Arguing pain-brain relationships in the fetus

How does the physical growth of the fetal brain relate to pain function? Addressing this question is not just of research interest, but has profound consequences in guiding clinical use of analgesic and anesthetic intervention for in utero surgery. Adult brains appear structurally and functionally specialized for types of pain; for example, acute pain preferentially engages medial prefrontal cortical and subcortical limbic regions [1,2]. However, the question of the relationship between such specializations and pain is still controversial in the debate concerning fetal pain [3, for review]. One ‘maturational’ perspective is that brain growth and pain function co-develop through innate genetic and molecular mechanisms, and that postnatal experience merely has a role in the final ‘fine tuning’ [4,5,6,7]. Evidence concerning the differential neuroanatomical development of brain regions is used to determine a lower gestational age when particular regions likely become functional for pain. Several authors claim that maturation within subcortical brain regions enables pain function as early as 20 weeks gestation [6,7], others claim expansion of thalamocortical regions at 24 weeks is necessary and sufficient. An alternative ‘expertise’ view is that brain development and pain function involve a prolonged process of co-specialization that is shaped by postnatal experience [3,8,9,10]. Based on this approach, some authors argue that the fetal brain is not functional for pain at any gestational stage because skills such as sense of self and mind-reading learnt in postnatal life are necessary for pain [3,8,9,10].

Maturational views of functional brain development assume that brain growth and the appearance of functions are equivalent or the same thing, in the way that water and H2O are equivalent or the same thing, which implies that concerning the question of fetal pain, the sequential coming ‘on-line’ of specific brain regions during fetal development is identical with the appearance of pain function. That is, pain function numerically shares all its properties or qualities with the brain. Things with qualitative identity share properties, so things can be more or less qualitatively identical. Apples and oranges are qualitatively identical because they share the quality of being a fruit, but two apples have greater qualitative identity. Maturational views of fetal pain demand more than this, however, since they imply numerical identity. Numerical identity implies total qualitative identity, and can only hold between a thing and itself. This means that a maturational view of fetal pain makes a very strong demand about pain capacity: specific brain regions and pain function co-develop in the fetus because they are numerically identical, one and the very same thing. Pain is in the brain.

Expertise views of fetal pain challenge the core maturational commitment of brain-pain numerical identity and present philosophical arguments and data which claim instead to show the non-identity of brain-pain relationships in the fetus and the necessity of postnatal experience and learning [3,8,9,10]. A representative philosophical argument driving expertise views of fetal pain is the following: All pains are personal experiences and therefore entirely subjective; All brains are physical objects and therefore entirely objective; There is a fundamental divergence between pain and the brain. Therefore, pain cannot be numerically identical to the brain. Thus, the argument:

1. Pains are subjective.

2. Brains are objective.

Therefore, since pains and brains fundamentally diverge,

3. Pain is not numerically identical to the brain.

I will now critically examine and discuss this argument. Take the first premise: ‘pains are subjective.’ On a reasonable interpretation of its meaning, to say that ‘pains are subjective’ is to say that pains are knowable by direct personal experience. However, since brain events such as brain growth are not knowable by direct personal experience, pains cannot be one and the same thing as brain events. Here is the argument:

1. Pains are knowable to me by direct personal experience.

2. Brain events are not knowable to me by direct personal experience.

Therefore, since pains and brains fundamentally diverge,

3. My pain is not numerically identical to my brain.

Once the argument is represented in this form, it is clear that it is fallacious. This can be observed if we compare the argument with the following example:

1. Ibuprofen is known by me to relieve pain.

2. Iso-butyl-propanoic-phenolic acid is not known by me to relieve pain.

Therefore, since ibuprofen and iso-butyl-propanoic-phenolic acid fundamentally diverge,

3. Ibuprofen cannot be identical to iso-butyl-propanoic-phenolic acid.

The premises in the example are true, but the conclusion is known to be false. The argument is fallacious because its core assumption – ‘fundamental divergence’ – is mistaken: it mistakenly assumes that a thing must be known by somebody somewhere. But the property ‘being known by somebody’ is not a necessary feature of anything, much less a property that might establish its identity or non-identity with something otherwise known. The truth of the premises may be due to nothing else but my ignorance of what turns out to be identical with what. This point entails that ‘being known by somebody’ is not a necessary feature of pain that might explain its identity or non-identity with the brain. The non-identity of fetal brain development and pain function cannot be established by this argument.

The argument needs to produce independent evidence for the idea of ‘fundamental divergence’, since it is not self-evident. To illustrate this point, consider the argument for pain-brain numerical identity that personal pain would have no influence on mammalian behaviour were it not numerically identical with brain events [11]. This apparently simple argument wasn’t established until fairly recently because a crucial premise was not available. This is the premise that physical effects like pain are determined by prior physical causes. This is an empirical premise, and one which scientific theories of pain didn’t take to be fully evidenced until the middle and late twentieth century [12, for review]. It is this evidential shift, and not the apparently obvious, which is responsible for the argument’s persuasive power. It remains to be seen if stronger evidence for pain-brain identity in the fetus is forthcoming.

Of course, the failure of this particular argument to establish its conclusion does not thereby abolish the expertise perspective and self-guarantee its opposite, the maturational perspective, or even prove that the two perspectives are mutually exclusive. Rather, what the failure of the argument shows is that apparently obvious logic is sometimes a poor guide to reality. Whether pain-brain identity is true or false is impossible to tell simply by arguing personal appearances.

References

[1] Apkarian AV, Hashmi JA, Baliki MN. Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. Pain 2011; 152(3 Suppl): S49–S64.

[2] Wager TD, Atlas LY, Lindquist MA, Roy M, Woo CW, Kross E. An fMRI-based neurologic signature of physical pain. New England Journal of Medicine 2013; 368(15): 1388–1397.

[3] Derbyshire SWG, Raja A. On the development of painful experience. Journal of Consciousness Studies 2011; 18: 9–10.

[4] Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. New England Journal of Medicine 1987; 317(21): 1321–1329.

[5] Anand KJ. Consciousness, cortical function, and pain perception in nonverbal humans. Behavioral and Brain Sciences 2007; 30(1): 82–83.

[6] Lowery CL, Hardman MP, Manning N, Clancy B, Whit Hall R, Anand KJS. Neurodevelopmental changes of fetal pain. Seminars in Perinatology 2007; 31(5): 275–282.

[7] Brusseau RR, Mashour GA. Subcortical consciousness: Implications for fetal anesthesia and analgesia. Behavioral and Brain Sciences 2007; 30(01): 86–87.

[8] Derbyshire SWG. Controversy: Can fetuses feel pain? BMJ: British Medical Journal 2006; 332(7546): 909–912.

[9] Derbyshire SWG. Fetal analgesia: where are we now? Future Neurology 2012; 7(4): 367–369.

[10] Szawarski Z. Do fetuses feel pain? Probably no pain in the absence of “self”. BMJ: British Medical Journal 1996; 313(7060): 796–797.

[11] Papineau D. Thinking about consciousness. Oxford: Oxford University Press; 2002.

[12] Perl ER. Pain mechanisms: a commentary on concepts and issues. Progress in Neurobiology 2011; 94(1): 20–38.

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Pain in the brain? The question of fetal pain

There is broad agreement among researchers that the minimal necessary neural pathways for pain are in the human fetus by 24 weeks gestation [1, for review]. However, some argue that the fetus can feel pain earlier than 24 weeks because pain can be enabled by subcortical brain structures [2,3,4,5]. Other researchers argue that the fetus cannot feel pain at any stage of gestation because the fetus is sustained in a state of unconsciousness [6]. Finally, others argue that the fetus cannot feel pain at any stage because the fetus lacks the conceptual postnatal development necessary for pain [7,8,9]. If a behavioral and neural reaction to a noxious stimulus is considered sufficient for pain then pain is possible from 24 weeks and probably much earlier. If a conceptual subjectivity is considered necessary for pain, however, then pain is not possible at any gestational age. According to [1], much of the disagreement concerning fetal pain rests on the understanding of key terms such as ‘wakefulness’, ‘conscious’ and ‘pain’.

A motivation for thinking conceptual subjectivity is necessary for pain is the idea that subjective experiences such as pain cannot be reduced to or identified with the objective features of the brain [7,8,9]. All pains are personal experiences and therefore entirely subjective; all brain states are physical events and therefore entirely objective. There is a fundamental divergence between pain and the brain. Thus, pain cannot be in the brain. The basic argument:

1. Pain experiences are subjective.

2. Brain events are objective.

Therefore, since pain experiences and brain events fundamentally diverge,

3. Pain experiences are not identical to brain events.

Is this a good argument? Let’s examine its first premise – ‘pain experiences are subjective.’ On a reasonable interpretation of its meaning, to state that ‘pain experiences are subjective’ is to state that pain experiences are knowable by introspection. However, since brain events are not knowable by introspection, pain experiences cannot be identical to brain events. Here is the argument:

1. Pain experiences are knowable to me by introspection.

2. Brain events are not knowable to me by introspection.

Therefore, since pain experiences and brain events fundamentally diverge,

3. My pain experiences are not identical to any of my brain events.

Once the argument is represented in this form, it is clear that it is fallacious. This can be clearly observed if we compare the argument with the following example:

1. Ibuprofen is known to me to relieve pain.

2. Iso-butyl-propanoic-phenolic acid is not known by me to relieve pain.

Therefore, since ibuprofen and iso-butyl-propanoic-phenolic acid fundamentally diverge,

3. Ibuprofen cannot be identical to iso-butyl-propanoic-phenolic acid.

The premises in the example are true, but the conclusion is known to be false. The argument is fallacious because the core idea of the argument – ‘fundamental divergence’ – makes an erroneous assumption; namely, it assumes that a thing must be known by somebody. But the property ‘being known by somebody’ is not a necessary feature of any thing, much less a property that might establish its identity or non-identity with some thing otherwise known. The truth of the premises may be due to nothing else but my ignorance of what turns out to be identical with what. These considerations challenge the assumed epistemology in the conceptual subjectivity view of pain.

They also challenge the related claim made by proponents of conceptual subjectivity that any description of a pain given in objective scientific terms will necessarily always exclude the personal experience of that pain [7,8,9]. The argument made here is by now familiar: since descriptions of pain in personal subjective terms are different from scientific descriptions of pain, it follows that a pain and its private subjectivity cannot be identical with a brain event and its public objectivity. Only persons can feel pain – brain cells and protein channels can’t. Clearly, the argument begs the issue in question: whether or not the subjective features of a pain I personally experience are identical with some objective features of my brain that might be discovered by neuroscience is precisely the question at issue [10,11].

Besides, in order to understand a scientific explanation of pain, neuroscience does not require of a person that he both understands the explanation and feels pain as a condition of understanding. Neuroscience aims to explain pain, that is its main purpose. Too much is demanded of neuroscience if, in addition to formulating an explanation of pain, it is meant to re-create pain in somebody as a requirement of understanding [10,11]. This expectation is therefore much too strong.

References

[1] Derbyshire SWG, Raja A. (2011). On the development of painful experience.Journal of Consciousness Studies18, 9–10.

[2] Anand KJ, Hickey PR. (1987). Pain and its effects in the human neonate and fetus. New England Journal of Medicine, 317(21), 1321–1329.

[3] Anand KJ. (2007). Consciousness, cortical function, and pain perception in nonverbal humans. Behavioral and Brain Sciences30(1), 82–83.

[4] Lowery CL, Hardman MP, Manning N, Clancy B, Whit Hall R, Anand KJS. (2007). Neurodevelopmental changes of fetal pain. In Seminars in perinatology, 31(5), 275–282.

[5] Merker B. (2007). Consciousness without a cerebral cortex, a challenge
for neuroscience and medicine. Target article with peer commentary and author’s response. Behavioral and Brain Sciences, 30, 63–134.

[6] Mellor DJ, Diesch TJ, Gunn AJ, Bennet L. (2005). The importance of ‘awareness’ for understanding fetal pain. Brain research reviews49(3), 455-471.

[7] Derbyshire SWG. (2012). Fetal analgesia: where are we now? Future Neurology7(4), 367-369.

[8] Derbyshire SWG. (2006). Controversy: Can fetuses feel pain? BMJ: British Medical Journal332(7546), 909.

[9] Szawarski Z. (1996). Do fetuses feel pain? Probably no pain in the absence of “self”. BMJ: British Medical Journal313(7060), 796–797. 

[10] Churchland PS. (2002). Brain-wise: V: Studies in Neurophilosophy. MIT press.

[11] van Rysewyk S. (2013). Pain is Mechanism. PhD Dissertation, University of Tasmania.

Links between the intrauterine theory of gender identity, transsexualism and mind-brain-body identity

The intrauterine view of gender identity and sexual orientation

The intrauterine theory of gender identity proposes that gender identity is encoded in brain during intrauterine development (e.g., Savic et al. 2011; Swab, 2007). The brain is thought to develop in the male ‘direction’ through a surge of testosterone on nerve cells, likely in the bed nucleus of the stria terminalis (BSTc) in the limbic system (Chung et al. 2002; Krujiver et al. 2000; Zhou et al. 1995), whereas in the female ‘direction’ this surge is absent. This view of gender identity has been adapted to explain transsexualism: since sexual differentiation of the brain occurs in the second half of pregnancy, and sexual differentiation of the sexual organs occurs in months 1-2 of pregnancy, transsexuality is possible. Thus, the relative masculinization of the brain at birth may not reflect the relative masculinization of the genitals (e.g., Bao & Swab, 2011; Savic et al. 2011; Veale et al. 2010).

fp4-5.jpg (836×591)

The intrauterine theory implies that transsexualism is entirely dependent on a specific and dedicated neuroanatomical brain ‘module’, the BTSc). At a time during the second half of pregnancy, the BSTc comes ‘on-line’, and sexual  – or transsexual  – identity is thereby formed in the individual.

The intrauterine theory as a maturational theory

As a maturational brain theory, the intrauterine theory assumes functional localization of gender identity as an attribute of a specific brain structure or region (i.e., the BSTc) and its patterns of functional connectivity, rather than its patterns of functional connectivity to other structures or regions, to the whole brain and its external environment (van Rysewyk, 2010). Developmentally, a maturational view assumes establishment of intraregional connections, rather than interregional connectivity. It follows that the intrauterine view implies that transsexualism involves a process of organizing intraregional interactions within the BSTc. The bed nucleus of the STc appears to be critically involved.

Extending the maturational aspect of the intrauterine view to gender development also means that we should observe changes in the response properties of the BSTc during pregnancy as regions within the BSTc interact with each other to establish their functional gender roles. Thus, the onset of transsexual identity during intrauterine development will be associated with reliable changes in several regions in the BSTc.

Gray691

 

 

 

 

 

 

 

 

 

 

ST ‘off-line’

Gray691 (1)

         

 

 

 

 

 

 

 

 

 

ST ‘on-line’; onset of transsexual identity

The intrauterine theory and mind-brain identity theory

Philosophically, the intrauterine view is also highly compatible with mind-brain identity theory, a philosophy of mind and consciousness (van Rysewyk, 2013). Mind-brain identity theory claims that mental states are identical to brain states. This implies that a person’s indubitable sense of gender identity as manifested in real-time feelings, sensations, thoughts and reports made to others of being a woman or a man are numerically identical to specific brain states, possibly states of a single brain structure or region. Are the brain states in question states of one brain structure – the BSTc? It appears not, for Chung et al. (2002) found that significant sexual dimorphism in BSTc size and neuron number does not develop in humans until adulthood. However, most male-to-female (MTF) transsexuals self-report that their feelings of gender dysphoria began in early childhood (e.g., Lawrence, 2003).

Clearly, these important findings are not compatible with the maturation of one brain structure or region, but with inter-regional brain development, of which the BSTc may feature as merely one, but significant, contributor. Thus, following the onset of transsexual identity, there is a reorganization of interactions between different brain structures and regions. This reorganization process could change previously existing mappings between brain structures and regions and their functions. It follows that the same phenomenal sense of gender identity in a person (e.g., recurring feelings of gender dysphoria) could be supported by different neural substrates at different ages during development. This possibility doesn’t necessarily exclude a maturational theory of transsexual identity, since the BSTc may be stimulated to reorganize its intrauterine functional connectivity following appropriate stimulation during postnatal development.

Future experimental questions for the function of the BSTc in gender identity and sexual orientation

1. The extent of BSTc localization in gender identity: how diffuse or focal is BSTc activity that results from gender-identity based stimulation?

2. The extent of BSTc specialization in gender identity: How coarsely or finely-tuned is BSTc activity that results from gender-identity based stimulation?

The inter-regional interaction theory of gender identity assumes that as brain tissue becomes more specialized (i.e., finely-tuned), it will become activated by a narrow range of gender-based experiences. With increased specialization, less extensive areas of brain tissue (BSTc?) will identify with gender-based phenomenology.

References

Bao, A. M., & Swaab, D. F. (2011). Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders.Frontiers in neuroendocrinology32(2), 214-226.

Chung, W. C., De Vries, G. J., & Swaab, D. F. (2002). Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood. Journal of Neuroscience, 22, 1027-1033.

Kruijver, F. P., Zhou, J. N., Pool, C. W., Hofman, M. A., Gooren, L. J., & Swaab, D. F. (2000). Male-to-female transsexuals have female neuron numbers in a limbic nucleus. Journal of Clinical Endocrinology and Metabolism, 85, 2034-2041.

Lawrence, A. A. (2003). Factors associated with satisfaction or regret following male-to-female sex reassignment surgery. Archives of Sexual Behavior, 32, 299-315.

Savic, I., Garcia-Falgueras, A., & Swaab, D. F. (2010). Sexual differentiation of the human brain in relation to gender identity and sexual orientation. Progress in Brain Research, 186, 41-65.

Swaab, D. F. (2007). Sexual differentiation of the brain and behavior. Best Practice & Research Clinical Endocrinology & Metabolism21(3), 431-444.

van Rysewyk, S. (2010). Towards the the developmental pathway of face perception abilities in the human brain. In: A. Freitas-Magalhães (Ed.), ‘Emotional Expression: The Brain and the Face’ (V. II, Second Series), University of Fernando Pessoa Press, Oporto: pp. 111-131.

van Rysewyk, S. (2013). Pain is Mechanism. PhD Dissertation, University of Tasmania.

Veale, J. F., Clarke, D. E., & Lomax, T. C. (2010). Biological and psychosocial correlates of adult gender-variant identities: a review. Personality and Individual Differences48(4), 357-366.

Zhou, J. N., Hofman, M. A., Gooren, L. J., & Swaab, D. F. (1995). A sex difference in the human brain and its relation to transsexuality. Nature, 378, 68-70.

‘The human fetus cannot feel pain’

Fetal pain perception is often modelled on the same neural structures as in the adult.

However –

(1 The neural structures involved in pain processing in early development are unique and different from adults.

(2 Some of these structures and mechanisms are not maintained beyond specific developmental periods.

The immature pain system plays a signalling role during each stage of development, and fulfils this role using different neural resources available at specific developmental times.

Thus, the error here is reading the adult into the fetus.