar to anxiety, depression and heart disease (0.63) [96].

The treatment of AD follows a stepwise approach that is tailored according to disease severity and extension [85, 97]. Patient's education and basic skin care must be carried out in all patients, including those without active skin lesions. It consists of the frequent application of skin moisturizers, warm baths or showers using non-soap cleansers and avoidance of skin irritants. For mild and localized disease, treatment involves the use of topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). For moderate-to-severe and extensive disease, phototherapy or systemic drugs are indicated. Systemic immunosuppressants, such as cyclosporine, methotrexate, azathioprine and mycophenolate mofetil can be used [75, 85]. Dupilumab, a monoclonal antibody which acts as a targeted therapy for AD, is currently the most effective therapy por severe AD. It acts through the blockage of the IL-4 receptor alpha-chain [85, 98]. Emerging therapies include anti IL-13 and anti IL-31 antibodies, JAK inhibitors, and inhibitors of PDE-4 [85, 98].

#### *Quality of Life in Patients with Skin Disease and Their Cohabitants DOI: http://dx.doi.org/10.5772/intechopen.97450*

Finally, AD places a high financial burden on patients, families and society through direct medical costs and decreased productivity. Taking this into account, a conservative estimate of the annual costs of atopic dermatitis in the United States (2015) is \$5.297 billion [99]. Regarding the current development of novel treatments, which involve higher costs [100], these costs is likely to increase over the time.

#### **2.5 Alopecia**

Alopecia is a heterogeneous group of common skin disorders. This group can be divided into two minor groups: a) Non-cicatricial alopecia: Follicular epithelium is not replaced by connective tissue, so it is potentially reversible; b) Cicatricial alopecia: Follicular epithelium is replaced by connective tissue, so it is assumed that permanent injury of the follicular stem cell region has occurred.

#### *2.5.1 Non-cicatricial alopecia*

Many different skin conditions can be classified into this category. Most common and most representative non-cicatricial alopecia will be reviewed below.

#### *<IP_ADDRESS> Androgenetic Alopecia (AGA)*

AGA is an androgen-dependent hereditary disorder resulting from the conversion of scalp terminal hairs into miniaturized vellus hairs in a characteristic pattern. Androgens act on the epithelial cells of genetically susceptible hair follicles in androgen-dependent areas, leading to follicular miniaturization [101]. Its frequency and severity increase with age, with at least 80% of Caucasian men and 50% of women showing signs of AGA by age 70 years [102, 103]. In male pattern hair loss, there is a progressive loss of hair in the frontal and bitemporal line, and also in the vertex. In the female pattern hair loss, the frontal hairline is spared with a diffuse central thinning of the crown.

In some studies, AGA has associated to age and family history of AGA. Moreover, some factors related to metabolic syndrome have also been related to AGA in both genders: Hypertension, diabetes mellitus and waist circumference [104].

As AGA is frequent and affects a visible area such as the scalp, it can lead to a significant impairment in the quality of life and social inhibition in patients. There is evidence of the impairment in quality-of-life scores in both males and female suffering from AGA: DLQI [105–107], Hairdex scale [105] and Skindex-29 scale [106]. Moreover, AGA has a negative impact on sexual function in premenopausal women, reflected in a decreased FSFI compared to healthy females [108].

Only two therapeutic agents have been approved by the Food and Drug Administration and European Medicines Agency for the treatment of AGA: Topical minoxidil (in both males and females), and oral finasteride (in males) [109]. Minoxidil was first introduced as an oral treatment for severe hypertension in the 1970s [110]. When hypertrichosis was observed as a side effect of this medication, both topical and oral formulations of minoxidil were developed to treat alopecia. Minoxidil changes the micro-environment of the hair follicle, inducing a prolonged anagen phase and increased hair growth. Most common presentations of topical minoxidil include 2% and 5% lotions which are applied 1 ml/12 hours. Although oral minoxidil seems to be effective to treat AGA, it is not yet approved [111]. Oral finasteride is approved for AGA in men with a dosage of 1 mg/24 hours. It acts through the inhibition of 5-alpha reductase and is effective and safe [109] in the treatment of AGA.

#### *<IP_ADDRESS> Alopecia Areata (AA)*

AA is a common inflammatory hair loss, characterized by an autoimmunemediated hair follicle destruction, due to the upregulation of inflammatory pathways. The lifetime incidence of AA is approximately 2% worldwide [112]. The etiology is still not fully understood, but the loss of immune privilege in the hair follicle seems to play a crucial role in the development of AA [113]. Clinical features of AA vary from the appearance of small, well-circumscribed patches of hair loss to a complete absence of body and scalp hair.

As AA is an autoimmune disorder, patients suffering from AA have a higher risk of developing autoimmune diseases: thyroid disorders [112, 114], with an incidence in AA between 2,3-14,6%; diabetes mellitus, with an incidence in AA between 0,4-11,1% [115]; and vitiligo, with an incidence in AA between 1,8-7,0% [115] are some of the most common. AA have also been associated with atopic diseases, metabolic syndrome, Helicobacter Pylori infection, and vitamin D deficiency [116]. Moreover, a 66–74% of lifetime prevalence of psychiatric disorders have been reported in AA patients, with a 38–39% lifetime prevalence of depression and a 39–62% prevalence of generalized anxiety disorder [117–120].

Regarding the quality of life in people suffering from AA, there is increasing evidence of the strong impact of AA in quality-of-life scores, which affects up to 76.7% of children and 77.6% of adults [121]. Impairments in DLQI as well as in alopecia specific scores have been reported [115, 121, 122]. Role-emotional, mental health and vitality domains seem to be the most affected [121]. Moreover, scalp involvement, anxiety and depression have a negative impact on the quality of life of patients with AA [121]. AA also impacts on sexual quality of life [123]. One study showed that both males and females suffering from AA had decreased sexual quality of life with low Sexual Quality of Life for Females (SQOL-F) and Sexual Quality of Life for Males (SQOL-M) scores. In this study, men strongly identified with the statement "I fell anxious" and women with the statement "I feel embarrassed".

Preliminary outcomes of a research conducted in the Hospital Virgen de las Nieves (Granada, Spain), which were presented at the national congress of the Spanish Dermatology Academy showed also a significant burden in cohabitants of patients with AA. Cohabitants of patients with AA had high FDLQI scores, which correlated to DLQI from patients. Anxiety in cohabitants also showed correlation with the time of evolution of the disease [124].

There are different therapeutic options for AA, depending on the age of the patient and the extension of the disease. Briefly, in adult patients suffering from isolated patches of hair loss or less than 25% of scalp hair loss are the best candidates to therapy with intralesional injections of potent corticosteroids (such as triamcinolone). In the case of adult patients who refuse the injections and children, potent topical corticosteroids (betamethasone, clobetasol) are considered the first-line therapy. An alternative for mild cases is the use of topical anthralin. When AA is extensive, systemic drugs are recommended. Systemic corticosteroids taken in low doses can be effective but involve serious long-term adverse events. Other systemic immunosuppressive agents can be useful in AA: methotrexate or azathioprine. JAK inhibitors (tofacitinib, baricitinib) are novel promising therapies for severe cases of AA [125, 126].

#### *2.5.2 Cicatricial alopecia*

A wide variety of diseases can be classified into this group, both primary skin diseases and secondary cicatricial alopecia. Given that most of cicatricial alopecia are relatively uncommon, there is scarce evidence regarding their comorbidities and

#### *Quality of Life in Patients with Skin Disease and Their Cohabitants DOI: http://dx.doi.org/10.5772/intechopen.97450*

their treatment. Moreover, almost any studies report data about the impairment in quality of life associated with these skin disorders.

Few studies address the issue of quality of life in patients with Frontal Fibrosing Alopecia (FFA) [127]. FFA is a cicatricial alopecia, typically appearing in postmenopausal woman, characterized by slowly progression of hair loss in the frontal, temporal or frontotemporal scalp and eyebrows. Hair follicles show perifollicular erythema and scale. Patients with FFA have been found to show impairments in DLQI, and anxiety and depression scores [127].

Preliminary outcomes of a research conducted in the Hospital Virgen de las Nieves (Granada, Spain), which were presented at the national congress of the Spanish Dermatology Academy showed a significant burden in cohabitants of patients with FFA. Cohabitants of patients with FFA had high FDLQ ) scores, which correlated to DLQI from patients. Anxiety in cohabitants also showed correlation with the time of evolution of the disease. However, the impact on the quality of life in cohabitants of patients with FFA was lower than the impact on the cohabitants of patients with AA [124].

### **3. Discussion**

Skin diseases have a great impact on patients and cohabitants quality of life. Clinicians should be aware of this issue so they can provide an individualized medicine, targeting not only the visible symptoms of the disease but also the impact on quality of life. Researchers should also include quality of life impairment scales for patients and cohabitants to measure the effectiveness of treatments. Universal scales are needed to homogenize results. Further research regarding skin conditions should include the impact of both patients and cohabitants' quality of life assessed by validate scales. Moreover, healthcare policy should also consider not also patients' needs but also cohabitants'.

The most common tools to assess impairment in quality of life were the DLQI (for patients) and the FDLQI (for cohabitants), **Table 1**. HS and psoriasis are the diseases that have a greater impact on patients and cohabitant quality of life. The media DLQI scores for HS was 13.34 points and the media FDLQI was 9.76 points [51–53]. Psoriatic patients reported a media of 10.79 points in the DLQI and their cohabitants reported a media of 12.8 points in the FDLQI [6, 7, 32]. The greater impairment of this disease could be explained because of the symptoms, chronicity and comorbidities associated. The clinical manifestations of HS cause pain, itching, malodor and suppuration, among other symptoms, which make life difficult for patients [35]. Pain is one of the most important problems in patients with HS, usually related to the inflammation of the nodules. Psoriatic plaques are also associated with itching and pain what cause an important physical burden in patients [15]. The lesions of these disease frequently appear on the genital area, having an impact on sexual life [15, 35]. The sexual impairment could also explain the great cohabitants impairment of quality of life [6, 52], apart from the chronicity of this disease and the caregiver burnout syndrome. The following disease with higher points in the DLQI was AD (media of 10.78) [86, 87, 89]. This could also be explained because of the itching and the sleep disorder associated with this disease [79]. Acne and alopecia were scored with the lowest rate quality of life impairment. Acne patients scored a media of 7.56 points in the DLQI and their cohabitants a media of 6.46 in the FDLQI [68]. This could be explained because it is a disease that usually happens in adolescent and it is temporary [65]. Alopecia patients recorded a media of 6.1 points in the DLQI and their cohabitants a media of 6.13 points [124]. This might be explained because they are not usually associated with other symptoms and

#### *Quality of Life in Patients with Skin Disease and Their Cohabitants DOI: http://dx.doi.org/10.5772/intechopen.97450*


**2. Materials and methods**

In this study, probiotic juices containing 2 × 109 cfu *Bacillus coagulans* were prepared. 60 male runner athletes with an age range of 18 to 20 years and an average weight of 68 to 72 kg were randomly divided into two groups of 30 people. The criterion for participating in the study of complete physical health and was nonsmoking. During the 12 weeks of the study, the experimental group received a glass of probiotic juice containing *Bacillus coagulans* daily, and the control group received fruit juice Without supplemental.


**4. Conclusions**

The economic impacts of cattle disease on the beef cattle industry still remain significant, with BRD being the most significant health problem in modern feedlot industry in North America. The BRD is commonly associated with pneumonia in nursing beef calves and recently weaned feedlot cattle and often occurs within the first 45 days after feedlot placement. The BRD is considered as one of the most significant health problems in the beef industry accounting for economic losses that surpass those incurred by all other diseases of cattle combined. Treatment and control of BRD in the beef sector are aimed mainly at bacterial pathogens through antimicrobial use (therapeutic and non-therapeutic administration) and vaccination programs. However, recent studies have shown the emergence of bacterial pathogens associated with BRD that are resistant to all classes of antibiotics used to treat BRD. The increase in the multidrug resistance towards these antimicrobials that are being used as metaphylaxis in feedlots necessitates the development of novel methods to mitigate bovine respiratory pathogens in feedlot cattle as alternatives to metaphylactic antimicrobial use. Probiotic and EOs, being two major natural antimicrobial sources, display the potential application of antimicrobial alternative agents against bovine respiratory bacterial pathogens. More research is needed to develop nasal-delivered probiotics or EOs that can inhibit pathogenic bacteria, with limited effects on commensals and respiratory tract, after intranasal administration.


**Acknowledgements**

The invitation of the editor, Dr. Y. Itoh, to submit this manuscript is highly appreciated. The early version of the manuscript is greatly improved by constructive comments by reviewers (Y. Itoh and O. Takano). The following people are thanked for discussion and helpful sugges‐ tion: K. Arita, K. Sawada, S. Furota, T. Nakajima, T. Watanabe, S. Ohtsu, and M. Kawamura.

## **Author details**

Gentaro Kawakami\*

Address all correspondence to<EMAIL_ADDRESS>
Geological Survey of Hokkaido, Hokkaido Research Organization, Japan

#### **References**

ry Facies in the Active Plate Margin. Tokyo: Terra Scientific Publishing Company (TERRAPUB); 1989. P689-709.

[4] Kimura G. Collision orogeny at arc-arc junctions in the Japanese Islands. The Island Arc 1996; 5: 262-275.

differences in the degree of tectonic disturbance caused variations in stratigraphic/sedimen‐ tary architecture between the separately developed depressions in the foreland basin area. Limited tectonic activity resulted in trapping of coarse-grained deposits in the inner foredeep setting. Thick muddy deposits filled the sediment-starved and abandoned axial foredeep. Moderate to high thrust activity formed turbiditic successions several thousand meters thick in the axial foredeep. Progressed thrusting caused an increase in coarsergrained sediment-input to the foredeep and the sedimentary style changed from the basinal turbidites by efficient-flows to the slope-apron turbidites by poorly-efficient flows. The longterm shallowing of the foreland basin area can be explained by lithospheric flexural rebound caused by the isostatic readjustment for a thinning orogen and/or decreased horizontal compressional stress due to a gradual or stepwise decline of thrust activities in central

148 Mechanism of Sedimentary Basin Formation - Multidisciplinary Approach on Active Plate Margins

The invitation of the editor, Dr. Y. Itoh, to submit this manuscript is highly appreciated. The early version of the manuscript is greatly improved by constructive comments by reviewers (Y. Itoh and O. Takano). The following people are thanked for discussion and helpful sugges‐ tion: K. Arita, K. Sawada, S. Furota, T. Nakajima, T. Watanabe, S. Ohtsu, and M. Kawamura.

[1] Allen PA., Homewood PN. Foreland Basins. IAS Special Publication 8. Oxford:

[2] Hoyanagi K. Progradational lithofacies change of turbidite sequence, Middle Mio‐ cene Kotambetsu Formation, central Hokkaido, Japan. Journal of the Geological Soci‐

[3] Hoyanagi K. Coarse-grained Turbidite Sedimentation resulting from the Miocene Collision Event in Central Hokkaido, Japan. In: Taira A., Masuda F. (eds) Sedimenta‐

Hokkaido.

**Acknowledgements**

**Author details**

Gentaro Kawakami\*

**References**

Blackwell Science; 1986.

ety of Japan 1989; 95: 509-525.

Address all correspondence to<EMAIL_ADDRESS>
Geological Survey of Hokkaido, Hokkaido Research Organization, Japan

[16] Kawakami G., Arita K., Okada T., Itaya T. Early exhumation of the collisional orogen and concurrent infill of foredeep basins in the Miocene Eurasian - Okhotsk Plate boundary, central Hokkaido, Japan: inferences from K-Ar dating of granitoid clasts. The Island Arc 2004; 13: 359-369.

[27] Takahashi K., Kiminami K. Sedimentation of the Miocene Kotanbetsu Formation around the Haboro dome. Earth Science (Chilyu Kagaku) 1983; 37: 250-261.

Foreland Basins at the Miocene Arc-Arc Junction, Central Hokkaido, Northern Japan

http://dx.doi.org/10.5772/56748

151

[28] Matsuno K. The deposition of the sedimentary basin of the Kotambetsu Formation. Journal of the Japanese Association for Petroleum Technology 1958; 23: 19-21.

[29] Kanno S., Ogawa H. Geology of the Tertiary System in the Momijiyama-Takinoue district, Yubari City, Japan. Journal of the Geological Society of Japan 1963; 69:

[30] Hoyanagi K., Mito N., Yoshioka M., Miyasaka M., Watanabe Y., Matsui M. Stratigra‐ phy and sedimentology of the Miocene sediments in the southern part of the Ishi‐ kari-Teshio Belt, Hokkaido, Japan. Earth Science (Chilyu Kagaku) 1985; 39: 393-405.

[31] Kawakami G., Shiono M., Kawamura M., Urabe A. Koizumi I. Stratigraphy and dep‐ ositional age of the Miocene Kawabata Formation, Yubari Mountains, central Hok‐

[32] Sagayama T., Hoyanagi K., Miyasaka S. Diatom biostratigraphy and the stage of Ne‐ ogene coarse-grained deposits in the Hidaka coastal land, central Hokkaido, Japan.

[33] Itoh Y., Tamaki M., Takano O. Rock Magnetic Properties of Sedimentary Rocks in Central Hokkaido: Insights into Sedimentary and Tectonic Processes on an Active Margin. In Itoh, Y., ed., Mechanism of Sedimentary Basin Formation - Multidiscipli‐

[34] Covault JA., Graham SA. Turbidite architecture in proximal foreland basin-system deep-water depocenters: insights from the Cenozoic of Western Europe. Austrian

[35] Mutti E., Tinterri R., Remacha E., Mavilla N., Angella S., Fava L. An Introduction to the Analysis of Ancient Turbidite Basins from an Outcrop Perspective. AAPG Course Note 39. Tulsa, Oklahoma: The American Association of Petroleum Geologists; 1999.

[36] Soh W., Tanaka T., Taira A. Geomorphology and sedimentary processes of a modern slope-type fandelta (Fujikawa fandelta), Suruga Trough, Japan. Sedimentary Geology

[37] Sinclair HD., Tomasso, M. Depositional evolution of confined turbidite basins. Jour‐

[38] Itoh Y., Kusumoto, S., Inoue, T. Magnetic properties of siliceous marine sediments in Northern Hokkaido, Japan: a quantitative tectono-sedimentological study of basins

[39] Fukusawa H. Sedimentary mechanism of Neogene bedded siliceous rocks – on late Miocene Wakkanai Formation of northern Hokkaido, Japan. Journal of the Geologi‐

kaido, Japan. Journal of the Geological Society of Japan 2002; 108: 186-200.

Journal of the Geological Society of Japan 1992; 98: 309-321.

nary Approach on Active Plate Margins (this volume).

Journal of Earth Sciences 2008; 101: 36-51.

nal of Sedimentary Research 2002; 72: 451-456.

along an active margin. Basin Research in press.

cal Society of Japan 1988; 94: 669-688.

1995; 98: 79-95.

262-278.

[27] Takahashi K., Kiminami K. Sedimentation of the Miocene Kotanbetsu Formation around the Haboro dome. Earth Science (Chilyu Kagaku) 1983; 37: 250-261.

[16] Kawakami G., Arita K., Okada T., Itaya T. Early exhumation of the collisional orogen and concurrent infill of foredeep basins in the Miocene Eurasian - Okhotsk Plate boundary, central Hokkaido, Japan: inferences from K-Ar dating of granitoid clasts.

150 Mechanism of Sedimentary Basin Formation - Multidisciplinary Approach on Active Plate Margins

[17] Mutti E., Tinterri R., Benevelli G., di Biase D., Cavanna G. Deltaic, mixed and turbi‐ dite sedimentation of ancient foreland basins. Marine and Petroleum Geology 2003;

[18] Roveri M., Ricci Lucchi F., Lucente CC., Manzi V., Mutti E. Part III Stratigraphy, fa‐ cies and basin fill history of the Marnoso-Arenacea Formation. In: Mutti E., Ricci Luc‐ chi F., Roveri, M. (eds) Revisiting turbidites of the Marnoso-arenacea Formation and their basin-margin equivalents: problems with classic models. Excursion guidebook of the workshop organized by Dipartimento di Scienze della Terra, (Università di Parma) and Eni-Division Agip for the 64th EAGE Conference and Exhibition, Flor‐

[19] Yanagisawa Y., Akiba F. Refined Neogene diatom biostratigraphy for the northwest Pacific around Japan, with an introduction of code numbers for selected diatom bio‐

[20] Takahashi K., Fukusawa H., Wada N., Hoyanagi K., Oka T. Neogene stratigraphy and Paleogeography in the Area along the Sea of Japan of northern Hokkaido. Earth

[21] Hokkaido Mining Industry Promotion Committee. Petroleum and Natural Gas Re‐ sources in Hokkaido: Exploration and Development in 1977-1988. Sapporo: Hokkai‐

[22] Mitani K., Saito N., Osanai H. Oil and natural gas: from the Masuporo anticline to northern Tenpoku oil field area. Report of the geological resources in Hokkaido 1962;

[23] Mitani K., Saito N., Matsushita K., Osanai H. Oil and natural gas: from the headwa‐ ters of the Masuporo River and its southern side area to northern Tenpoku oil field

[24] Hirooka E. Petroleum geological study on Tenpoku district in Hokkaido, Japan. Jour‐ nal of the Japanese Association for Petroleum Technology 1962; 27: 113-134.

[25] Motoyama I., Nakamura S. Radiolarian biostratigraphy of the Miocene Masuporo and Wakkanai formations of the Uruyagawa section, Wakkanai, Hokkaido, Japan, with special reference to unconformity. Journal of the Geological Society of Japan

[26] Hokkaido Mining Industry Promotion Committee. Petroleum and Natural Gas Re‐ sources in Hokkaido: Exploration and Development in 1968-1976. Sapporo: Hokkai‐

area. Report of the geological resources in Hokkaido 1963; 88: 1-16.

horizons. Journal of the Geological Society of Japan 1998; 104: 395-414.

The Island Arc 2004; 13: 359-369.

ence (Italy), May 27-30; 2002. III1-26.

Science (Chilyu Kagaku) 1984; 38: 299-312.

do Mining Industry Promotion Committee; 1990.

do Mining Industry Promotion Committee; 1979.

20: 733-755.

79: 1-16.

2002; 108: 219-234.

[40] Yamamoto M., Watanabe Y., Watanabe M. Paleoceanographic controls on the deposi‐ tion of Neogene petroleum source rocks, NE Japan. Bulletin of the Geological Survey of Japan 1999; 50: 361-376.

**Chapter 7**

**Late Cenozoic Tectonic Events and Intra-Arc Basin**

On 11 March 2011, a catastrophic earthquake (Mw 9.0) took place along the Japan Trench off the Pacific coast of northeast Japan and about 20 thousands people were lost mainly by Tsunamis. The 2011 great earthquake occurred along a subduction zone where the Pacific Plate subducts perpendicularly toward the North American Plate at a rate of 8~9 cm/year (Figure. 1). Coseismic slip caused by the 2011 earthquake exceeded 50 m around the epicenter [1]. There has been a discrepancy between short-term (geodetic) and long-term (geologic) strain rates in both horizontal and vertical directions over the northeast Japan arc [2-3]. Geodetic observations [1, 3] have revealed horizontal shortening rate at around several tens mm/yr across northeast Japan arc, which is almost half of the subduction rate, whereas geological observations [4] have revealed horizontal shortening rate at around 3~5 mm/yr, which is one order of magnitude slower than geodetic observations [3]. Only a fraction (~10%) of plate convergence is, therefore, accommodated within the northeast Japan arc as long-term deformation. The 2011 great earthquake was one of the decoupling events that effectively released the accumulated elastic strain due to a plate coupling[3]. Study on long-term (geologic) deformation within the northeast Japan arc was thus proved to be crucial for assessing such extraordinary large decoupling events because they are too rare events (~one per kyr) to be detected by short-term

The Japanese Islands are divided into northeast and southwest Japan by an inter-arc rift system called "Fossa Magna" bounded by the Itoigawa-Shizuoka tectonic line (ISTL; Figure. 1) and the Tonegawa tectonic line (TTL; Figure. 1) that divides northeast Japan from southwest Japan [5]. This chapter focuses on the Northeast Honshu where three lines of ranges, the Kitakami and Abukuma mountains, the Ou backbone Range, and the Dewa Hills from east to west, run parallel to the Japan Trench (Figure. 1). This chapter aims to clarify Late Cenozoic tectonic

> © 2013 Nakajima; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 Nakajima; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and reproduction in any medium, provided the original work is properly cited.

**Development in Northeast Japan**

Additional information is available at the end of the chapter

Takeshi Nakajima

**1. Introduction**

(geodetic) observations.

http://dx.doi.org/10.5772/56706


**Machine Learning Modeling for Spatial-Temporal Prediction of Geohazard**

Editors

**Junwei Ma Jie Dou**

*Editors* Junwei Ma China University of Geosciences Wuhan, China

Jie Dou China University of Geosciences Wuhan, China

*Editorial Office* MDPI St. Alban-Anlage 66 4052 Basel, Switzerland

This is a reprint of articles from the Special Issue published online in the open access journal *Sensors* (ISSN 1424-8220) (available at: https://www.mdpi.com/journal/sensors/special issues/ spatial temporal prediction geohazard).

For citation purposes, cite each article independently as indicated on the article page online and as indicated below:

Lastname, A.A.; Lastname, B.B. Article Title. *Journal Name* **Year**, *Volume Number*, Page Range.

**ISBN 978-3-0365-9786-7 (Hbk) ISBN 978-3-0365-9787-4 (PDF) doi.org/10.3390/books978-3-0365-9787-4**

© 2023 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) license.


*2.1.1. Physiological act on muscle cells*

Though its detailed mechanism has not been elucidated, vibration stimulation acts directly on the contracted muscle cells to relax them (Vukas 1978, Ljung 1972, Ljung 1975).


**1.1 History of photodynamic therapy**

The therapeutic properties of light were observed already in ancient Greece, Egypt, and India. However, they were not widely used for many centuries [1]. The history of modern photodynamic therapy (PDT) dates back to 1900, when Oscar Raab discovered the toxic properties of the dye acridine red on *Paramecium* spp. [2]. He and his supervisor, Hermann von Tappeiner, noticed a positive effect of illumination on the toxic activity of this dye. In his later work, von Tappeiner and his colleagues applied this approach to inactivation of bacteria [3] and to treatment of skin cancer [4]. In 1909, von Tappeiner introduced the term "Photodynamic Action" and showed that oxygen is essential for this procedure [5]. PDT has been studied and developed as an anticancer therapy for a long time and was approved by the Food and Drug Administration in the 1990s for various applications in this area of medicine [6–8]. The antimicrobial properties of this approach were unfairly forgotten for several decades. However, interest in antibacterial PDT has been rekindled and is continuously increasing because multidrug resistance of pathogenic microorganisms has become a serious threat to public health. Photodynamic antibacterial chemotherapy (PACT) has become a promising approach for combating bacterial infections, which are resistant to modern antibiotics.