Brain= Perception: Research Implications

Introduction
    The late neuroscientist, Paul Bach-y-Rita, once said, “We see with our brains not with our eyes”. This notion implies that our perceptions of the world and universe—our very realities—are determined by our own unique brain structures as well as neuronal activity within the organ. In other words, brain equals perception of the world, which in turn, equals behavior. With the notion of cognitive and behavioral determination via neurophysiology, I will explore a varied perception of the physical world through a mental illness viewpoint (in particular, Schizophrenia) and perception of an intangible world through religious faith. In investigation of these two topics, I argue that we are limited in our access to the real world due to our neurophysiologies and that, in addition, objectivity is unattainable. Implications of a subjective observation of our present realm challenge our notion of normality.

Schizophrenia
    Schizophrenia is a severe and chronic mental illness characterized by cognitive deficits, social withdrawal, and perturbed perception (i.e. hallucinations and delusions). It is estimated that approximately 1 in 100 adults are affected globally. Originally thought to be a disease caused by neurodegeneration, recent studies suggest that the pathogenesis of schizophrenia begins with atypical neurodevelopment caused by genes and then triggered by social/psychological factors during early adulthood. Though various genes have been implicated in schizophrenia pathogenesis, studies on the NRG1 gene are of particular interest since Neuregulin1 growth factor for which it encodes is essential to neurodevelopment.

Formation of Neuregulin1
    Neuregulins (NRG) are trophic factors that belong to the epithelial growth factor (EGF) family responsible for growth and differentiation of epithelial, glial, and muscle cells 1,3. Neuregulins signal through interactions with ErbB receptor tyrosine kinases 1,2,3. NRG1, in particular, is found predominantly in the brain thus suggesting its major role in neurodevelopment 2. The NRG1 gene encodes for six types of NRG1 proteins (Types I-VI) 3. Synthesis for these NRG1 isoforms comes about through the cleavage of membrane-anchored precursors named pro-NRG1s 3.  Figure 1 illustrates NRG1 isoform synthesis. 
 (Mei and Xiong, 2008)

Initially, the structures that give rise to mature NRG1 isoforms (pro-NRG1s) consists of polypeptides with EGF-like complexes and type-specific complexes located in the extracellular region. Proteolytic cleavage at the membrane dislodges the EGF-like as well as the type-specific complexes except for Type III that remains wedged in the membrane. The EFG-like complexes together with the type-specific complexes form the NGR1 isoforms. 

NRG1-ErbB Interaction in Neural Development
    According to Mei and Xiong, NRG1-ErbB signaling is instrumental in neurodevelopment from the fetal to adult brain stages as “NRG1 and ErbB proteins are expressed in regions of both the developing and adult brain that undergo proliferation or neurogenesis” 3. In neuronal migration, assays of Erbb4-mutant mice showed perturbed brain patterning. This indicates that NRG1 is essential to brain development such that its signaling in the hindbrain provides organizational information to the cranial paraxial mesenchyme responsible for the migration of neural crest cells 1,3. In the cortex, NRG1-ErbB interaction has been shown to influence “radial migration of glutamatergic neurons and the tangential migration of GABAergic neurons” 3.
   

    In addition to cellular migration, NRG1 plays a role in the development and proliferation of glial cells as well as the protection of axons. NRG1 induces radial glial proliferation, which is key to the organization of the cerebral cortical neurons and cerebellar granule cells 2,3. Inhibition of ErbB receptors in glial cells has been shown to sufficiently stop neuronal migration along radial glia fibers thus implicating that NRG1 promotes radial glia formation and maintenance 3. In the adult brain, radial glia are responsible for synaptic plasticity.

    In the CNS, NRG1 is believed to signal oligodendrocyte (a glial cell particular to the CNS) proliferation though more studies are needed 3. Several studies with mice support the necessity for NRG1-ErbB signaling in oligodendrogenesis. Nrg-1 knockout mice initially failed to produce oligodendrocytes in vivo, but exogenous NRG1 Type III rescued the phenotype 3.  Furthermore, Kim, J.Y. et al. (2003) showed that NRG1 signaling interference inhibits oligodendrocyte differentiation from progenitor cells 3.     

    Since oligodendrocytes myelinate axons, there is a likely role of NRG1’s influence over axon protection. Roy K. et al. (2007) showed that mice mutant for ErbB4 such that they expressed DN-ErbB4, a transgene, had thinner myelin sheaths and thereby slower conductivity in the CNS axons compared to wild type mice 3. Mei and Xiong (2008), point out that this experiment did not affect myelination in the optic nerve or the corpus callosum (structures located deep with the brain) thus suggesting NRG1 is required for axon protection in brain structures located on the periphery 3. 

   
A Proposed Mechanism for Schizophrenia Pathogenesis
    Since the aforementioned studies suggest NRG1 necessity in oligodendrogenesis and myelination, disturbed NRG1 signaling would therefore account for the emergence of schizophrenia, which is generally thought to be a result of “faulty wiring in the brain”. That said, a hypothesis for schizophrenia proposes that altered levels of NRG1 signaling as a result of the mutated NRG1 gene, in turn, causes abnormal oligodendrogenesis and myelination. The perturbed development of these cerebellar structures then slows synaptic conductivity of the axons thus leading to a faulty wiring system in the brain. In fact, assays of genetically homologous populations point to polymorphisms in the NRG1 gene as something in common among diagnosed Schizophrenics within said populations.

    According to Corfas et al., a genome-wide scan of the Icelandic population (a population of relative genetic isolation) revealed a haplotype associated with the NRG1 gene present in 15.4% of affected individuals compared to 7.5% in control participants thus a risk ratio of 2.1 2. This haplotype consists of five polymorphisms and two microsatellites in the 5’ region of the NRG1 gene on chromosome 8 3.  This haplotype was subsequently name the “deCode haplotype” after deCode Genetics, the Icelandic genetic research facility that identified it 3. A follow-up study conducted on Scottish patients estimated a risk ratio of the haplotype as 1.8, nearly the risk level as displayed in the Icelandic population 2. A third but independent study on unrelated Welsh patients revealed a risk ratio of 1.2 a slightly lower ratio compared to the previous two studies 2. Analysis of these three studies by Loemuller et al. (2003) showed a significant association between the haplotype in the NRG1 gene and schizophrenia 2. To further support this claim, two studies conducted on two Chinese populations by Yang, J. Z. et al. (2003) and Tang, J. X. (2004), replicated the results of the three previous studies in both identifying the haplotype on the 5’ end of the NRG1 gene on chromosome 8 as well as in calculating similar rick levels of the deCode haplotype 2.

    As a result of these studies, scientists point to NRG1 as a potential mechanism for schizophrenia pathogenesis if mutated. Since NRG1 signaling is instrumental in oligodendrogenesis and myelination, and myelination typically finishes during early adulthood in humans (a time frame when schizophrenia usually emerges in affected individuals), there is a strong connection between the mutated NRG1gene and schizophrenia 2. This late myelination is noticeable in the frontal and temporal lobes 2, regions of the brain associated with cognitive thinking and emotions, respectively. To support this idea, Uranova, N. et al (2001) showed myelin sheath damage as well as a decrease in oligodendrocyte mitochondria density in schizophrenic patients 2. Further studies by Bartzokis, G. et al. (2003), Flynn, S. W. et al. (2003), and Foong, J. et al. (2002) revealed altered white matter (cells sheathed in myelin) development and integrity as well as reduced myelin volumes in the frontal and temporal lobes of schizophrenic subjects 2. The implications of these aforementioned studies combined, strongly support NRG1 gene’s role in schizophrenia if mutated.

The Hollow Mask Illusion
    As aforementioned, schizophrenia is characterized by cognitive deficits, social withdrawal, and perturbed perception. The last characteristic is most often associated with schizophrenia, as notions of people plagued by hallucinations and delusions have fueled stigmatization of the condition. As a result of these mirages, those unaffected by schizophrenia often define the condition as an inability to perceive reality.

    However, this is not always the case. In the Hollow Mask Illusion, participants look inside a hollow mask, a concave object.  Non-schizophrenic participants are “fooled” and see a convex face pointing towards them. Schizophrenic participants are not “fooled” and see what the hollow mask really is—a concave indentation of a face.

(www.wired.com/.../images/2009/04/06/mask.jpg)

    It has been implicated that this interpretation of the hollow mask by schizophrenic participants is a product of disconnectivity among brain regions responsible for bottom-up and top-down processing. Dima et al. (2009) suggest that a disruption in fronto-parietal interaction involved in top-down processes with the lateral occipital cortex involved in bottom-up processes is instrumental in “beating” the illusion 4. The researchers believe that in non-schizophrenic participants, perception involves uniting what is seen (a bottom-up process) with the brain’s expectation based on memories (a top-down process) 5. These researchers also hypothesize that there are three components to perception in illusion: the lateral occipital cortex which is responsible for vision (bottom-up process), the fronto-parietal cortex which is responsible for memory storage and expectations (top-down processes) and the censor which is not a region of the brain but is instead characterized as the interaction between the bottom-up and top down processes 4. When these processes conflict in such cases as optical illusions, the top-down processes override the bottom-up processes 5. In the case of facial recognition, human memory dictates that human faces point toward the viewer in a convex manner rather than a concave one 4,5. So when non-schizophrenic participants look inside a concave mask of a human face, the top-down processes override what is seen therefore the viewer perceives a convex human face 4,5.

    In the case of schizophrenic participants, a conflict between the top-down and bottom-up processes does not occur. As a result of reduced synaptic plasticity and axonal conductivity, a phenotype displayed by schizophrenic participants, there is “a failure to invoke top-down prior expectations during perceptual inference on the sensory stimuli” 4. Therefore, schizophrenic participants perceive a concave face inside of a hollow mask.

Implications of the Hollow Mask Illusion
    Those unaffected by schizophrenia know that they are looking inside a concave object yet try as they might; they see a convex object instead. Essentially, “normal” people are fooled by virtue of their neurophysiology yet, at least in this case, schizophrenic participants are not fooled by their neurophysiology. Through this hollow mask example, I argue that notions of “normal” being “true” is incorrect because schizophrenic people see what the hollow mask for what it is while non-schizophrenic people cannot. Therefore, while schizophrenic people see the world differently from non-schizophrenic people, their reality offers a benefit that is not afforded to non-schizophrenic individuals.

    I believe that this benefit can be extrapolated to the world which then poses the question: do schizophrenic people have a more accurate perception of the world than non-schizophrenic people since a conflict between top-down and bottom-up processes does not occur in their brains? Schizophrenic individuals may very well have a more accurate view of the world. Personally, I find it unsettling that non-schizophrenic brains such as mine, are hard-wired to perceive only the things to which they have the capacity. However, instead of subjecting brain structures to “right” and “wrong”, “better” or “worse” dichotomies, I propose that our current civilization see the benefits to each unique brain and thereby, each unique perception. I believe that the investigation of an example in which the perception of schizophrenic individuals is beneficial compels our society to re-think stigmatization of conditions labeled as mental illnesses and furthermore, to not be so eager to pathologize perceived odd behavior.

Religion
    While schizophrenia offers a different perception of the physical world, religious faith offers a perception of an intangible realm. For believers, faith is undeniably a powerful tool. It is a source of comfort, spiritual fulfillment and a guide for everyday living. Considering the variety of religions that all ultimately share similar social and personal purposes does this suggest a neurophysiological mechanism responsible for a distinctly human belief in something supernatural and beyond reasoning?

Evolutionary Origins for Faith
    The idea of faith having neurobiological origins is relatively recent with only a handful of scientists participating in the field during the 1980’s. Since then, with the backdrop of the Evolution versus Intelligent Design debate, the idea has gained ground and momentum with neurobiologists, evolutionary biologists, anthropologists, psychologists, and philosophers partaking in research—research in not whether God exists, but why humans seem to believe that God exists.

    Most of the scholars involved in these faith studies agree that religious belief is a product of evolutionary processes in brain formation that are distinct to human evolution. The theory is that the mutation that caused humans to evolve smaller jaws that then led to larger brains (i.e. the development of the frontal lobe) helped humans achieved more cognitive function. This increased cognitive function then led to certain “tools”, albeit accidentally, that facilitated a propensity for belief in the supernatural. Scholars have named these “tools” agent detection, causal reasoning, and folkpsychology 6.

    In agent detection, humans have the tendency to assume any movement as being caused by the presence of creatures with independent behavior. Robin Marantz Henig uses the example of the caveman who is better off assuming that the motion detected out of the corner of his eye is of a hyena about to pounce rather than just the wind jostling leaves 6. This agent detection mechanism proved advantageous to the survival of the caveman and to this day humans still have the capacity to personify inanimate objects such as mistaking a rock for a bear. But while we humans personify inanimate objects we, however, rarely mistake living creatures for inanimate objects. This mono-directional tendency of the brain supports the idea that human brains are equipped to presume the presence of agents whether they are actually there or not. From this idea arises the notion the God is an imagined agent facilitated by brain architecture.

    In causal reasoning, human brains have evolved such that we constantly look for an explanation as to why certain events happen. In other words, we have the tendency to create stories with chronology and cause-and-effect logic to account for events. Marantz Henig uses the cancer patient example. In this example, a cancer patient is more likely to believe that she survived despite a small chance for living because of a miracle rather than because of luck 6.

    In folkpsychology, empathy is a driving force. With this ability to understand others we then have a tool to anticipate others’ actions and persuade people to believe what we believe. Experiments on children suggest that as we grow older and our brains further develop, we also develop this sense for empathy. False-belief experiments in which children of varying ages anticipate what someone else might think given a situation consistently suggest this sense of empathy.

    In the rock box experiment conducted by psychologist Justin Barrett, children from ages 3-5 years old were shown a box labeled “Crackers” 6. They were then prompted to guess what the box contains to which they understandably responded “Crackers”. However, the box contained rocks, which is then revealed to the children. They were then asked to guess what their mother (who was not present in the room) would say if she were asked that question and what God would say. Barrett found that 3-and4-year-olds thought mom and God were both all-knowing figures and therefore, they would say “Rocks”. However, 5-and 6-year-olds knew that since their mothers were not present at the time of the reveal they too would be fooled and therefore answer “Crackers”. In the case for God however, these children (all reared in a Protestant religion) learnt that God is an omnipresent and omniscient being who would know that the box contained rocks.

    According to Barrett, these findings support the idea that people can be fooled even beloved and admired people such as mothers but God, however, cannot 6. His study further suggests that as people grow older, they further develop a sense for empathy such that they can anticipate the actions of others based on their own actions in similar situations. And because empathy also allows one to persuade others to believe in the same thing, the fact that these children were raised in the Protestant faith is responsible for their belief that God would know the box contained rocks.

    Considering our capacities to believe in agents that may or may not be present, to create stories no matter how random an event, and to empathize with a ready belief in other belief systems, these strongly suggest that humans are hard-wired to believe in the supernatural especially a religious faith when they are reared in a religious culture.

 
A Theist’s Brain and An Atheist’s Brain: The Differences 
      So if the human brain has the propensity for belief in the supernatural—for a belief in a deity—then how would the brains of atheists differ from those of theists? Dr. Andrew Newberg, a neuroscientist at the University of Pennsylvania, has long studied the effects of faith on brain activity. In his investigation of mystical experiences that Buddhists and Franciscan nuns, Newberg has found through fMRI scans that there is the simultaneous activation of the frontal lobe as well as deactivation of the parietal lobe 7. These neural patterns affirm the sense of increased focus (a characteristic associated with the frontal lobe) as well as a lost sense of time and space (a characteristic associated with the parietal lobe) that occur during meditation 7. However, in the case for people speaking in tongues, a distinct religious experience from meditation, Newberg found that their frontal lobes dramatically decreased in activity 7. This loss of focus is consistent with the person’s sensation of having their bodies taken over by the Holy Spirit. 

    In the case of an atheist’s brain scan, Newberg found that their brains did not display similar patterns of neuronal activity. In fact, their frontal lobes did not “light up” like the way the frontal lobes Buddhist monks and Franciscan nun did nor did they “go dark” like the way people who speak in tongues did 7. Newberg suggests that this difference in neuronal activity is due to certain brain circuitry that is present only in religious and spiritual individuals and that this predisposition is inherited.

Neuroplasticity
    Though Newberg found brain patterning that differed between religious/spiritual individuals and atheists, I do not think that their brains are structurally different upon birth. According to anthropologist Scott Atran, there “is no God part of the brain, but there are many different kinds of universal process involved in religious thinking that converge to generate a set of family resemblances between religions across cultures” 8. Thus there is no designated “God region” in the brain. Instead, I believe that considering the evolutionary origins of the belief in the supernatural—that our brains are hard-wired to believe in God—and the cultural aspect of religion, religious belief is a product of predisposed brain architecture and being reared in a religious setting. 

    To investigate the impact of external stimuli, such as culture, on brain architecture, I point to a relatively new field in biology: neuroplasticity. Just as what the name hints at, it is the belief that the brain is plastic, a malleable organ. As science writer, Sharon Begley explained in a February 2007 NPR program, neuroplasticity is based on the idea that one’s brain has the ability to physically alter itself through one’s personal experiences, the way one thinks, and the life one leads 9. Since the “brain is the organ of behavior” we can change brain structure simply through our thoughts and actions. These thoughts and actions “rewire” our brains by making new or different connections among neurons in various regions of the brain 9.

    This notion of brain structure plasticity is supported by Newberg’s analysis of a man’s brain scan after meditation. The man, having no previous strong religious belief, answered a questionnaire about memory improvement. After eights weeks of meditation, his brain scans showed more symmetrical activity in the basal ganglia (a structure associated with motor skills and motivation) than in the initial scans of his brain taken before his eight-week meditation regimen 10. The man has then claimed that since his meditation exercises, he has become a calmer person, resorting to anger less frequently in the face of stressful situations.

    Considering the human brain’s evolutionary propensity to believe in the supernatural and the idea that the brain is in a constant state of flux as proposed by neuroplasticity, I hypothesize that religious belief arises from the coordination of brain structure predisposition and external stimuli such as culture. Since religion often encompasses ritual practices such as meditation, I believe that being reared in a religious culture induces neuronal connectivity and arrangement in such a way to explain the differences in brain activity perceived in religious and non-religious individuals.          

A Theist’s Brain and An Atheist’s Brain: The Benefits 
    Even though religious and non-religious brains differ neurophysiologically, there are benefits to both differing perceptions nevertheless. According to Atran, although religious belief may very well have been a byproduct of other evolutionary events particular to the human brain, it ultimately proved advantageous in the survival of large-scale societies 6,8. He hypothesized that religious belief facilitated a sense of solidarity among individuals in the population that was conducive to building cooperative relationships. In addition, Atran suspected that religious belief also “helped enforce moral and altruistic norms, and punish free-riders on the public good” 8. To this day religion as a moral code is prevalent in our current society as evidenced in the survival of the Constitution that has ideas rooted in the Christian faith. In terms of group altruism, the influence of religion is evidenced in such massive congregations as Creation Music Festival. This festival is a weeklong Christian rock concert and besides showcasing music, acts of generosity such as sponsoring underprivileged children in Third World countries are also promoted. And as aforementioned in my neuroplasticity discussion, the practice of meditation (a ritual often associated with spirituality and religious belief) leads to better control over one emotions and thus enables one to become a calmer person.

    As for the benefits of atheist thinking, I believe that atheists are less likely to follow/create dictator regimes that inhibit free thought. In a quick glimpse of world history, wars have often been sparked by political/social turmoil yet fueled by religious differences. Hitler used Christianity as a tool to invoke hatred of the Jews and thus he was able to convince a predominantly Christian Germany to declare war against those of dissimilar faith. To this day, terrorist campaigns are facilitated by religious promises in exchange for martyrdom. In addition, I argue that atheists are more altruistic in their endeavors for public good because these acts do not serve to win points with God. Therefore, atheists display higher moral growth because their generosity does not serve an ulterior motive thus they show more genuine care. Now, I do not accuse all religious people of having selfish motivations for doing public good, but in light of the rewards promised in the religious teachings for doing good, there is room for that accusation.    

Implications for Human Inquiry  
    My investigation of schizophrenia’s impact on perception of the physical world as well as my exploration of religion’s emergence into society has led me to an alarming conclusion: our brains are hard-wired to perceive only that which they have the capacity.    

    The hollow mask illusion has shed light on the mechanisms involved in human interpretation of the physical world. In non-schizophrenic brains, a conflict between top-down and bottom-up processes leads to the eventual win of the top-down processes thus non-schizophrenic individuals are only capable of perceiving that to which they are equipped, in the case of the hollow mask illusion. 

    In the case for religion, our human brains are predisposed to believe in the supernatural. Increased cognitive ability in our distinct evolutionary history has given us “tools” to perceive agents when they do not actually exist (a response that may have proved advantageous to the caveman’s survival), to create stories to explain events and natural phenomena, and to empathize with other individuals. Those tools in conjunction with rituals, have led to the emergence and proliferation of religious thought. 

    In diametrically opposed perceptions arising out of different neurophysiologies (schizophrenic and non-schizophrenic; religious and non-religious), each perception has its own set of advantages. Schizophrenic people are able to beat optical illusions, which poses the idea that perhaps their perceptions of the world are more accurate than those of non-schizophrenic people since their neural processes do not conflict in the hollow mask illusion. Non-schizophrenic individuals do not experience the cognitive deficits and social withdrawal that schizophrenic people do. Religious individuals attest to the evolutionary advantage of religious belief and thereby, cooperative thinking. Atheists are less likely to engage in the inhibition of free thought and, in addition, display higher morality growth since their generous actions cannot be misconstrued as serving an ulterior motive.

    So, different neurophysiologies constitute unique realities.

    Therefore, reality is subjective. Though I do not promote a general distrust of professors and other educators, I would use this idea to encourage students to investigate scientific notions for themselves—to critically analyze new scientific findings since science itself is a constantly evolving discipline.   

    Therefore, we have limited access to the “real world”. I think this idea further supports the need for the replication of scientific finds.

    Therefore, notions of normality more accurately depict average neurophysiological occurrences and do not implicate “right” versus “wrong” dichotomies. Thus, we need not be so eager to pathologize perceived odd behavior in the case of schizophrenia and need not be so narrow minded in our religious beliefs or lack thereof.

References

[1] Meyer, D. and Birchmeier, C. (1995). Multiple Essential Functions of Neuregulin in Development. Nature 378, 386-390.

[2] Corfas, G. et al. (2004) Neuregulin 1-erbB signaling and molecular/cellular basis of schizophrenia. Nature Neuroscience, 7, 575-580.

[3] Mei, L. and Xiong, W.C. (2008). Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nature Reviews Neuroscience, 9, 437-452.

[4] Dima, D. et al. Understanding why patients with schizophrenia do not perceive the hollow mask illusion using dynamic causal modelling. NeuroImage, 2009; DOI: 10.1016/j.neuroimage.2009.03.033

[5] Bunchen, L. (7 April 2009). Schizophrenia Brains Not Fooled by Optical illusion. Wired. Retrieved December 2, 2009 from the World Wide Web: http://www.wired.com/wiredscience/2009/04/schizoillusion/.

[6] Robin Marantz Henig,"Darwin's God." The New York Times, 4 March 2007.   

[7] Juju Chang and Michael Pressman. "Faith in the Brain: Are Some People Hard-wired to Believe in God?" ABC News. (10 May 2007). Retrieved December 10, 2009 from the World Wide Web: http://a.abcnews.go.com/2020/story?id=3157321&page=1.

[8] Dan Jones, "Human Nature: The Remix," Nature 457 (2009): 780-783.

[9] Sharon Begley, interview by Ira Flatow, "Can Thoughts and Actions Change Our Brains?," NPR, 7 February 2007.

[10] Andrew Newberg, interviewed by Lucky Severson, "Faith and the Brain," Religion and Ethics Newsweekly, 17 July 2009.