Monday, January 30, 2012

Ow do we itch?



Trust me, there is a point to the quirky title. I just started my second rotation in Allan Basbaum's lab, whose mantra is 'Pain is in the brain'. The lab studies the neurological basis of pain and its control, with an emphasis on changes in the central circuitry in the spinal cord and the brain. The spinal cord is a fascinating, yet somehow glossed over component of the central nervous system; the few lectures we had on the anatomy of the spinal cord did not do it justice.As my rotation progresses, I am discovering a whole new area of highly complex plastic molecules and circuits and their importance in mediating our ability to detect a range of thermal, mechanical and chemical stimuli and how they are changed in the setting of nerve or tissue injury. More importantly, I am gaining new insight and appreciation of chronic pain as a physiologically and psychologically debilitating condition and the need to elucidate the molecules and cells that are involved in pain processing. 

Before I delve into the actual topic of my post, I just want to give a very brief description of the primary afferents bringing sensory information to the spinal cord (and show off my new found knowledge of neuroanatomy). Firstly, the process by which intense thermal, mechanical or chemical stimuli are detected is called nociception. The population of peripheral nerve fibers that carry this sensory information are appropriately called nociceptors   The cell bodies of nociceptors are located in the trigeminal ganglion for the face and the dorsal root ganglia (DRG) for the body, and have both a peripheral and central axonal branch that innervates their target organ and the spinal cord, respectively. Nociceptors are excited only when stimulus intensities reach a noxious threshold; this suggests that they possess biophysical and molecular properties that enable them to selectively detect and respond to potentially injurious stimuli. There are two major classes of nociceptors. The first includes medium diameter myelinated (Aδ) afferents that mediate acute, well-localized “first” or fast pain. These myelinated afferents differ considerably from the larger diameter and rapidly conducting Aβ fibers that respond to innocuous mechanical stimulation (i.e. light touch). The second class of nociceptor includes small diameter unmyelinated “C” fibers that convey poorly localized, “second” or slow pain. These fibers carry information up to supraspinal structures via distinct pathways; pain is carried by the C fibers and Aδ fibers travel via the spinothalamic tract, while non-painful stimuli are carried by the Aβ fibers  via the dorsal lateral lemniscus. 

A burgeoning interest in the field of pain research is the neuronal basis of itch. That's right, itch; I did a double take too when I found that was my rotation project. Itch was defined more than 340 years ago by the German physician Samuel Hafenreffer as an "unpleasant sensation that elicits the desire or reflex to scratch". The sensation of itch, formally known as pruritus, is most commonly associated with chemical irritants like histamine and a variety of skin diseases. Itch can also result from systemic disorders such as liver and renal dysfunctions. The discovery of neuropathic itch, or itch resulting from nerve damage, spurred investigators to determine specific mediators and neural pathways related to the central processing of itch. These studies have been essential in illustrating the interaction between itch and pain. Think about it, what do we do when we itch? We scratch, sometimes in a manner that causes pain. Animal and human studies have shown that scratch-induced pain can abolish itch, and pain-relieving opioids like morphine generate itch; this hints at an antagonistic interaction. So, what's going on? 

The antagonistic interaction between itch and pain supports the 'specificity theory', which stipulates that  distinct sets of neurons mediate itch and pain. This replaced initial theories on itch that indicated that itch and pain were closely related; weak activation of nociceptors results in itch while strong activation of nociceptors results in pain. This theory, termed as the 'intensity theory' underlined a common central pathway of itch and pain. However, observations that seemingly itch-specific neurons can respond, albeit weakly, to painful stimuli like capsaiscin has prompted researchers to abandon both the 'specificity theory' and 'intensity theory'  in favor of a more plastic 'selectivity theory'. Thus, while there may be distinct set of neurons for pain and itch, more and more studies are suggesting an astonishingly broad overlap between downstream mechanisms of itch and pain signaling. Protease-activated receptor 2 (PAR2) and members of the transient receptor potential (TRP) family have been implicated as targets for both pain and itch receptors, and sensitization of peripheral nerve endings by the protein nerve growth factor (NGF) is a known pathophysiological mechnanism in both chronic itch and pain. Parallels between pain and itch processing are even more evident in the pattern of central sensitization, or the changes that occur in the central nervous system that lead to enhanced responses and/or lower thresholds to a painful or itch-inducing stimulus. fMRI and PET have also identified certain common brain areas like the anterior cingulate cortex and the thalamus that are activated by both pain and itch. 

These similarities and differences in mechanisms of itch and pain sensitization are already being translated into therapeutic approaches to chronic pain and itch. However, as with the studies dealing with chronic pain, it will be important to identify molecules and circuits that are involved in the detection of acute itch in order to treat conditions of chronic itch. That is what I hope to do in my rotation project; aren't you itching to know what I end up finding out? Sorry, I couldn't resist. 

Monday, January 16, 2012

The Synapses of Religion



A couple of years ago when I was scouring topics to research as part of my independent study for Anthropology, I came across Andrew Newberg, director of research at the Myrna Brind Center of Integrative Medicine at Thomas Jefferson University and Hospital in Philadelphia and Adjunct Professor of Religious Studies and Radiology at the University of Pennsylvania. Dr. Newberg has spearheaded the field of neurotheology, the study of the neurobiology behind religion. My fascination with Dr.Newberg's research admittedly did not outlive the duration of my independent study, but a recent article in Scientific American about recent findings in the field rekindled my interest and I thought I would post an abridged version of my anthropological study, in an effort to shed light on the history and potential future of neurotheology. Enjoy! 

A dramatic crescendo of violins and soulful soprano voices greets viewers of the webpage of the European Society of Neurotheology. A pantheon of images of Gods from various religions emerges, with the message “Choose your Guide”. This guide subsequently takes you through the teachings of neurotheology, a concept first coined by the English writer Aldous Huxley in his novel Island. What Huxley used in somewhat of a satirical sense, at least for the purposes of his novel, soon attracted a mass following and a robust research field was evoked in order to find a physiological basis for religious or cosmic experiences. The field came into its own with the first book on the principles of neurotheology by Lawrence McKinney in 1994, titled Neurotheology: Virtual Religion in the 21st Century. In this book, Mckinney- the director at the American Institute of Mindfulness- attempts to create a working definition for the term neurotheology: the study of the physiological bases of religious experiences. Since then, neurotheology has garnered more attention in trying to answer some important questions regarding the validity of trying to find neurological underpinnings for religion: How is it that man’s purely physical brain has evolved the ability to connect with mystical events and the religious world? What neuronal systems or areas of the brain play a role in religious or spiritual experiences? Is religion indeed hardwired in the nerve connections in our brain? How does one go about measuring religiosity or spirituality?

WHAT IS NEUROTHEOLOGY?

Neurotheology, also known as biotheology or spiritual neuroscience, aims to study the activity of the brain during spritirual or religious experiences, thereby attempting to delineate neurological mechanisms for religiosity and religion. As such, neurotheologists believe strongly that all spiritual experiences are the result of neural impulses and brain patterns; the field favors this explanation over the converse possibility that spiritual experiences may be actually causing the neural impulses. While neurotheologists have been attacked for this somewhat reductionist approach to religion, it is important to understand the roots of these beliefs. In the early history of neurotheology, Mckinney postulated that pre-frontal development of the human brain occurs in a manner whereby the necessary connections to document the passage of time or chronicle events generally forms after the age of three. The inability of the adult brain to retrieve earlier images experienced by an infantile brain creates questions such as "Where did I come from?" and "Where does it all go?” which McKinney and other neurotheologists suggests led to the creation of various religious explanations. Neurotheologists like Andrew Newberg, have hypothesized that very specific neuronal structures and systems are involved in establishing these religious explanations and subsequent behaviors. Newberg and others describe repetitive, rhythmic stimulation of these neuronal systems which contribute to the experience of transcendental feelings of connection to a higher power. These researchers posit, however, that physical stimulation alone is not sufficient to generate cosmic experiences; there must be a blending of the rhythmic stimulation with philosophical ideas or psychological. This combination of the biological and psychological or philosophical ideas leads to the visceral experience of religiosity. Which neuronal systems are implicated in religious experiences and what are the ways in which to measure religiosity?

THE SCIENCE BEHIND NEUROTHEOLOGY

The Limbic System

According to Newberg and his colleague D’Aquili, the limbic system of the brain is highly implicated in the experience or induction of mystical states. The limbic system, sometimes also known as the emotional brain, is comprised of several brain structures, including the amygdala, hypothalamus, hippocampus, as well as the right frontal and right temporal lobes. The hypothalamus is concerned with all rudimentary aspects of emotion, homeostatic control of food and water intake, and controls the hormonal and related aspects of violent behavior and sexual activity. The amygdala also plays a highly significant role in sexual and violent behavior, and acting as a sensory filter to the various stimuli that we receive.  The hippocampus, which is contained in the temporal lobe, is a central structure in learning and memory, and relays essential contextual information to the amygdala. The right and left temporal lobes together control auditory, speech and language functions. According to Newberg and colleagues, the rich connections between the amygdala, hypothalamus, hippocampus, and temporal lobe enables a human to have religious, spiritual and mystical experiences.

Is the Temporal Lobe the ‘God Spot’?

What exactly is happening in the temporal lobe that elicits these spiritual or mystical experiences? One hypothesis is that during limbic hyperactivation, there is a resulting imbalance such that there is too much activity in the lower brain regions such as the limbic system and low activity in higher brain regions such as the cortices. Since areas of the cortex are important in controlling consciousness, the reduced activity leads to a lack of consciousness and the agitation of the limbic system leads to sensory arousal. This dichotomy persists because the higher regions of the brain are no longer able to interpret the information from the lower regions, and this uncertainty lends itself well to rationalization by way of spiritual and religious explications.

Another hypothesis proposed by the famous neuroscientist V.S Ramachandran, is that during seizures, the hyperactivity in the temporal lobes causes alterations in neuronal connections, either adding new ones or modifying existing ones. This process is referred to as kindling. Kindling was developed as a model to explain how it is that repeated stimulation of a specific area in the brain would cause the onset of epileptic seizures even after controlled stimulation ended in some cases. In this same manner it can be inferred that repeated stimulation of other parts of the brain can affect behaviors other than seizures. Ramachandran therefore postulates that religiosity is one such behavior that can be attributed to a kindling effect.

CURRENT RESEARCH

In their early research, Newberg and D’Aquili turned to a specific analysis of components of the central nervous system as crucial contributors to the religious experience. Firstly, there is the sympathetic system which is responsible for the arousal states that mediate activities such as hunting and mating. This system is also known as the ‘arousal’ system. The converse system is the parasympathetic system, responsible for activities such as sleeping, digestion, and cell growth. Appropriately, this system is known also called the ‘quiescent’ system. Newberg has found that while these ‘arousal’ and ‘quiescent’ systems normally act in an antagonistic fashion, maximal functioning in one system may spill over into the other system, thus leading to simultaneous activations of both systems. The investigators postulate that mystical experiences are most likely to occur during this ‘spill over’ effect. For example, mediation leads to a ‘hyperquiescent’ state of the ‘quiescent’ system, and this may in fact trigger the activation of the arousal system; this leads to a ‘burst of energy’ that leads to the feeling of being absorbed by an outside object. Buddhists refer to this notion as Appana samahdi. Literally meaning ‘fixed concentraion’. Conversely, the researchers assert that a state of ‘hyperarousal’ induced by ritualistic activity in the sympathetic system might spill over into the parasympathetic system; this breakthrough may contribute to the trancelike condition achieved in many religious experiences.

In addition to these systems, Newberg and colleagues found another neural complex that they called the Orientation Association Area (OAA) situated within the posterior parietal lobe, is also associated with such religious moments. The OAA is the area which enables us to orient ourselves in space and time and gives our bodies a sense of physical boundary. This physical boundary is used to give the self a sense of separateness from the rest of the uni­verse.  Using SPECT (single photon emission computed tomography) studies, Newberg and D’Aquili claim to capture the breakdown of these physical boundaries. Briefly, a radioactive tracer was injected into the arm of the subject, in this experiment, a Buddhist monk, on cue as they entered into deep meditative state. The tracer detected areas of the brain where there was an increase in neuronal activity and blood concentration. The imaging demonstrated minimal activity in the delineated OAA during peak meditation times. At the same time however, due to the intense concentration or appanna samadhi on a chant or prayer, the prefrontal cortex- termed as the Attention Association Area (AAA) - is strongly acti­vated; the AAA essentially takes over from the OAA as the brain’s new experiential center. This transfer of attention, Newberg claims, gives rise to another level of consciousness.

When the OAA is shut down the physical boundaries of the body and the resulting sense of separation disappears. The brain can no longer create a boun­dar­y between the self and the external world, or locate itself in physical reality. As a result, Newberg says, the brain is forced to perceive the self as infinite and coalesced with everyone and everything in the external environment. This is the state Newberg calls Absolute Unitary Being: the point at which we ‘feel’ God. The SPECT studies led Newberg and D’Aquili to believe that they had found the common biological root to all religious experience: “We believe that we were seeing colorful evidence on the SPECT's computer screen of the brain's capacity to make spiritual experience real. After years of scientific study, and careful consideration of our results, Gene and I further believe that we saw evidence of a neurological process that has evolved to allow us humans to transcend material existence and acknowledge and connect with a deeper, more spiritual part of ourselves perceived of as an absolute, universal reality that connects us to all that is.”

While these imaging studies need to be replicated and executed on a bigger scale, this data could explain the notions of God and ‘mingling’ with God that people described in the early experiments. Newberg’s data also implicates structures outside the limbic system, such as the prefrontal cortex and the parietal lobe, in the experience of religious or spiritual sentiments. Thus, their studies have broadened the so-called ‘God Circuitry’ in the brain and have added to Venkatraman’s theory of the temporal lobe and the kindling effect.

CAN NEUROTHEOLOGY BRIDGE THE GAP BETWEEN SCIENCE AND RELIGION?

The results from these various studies have been a double edged sword; it has encouraged neurotheologists to continue with their research, but it has also given fuel to atheists to assert that God is ‘all in our heads’. Not surprisingly, neurotheologists have faced a lot of heat from philosophers, theologists, scientists and religious practitioners. The approach that neurotheologists use has been considered highly reductionist; more specifically, individuals have questioned whether it is at all informative or necessary to characterize a subjective trait such as religion in objective or scientific terms?
Challenging the notion that religious beliefs are rooted in any specific neural substrate or function, David L. Smith, a Roman Catholic priest and clinical psychologist, questions: "If 'God neurons' or 'God neurotransmitters' actually exist in the brain, are they defective in the agnostic and absent in the atheist?"4 Indeed, Smith is holding neurotheologians to the same standard that neuroscientists would pursue when proposing a connection between a neural structure and some behavioral phenomenon: the neurons and neurotransmitters implicated in these connections must be shown to exist. Thus far, no neurotheologist has come forward to make confident claims of "God neurons" and "God neurotransmitters." Smith concludes that neurotheology is "a pseudoscience cloaked in the mantle of Cartesian dualism.”
There are some theologists who believe that neurotheology does hold some good in bridging the gap between science and religion. Ilia Deli is a member of the Roman Catholic Franciscan Order and holds doctoral degrees in pharmacology and historical theology. She appreciates how neurotheologists combine theology and neuroscience to make the case for a religious neural substrate. "It is tempting to speculate that there is a 'God module' in the brain and that such a module is located in the area of the limbic system; however, such speculation needs to be made cautiously. What these findings do point to, however, is that spirituality involves the brain. For the first time in human history we are beginning to understand spiritual experience not as something apart from the physical human but rather bound up with the matter of the brain. Thus, matter and spirit are no longer seen to be indeed mutually related, if not one and the same." 
One of the biggest criticisms of neurotheology addresses the fact that how and why we believe in God or religion are two very different questions. While researchers in the field have generated a lot of data, it is often hard to tell which question neurotheology is aiming to answer. Moreover, the media, the publishing industry, and the researchers themselves acknowledge the fact that the world at large wants the answers to both questions. While, the ‘how’ question traditionally belongs to scientists, and the ‘why’ to theologists, an answer that combines both types of information in a comprehensible manner is what the general public, the ultimate target audience of neurotheologists, wants. Furthermore, as most branches of science, neuroscience has experienced the phenomenon of sensationalism (termed "neuro-sensationalism"), exaggerated and sensationalized reports of neuroscientific findings have portrayed neuroscience as the key to understanding all of human thought and behavior. As a consequence, the field of neurotheology becomes caught in the conflicts between genuine science and hype.

Newberg cites this problem in his own work. "Skeptics have used my findings to conclude that religious experience was nothing more than a neural confabulation within the brain, and religious practitioners cited my work to confirm that human beings are biologically 'hardwired for God.'" However, Newberg seems relatively unphased by such comments and views the heated debates between believers and skeptics as more fuel for the field and the idea that "making our brains experience certain beliefs as real. When I take a brain scan of someone who says that they were in God's presence, the scan tells me what happens in the brain when they experience being in God's presence; it doesn't tell me if God was or was not actually there." In his book, Newberg professes himself as a "seeker," or one who is intrigued by the possibility of a transcendent reality underpinning everyday life. However, in recent years he has distanced himself from proposing conclusive answers to the "why" questions of human belief. This doesn't mean that he and other neurotheologists can't keep asking them or initiate conversations about them. However, in the eyes of steadfast critics, even the questioning is useless in the face of the perceived irreconcilability between science and spirituality.

The field of neurotheology has also faced criticisms of methodology, primarily from scientists. Their skepticism lies in the fact that it hard to use objective methods to quantify or qualify such a subjective notion as religion. Critics concede that neurotheologists are rational in the sense that if we discover how the brain informs us of reality, then this should help us understand how the brain differentiated between real experiences and virtual or ethereal experience. However, critics insist, with good reason, that the evidence thus far is not conclusive. Firstly, as a caveat to the field of neuroimaging, the statistical methods used in neuroimaging analysis can lead to false positives and also often provides correlations rather than causations. With that caveat in mind, critics also state that the types of experiences being studied are not homogeneous. Each person has a different type of experience; some feel the presence of God while others don’t. Ultimately, the applicability of neurotheology does not extend beyond the physical world: fMRI and SPECT scans can inform us of how the brain creates religious experiences, but not where these experiences come from. The search for neuronal markers exemplifies how consumers of popular science, like me, are interested in the ‘how’ and the ‘why’, but ultimately we want to know how the science can be applied to us as creatures of cultural, political and economic circumstance.