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Monday, December 20, 2010

A Theory of Mind III: Emotions

Introduction
In laying out the essential ingredients for a theory of mind, I previously elaborated on the crucial roles of language and memory with illustrative examples. A befitting saying proclaims that a stool needs three legs to stand. Emotions represent another important ingredient of our mind. They seem to narrow our choices by focusing or diverting our attention, thus limiting our choices and profoundly affecting our behavior. They strengthen our memory of particularly intense moments. Plenty important decisions in our lives are being made because of the emotions we attach to a loved one. Therefore, emotions constitute a worthy third leg for the theory I strive to construct. Multifarious types of emotions have been recognized. We may distinguish the simple emotions of “affect programs”, like fear and aversion, from the complex, more “cognitively penetrable” ones (see de Sousa, 2003 for review).

Complex Emotions
Complex emotions have been recognized since the middle of the 19th century, when the tragic fate of the railroad construction worker Phineas P. Gage in New England brought the fundamental role of emotions in defining our personality and their roots in the brain to public attention.

Phineas Gage and his tamping iron
(from the collection of Jack and Beverly Wilgus)
Phineas miraculously survived a grave accident at age 25 which destroyed primarily his left frontal lobe. On Sep. 13, 1848, he was tamping blasting powder down into a borehole with a solid iron rod that weighed 13.25 lbs and was 1.25 inches in diameter and 3 feet and 7 inches long. A spark triggered an explosion and the rod shot straight up like a missile, tapered end first, entirely penetrating Phineas' skull. The iron was found later 80 feet away from the site of the accident. Astoundingly, Gage reportedly did not lose consciousness. He was brought home where Dr. John Martyn Harlow found him sitting up and talking. Harlow was an observant physician who diligently recorded Gage's condition and the progress of his recovery. Phineas, by then a cause célèbre, was a changed man. Before the accident, he used to conduct himself in an even-keeled, considerate manner fit to work as a foreman for the railroad. After the accident, his behavior had become more irritable and irate, and he struggled with a lack of focus. Yet, he managed to hold down a job as a stage coach driver in Chile for several years and lived for another twelve. At the age of 37, he developed severe seizures and passed away within a few months.

Informed of Phineas' death, Harlow sought out the family and was able to procure the tamping iron. He gained permission for a brief exhumation of Phineas' remains during which he retrieved the skull. Harlow published his observations on Gage in a scientific journal (Harlow, 1848) as one of the first documented neurological case histories that related anatomical with behavioral findings. Skull and iron are in the possession of the Warren Anatomical Museum at Harvard Medical School today, and several attempts have been made to reconstruct the damage to Phineas' brain. Certainly, his left frontal lobe, but likely also a part of the right frontal lobe, were severely compromised by the rod's impact.

Phineas' terrible accident kindled intense scientific interest in the role that the frontal lobes play in our emotions and specific frontal lobe areas have been associated with distinct aspects of emotional behavior. For example, the anterior cingulate cortex near the juncture of the cortical hemispheres and the frontal orbital cortex, that is the very nose-ward aspect of the cerebral cortex, seem engaged in focus, decision making and judgment, notably of pain and danger, and are considered part of our attention and risk assessment mechanisms. In addition, anterior cingulate cortex influences autonomic functions like blood pressure and heart rate.

The anterior cingulate cortex sends output to insular cortex wedged between the frontal and the temporal lobe under the operculum, and frontal orbital cortex receives input from this region. Insular cortex receives sensory as well as visceral input, integrating information from inside and outside our body. Von Economo first discovered spindle cells there. Spindle cells are a particular morphological type of nerve cell peculiar to a select number of cortical areas of high-level functional specialization among which we also find anterior cingulate cortex. I have written about these cells in my post with the title "Constantin von Economo's Spindle Cells & The Mind" dated Aug. 21, 2009. Moreover, a special functional type of nerve cells, known as mirror neurons, have been found in anterior cingulate cortex (Rizzolatti and Sinigaglia, 2008). They have been implicated in empathy. I have written about them in my post with the title "fMRI III: Religiosity & Brain Activation" published Mar. 31, 2009. Anterior cingulate, frontal orbital and insular cortex are considered extended parts of the limbic system.

Simple Emotions
Simple emotions are processed by members of the limbic system that are phylogenetically older brain structures than the cortical regions discussed above. We widely share them with less developed vertebrates (Ebner, 1969), inspiring Paul McLean's hypothesis of the triune brain (McLean, 1990). Structures laying down long-term episodic memory have been included here. They comprise the hippocampus, composed of dentate gyrus, fornix, fimbria, and subiculum, as well as the parahippocampal gyrus, divided into perirhinal and the entorhinal cortex.  Particularly, the amygdalae, almond-shaped structures composed of histologically and functionally distinct, interconnected subregions at the bottom of the medial temporal lobe of cerebral cortex, are instrumental in startle and fear. They are strongly influenced by the neurotransmitter dopamine (Reynolds, 1983) and known to play an instrumental role in the influence of emotional arousal on the strength of the memory for our experiences (LeDoux, 1998).

The amygdalae provide output to the reticular formation, instrumental to alert and arousal, the striatum, involved in motor control, as well as structures in the brainstem, mesencephalon and diencephalon that control visceral, gustatory, nociceptive, motor and humoral functions. Moreover, they project to hippocampus, entorhinal cortex, prefrontal cortex, sensory cortical areas of all modalities and multimodal sensory association cortex. While the outputs can be either inhibitory or excitatory, inputs to the amygdalae are predominantly excitatory, utilizing the neurotransmitter glutamate. Fear conditioning in rats has been shown to increase their synaptic strength through a plastic mechanism known as long-term potentiation (Paré and others, 2003).

The inputs to the amygdala originate in most cortical and subcortical areas the structures project to, plus the olfactory bulbs (McDonald, 1998). Moreover, in opossums (Kudo and others, 1986), rats (Ottersen and Ben-Ari, 1979; Doron and Ledoux, 2000) and cats (Ottersen and Ben-Ari Y, 1979), the amygdalae also receive multimodal sensory direct input from the diencephalon, notably the visual (lateral posterior nucleus equivalent to the pulvinar in us) and auditory thalamus (medial geniculate body). The medial geniculate body is a relay station of the ascending auditory pathway. The direct connection with the amygdalae facilitates rapid responses to unexpected menacing stimuli. Alas, the input from the auditory thalamus does not appear to exist in us (Munoz-Lopez and others, 2010), and the one from the pulvinar seems to exert less impact on the amygdalae than in rodents (Pessoa and Adolphs, 2010). This paucity may manifest itself in a less abrupt startle reflex, because cortical processing is involved. Regardless, we immediately seem to duck when we hear a loud bang. When others take cover or flight, we do not hesitate either, as the video of this horrific incident shows. We only need to watch the beginning of the clip. Amygdala in action is visible at 10 seconds:


A story on National Public Radio's Talk of the Nation Science Friday with the title "No Fear" broadcast Dec. 18, 2010, informs us about patient S.M. whose amygdalae have been damaged on both sides (Feinstein and others, 2010). She literally knows no fear. The insights she provides may invaluably help advance treatments for people with anxiety and post-traumatic stress disorder.

Conclusion
Perhaps the founder of human ethology Irenäus Eibl-Eibesfeldt most strikingly revealed the prevalent and universal role of emotions in our lives. He developed camera lenses with a mirror that permitted him to record the facial expressions of unsuspecting bystanders unnoticed. By filming people around the world through these right-angle lenses, he and his colleagues were able to identify archetypal face expressions commonly used to communicate emotions across diverse cultures (Eibl-Eibesfeldt, 1989). The raising of the eye brows to signal readiness for social interaction constitutes one impressive example. Pictures of this behavior are shown on the home page of the Film Archive of Human Ethology. It is a wonderfully emotional scene.

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Saturday, November 20, 2010

Epilepsy, Ketogenic Diet & The Mind

In this informative essay entitled "Epilepsy's Big, Fat Miracle" published online in The New York Times Nov. 17, 2010, Fred Vogelstein tells us how a ketogenic diet helped drastically diminish petit-mal seizures in his eight-year old son Sam who suffers from epilepsy. Medication is still needed. But Sam had suffered up to 130 seizures a day, producing short, at times frightening, pauses of consciousness. Since he has been on the diet, their frequency dropped by 75 percent. Experience with patients like Sam tells that he may not need it anymore at some point in the future. Why the diet provides this effect has remained little understand.

A ketogenic diet consists almost entirely of fatty foods and very low sugar. When we deprive our body of sugar for an extended period of time, we begin to metabolize fat. The liver converts fat into ketone bodies that all cells can use instead of glucose to produce the energy they need to function. Nerve cells in the brain do not only utilize the ketone bodies as sources of energy, but also may produce the neurotransmitter glutamate, as a derivative of the intermediate  α-ketoglutarate in the same metabolic energy pathway in the mitochondria that consumes the ketone bodies as well as glucose derivative pyruvate, known as Krebs cycle.

Krebs Cycle (courtesy: Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins)
Glutamate constitutes the most prevalent excitatory neurotransmitter in the brain. Neurotransmitters pass information across the contacts between nerve cells known as synapses.  Glutamate receptors, notably the N-methyl D-aspartate receptor, play a crucial role in the shaping of nerve cell connections. The kainate receptor is known to be excitatory when located postsynaptically and modulate inhibition when located presynaptically. Kainic acid triggers epileptic seizures. During a seizure nerve cells release glutamate in unusually large amounts causing waves of excitation that the nerve cells otherwise do not experience. Under normal conditions, nerve cells manage to adapt their responses to increasing stimulation, keeping the released amounts of glutamate low (read my post with title "Good News for Brain Energy Use" dated Sep. 12, 2009).

However, when we are on a ketogenic diet, the glutamate that can be derived from ketone bodies is at best half of that derived from glucose. The diminished availability of glutamate may make the difference (but also see Morris, 2005).

Addendum
  • A wise biochemist made me aware of the possibility that ketogenic diets may take advantage of yet another metabolic mechanism. By far not all α-ketoglutarate in the Krebs cycle is converted into glutamate. Rather, the larger fraction is turned into succinate in a reaction that also produces guanosine triphosphate (GTP) from guanosine diphosphate (GDP). Neurotransmitter receptors can be divided into two fundamentally two different types: ionotropic and metabotropic. The first type of receptor is coupled to channel proteins in the nerve cell membrane that control ion fluxes instrumental for the generation and propagation of the electrical impulses encoding the information processed in the brain. The afore-mentioned NMDA and kainate receptors are ionotropic. The second type of receptor is coupled to G-proteins that effect molecular signals regulating ionotropic receptor function, gene expression and energy metabolism.  Eight metabotropic glutamate receptors have been identified. The activation of G-proteins depends on GTP. In addition to curtailing the availability of glutamate per se, a ketogenic diet may therefore diminish glutamate's action indirectly, diminishing metabotropic glutamate receptor activity (12/07/10).
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Sunday, October 17, 2010

Sensory Renewal: Goldfish Eyes & Hair Cells

The U.S. Census Bureau reports in its results from the 2006 American Community Survey that 7 million Americans older than five years possess a severe sensory disability. According to the National Eye Institute, 1.75 million Americans are losing vision, owing to age-related macular degeneration. In the year 2020, their ranks will swell to roughly 3 million. Gallaudet University suggests in informative, well-documented data analyses that about 1 million Americans are functionally deaf. Recent breakthroughs in regenerative medicine have decisively progressed toward promising treatments.

Carassius auratus (courtesy G. Blakemore)
I once was involved in research on plasticity of the goldfish retina (a micrograph of a beautifully stained cross section through a chicken retina similar to fish is shown here). Carassius auratus grows in size throughout its lifetime. Many of us may have encountered well-fed goldfish as long as a lower arm. With eyes growing continuously, the retina must keep up. It does not merely stretch. Rather, dividing pluripotent precursor stem cells are retained in a marginal zone, from which the needed retinal cells differentiate.

Retinal ganglion cells constitute the nerve cells that convey visual information from the retina to the optic tectum in the midbrain where their endings terminate in a topographic map of the retina. Because of this retinotopy, an image of the surrounding world cast on the retina retains its spatial relations when it is represented by nerve cell activity in the tectum. As the retina grows, retinotectal nerve fibers are added and new tectal terminations are formed, while old ones continue to process visual information. In our mature visual system nothing like this happens. Once our brain matured, the retinal nerve cells and their connections with the brain remain by and large unchanged.

In addition, the goldfish visual system is capable of an achievement even greater than the continuous addition of functionality. Maier and Wolburg (1979) discovered that goldfish retinae deprived of almost all cells by metabolic poisoning were able to reconstitute themselves from scratch within a few months. As we know now, surviving Müller glia cells and photoreceptor cells convert into multipotent stem cells that serve as dividing progenitors from whose offspring retinal cells differentiate  (Bernardos and others, 2007). The new ganglion cells innervate the optic rectum in roughly topographic fashion. My project was to examine with a functional imaging method whether the newly formed connections with the tectum were functional. Indeed, my colleagues and I found compelling evidence that the novel retinotectal inputs could be activated by visual stimulation.

Destruction & Renewal (Melzer & Powers, 2001)
The figure above shows pseudo-colored nerve cell activation (blue - low; red - high) in slices cut transversely through the fish brain at the level of the optic tectum, that is the outer rim transected by black lines on both sides (the bar in the lower left pertains to 0.5 mm; the fish's top is up; the fish's right side is on the left). The right eye had been injected with ouabain, a metabolic toxin that kills retinal nerve cells. The retinotectal pathway is crossed. Stimulation with black and white stripes of all orientations resulted in strong activation of the optic tectum on the side receiving input from the intact left eye (red band in the tectum on the left). One week after the ouabain injection (1w p.o.), the nerve cell response on the side that used to receive input from the poisoned eye was distinctly reduced (yellow band on the right). Fourteen weeks after ouabain injection (14w p.o.), tectal activation had recovered noticeably, owing to the reconstitution of the poisoned retina and the regrowth of retinotectal connections (Melzer and Powers, 2001).

Alas, the terminally differentiated cells in our mature retina do not possess the goldfish's power of spontaneous regeneration. However, much progress has been made since I conducted my research, unraveling the molecular mechanisms and identifying the genes that reconvert differentiated cells into multipotent stem cells or conditioned pluripotent embryonic stem cells to become progenitors. Recently, Advanced Cell Technology developed the first gene therapy for people with Stargard's macular dystrophy that will soon be tested in clinical trials, aiming to replace dysfunctional pigment epithelium cells in the retina with healthy ones generated from human stem cells.

By contrast, the effort to restore hearing in deaf people has not advanced to clinical trials yet, though stem cells have also shown promise. Oshima and others (2010) successfully directed induced pluripotent stem cells and embryonic stem cells from mice to change into skin cells. The skin cells were subsequently converted into progenitor cells. The researchers were then able to promote these progenitors' offspring to differentiate into hair cell-like cells with stereocilial bundles that exhibited stimulus transduction currents resembling those of immature sensory hair cells in the organ of Corti of the cochlea, that is the inner ear.
Schematic crossection through the organ of Corti showing the hair cells topped by the basilar membrane surrounded by support cells (courtesy Madhero88).
The organ of Corti is situated roughly in the middle of the cochlea running in its turns from base to apex. Sound vibrations are conveyed from the tympanic membrane via three small bones in the middle ear to the cochlea. The cochlea is filled with liquid. The sound vibrations move the organ of corti's tectorial membrane atop the hair cells, deflecting the cilia. The hair cells transduce the deflections into tiny electrochemical currents and pass them onto nerve cell endings of the auditory nerve the fibers of which convey the resulting electrical impulses to the brain. With decreasing sound frequency, the location on the organ of Corti that is stimulated most strongly shifts from the cochlea's base to its apex, providing the mechanical foundation for our ability to discriminate pitch.  The representation of pitch in discrete regions ordered by frequency is called tonotopy and remains preserved in all information-processing stations of the brain's central auditory pathway (I have written about tonotopy in my previous posts dated Sep. 30, 2009, and Oct. 12, 2009).

Only about 14,000 hair cells populate the human organ of Corti. Because of the inability of our hair cells in the inner ear to repair or replace themselves, drug- or sound volume-induced damage irreversibly leads to the persistent loss of hearing in the range of pitch associated with the location of the damage on the organ of Corti. In offering one possible resolution of this predicament, Oshima and others (2010) recently developed a three-step hair cell generation procedure, manipulating molecular signaling pathways that regulate cell fate and proliferation in tissue culture. In the first step, inhibition of the Wnt/TGF-beta pathways commits the stem cells to ectoderm. In the second step, FGF signaling promotes the ectodermal cells into otic progenitors. In the third step, the progenitors divide and differentiate into immature hair cell-like cells in a culture system with stromal cell-derived activity. The findings constitute a proof of concept, demonstrating that the replacement of hair cells from stem cells is possible. Whether the newly generated cells can be implanted in inner ears and form functional connections with nerve cells remains to be established.

Alternatives to the implantation of stem cells may exist. In vertebrates other than mammals lost hair cells are replaced by regeneration from support cells in the surrounding skin, known as phalangeal cells and Deiters' cells. The support cells convert into dividing pluripotent otic progenitor cells. In analogy, methods that may help de- or transdifferentiate support cells into dividing progenitor cells in vivo are being pursued (Izumikawa and others, 2005; Löwenheim and others, 1999). 

Regardless of the obstacles that still need to be overcome, there is now a good chance that stem cell therapies or regenerative medical procedures derived from this research may be able to help people with sensory disabilities regain function.

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Addenda
  • The picture of the retina mentioned above and other astounding renderings of the brain can found in Carl Schoonover's recent book with the title "Portraits of the Mind: Visualizing the Brain from Antiquity to the 21st Century" (11/07/10).
  • Today the Swedish Royal Academy awarded this year's Nobel Prize in Physiology or Medicine to John B. Gurdon from Great Britain and Shinya Yamanaka from Japan for their successes in converting differentiated cells into pluripotent stem cells (10/08/2012).
  • Almost a decade ago, Izumikawa and others (2005) showed in guinea pigs that the administration of adenoviral vectors containing the gene that encodes ATOH1, a transcription factor crucial for hair differentiation, to non-sensory support cells in the organ of Corti resulted in the regeneration of hair cells and recovery of hearing. Helen Thomson reports in her post with the title “Deaf people get gene tweak to restore natural hearing” published online by the New Scientist Apr. 23, 2014, that the first clinical trials using the principle of this method are going forward at the University of Kansas Medical Center (04/25/2013).
  • Schwartz and others (2012) have been testing ACT’s therapy. NPR’s Rob Stein reported in his Morning Edition segment published Oct. 14, 2014, with the title “Embryonic Stem Cells Restore Vision In Preliminary Human Test” for Morning Edition improvement of eyesight in 10 of 18 patients enrolled in the phase I trial (10/15/2014).

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