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Monday, June 23, 2008

The Brain: A Giant Self-Medicating Gland

The use of psychoactive drugs is older than humanity. Primates have been observed to deliberately feast on fermenting fruit rich with alcohol. The debate over the benefits and perils of treating mental disorders with psychoactive drugs has been unrelenting and passionate among patients, physicians and scientists. Alternative treatments promising improvement are hotly disputed. Two recent articles in The New York Times highlight the substantial public attention paid to these issues.

The first one, published online Apr. 15, 2008, was written by Richard Friedman M.D., a concerned physician who worries about the presently unknown health effects of life-long medication beginning at an age when our brain still develops. The prescription of anti-depressants to youngsters diagnosed with adolescent depression is used as an example. Brain and mind may develop differently with the constant exposure to these drugs. The body will be burdened with a foreign compound for a life time. The author argues convincingly that more research is needed to examine the long-term effects of the chronic exposure to psychoactive drugs. This concise, informed, and sensitive contribution initiated comments from 360 readers.

The second article, published online Jun. 16, 2008, is a post by Tara Parker-Pope describing therapies for Attention Deficit Hyperactivity Disorder alternative to conventional drug treatments. The article has attracted 160 comments to date. Prudence is advised when examining the options discussed in this post. The assessment of recently developed treatments is wrought with difficulty. The time for gathering experience with a novel therapy is commonly too short to allow a valid comparison with the risk/benefit analyses of established therapies supported by large bodies of data.

It is important to emphasize that any type of intervention will influence the biochemical make-up of the brain. The nerve cells in the brain produce psychoactive substances and modify their production at all times. The nerve cells excrete chemical substances known as neurotransmitters to communicate with each other. Neurotransmitters affect the behavior of nerve cells immediately. The predominant excitatory neurotransmitter is glutamate. Glutamate bound to specific receptors on the cell body surface stimulates the production of electrical signals known as action potentials. Action potentials travel along the nerve cell's outgoing arbor, i.e. its axon, and exact the release of neurotransmitters at its contacts with other nerve cells known as synapses. Gamma-aminobutyric acid, by contrast, inhibits the production of action potentials. Acetylcholine, norepinephrine, dopamine, and serotonin may influence neural behavior more persistently and are also known as neuromodulators, playing crucial roles in psychiatric disorders. Opiates constitute the purest type of neuromodulator, because they do not act as neurotransmitters. Eventually, it is important to understand that some neurotransmitters can excite or inhibit nerve cells, depending on the type of receptor they bind to.

Compared to neurotransmitters and neuromodulators, however, hormones exert the longest lasting effects on the brain. When I was a student I participated in research on the Siberian hamster Phodopus sungorus of Siberia in the laboratory of Professor Gerhard Heldmaier (Rafael and others, 1985). These amazing creatures are only the size of a mouse. Yet, they cope with the frigid temperatures of Siberian winters. They grow a thick white coat for the winter and can rely on paws padded with dense fur even on the palms. But, the key to the hamsters' survival is the brown body fat, known as brown adipose tissue or BAT for short, that they build up before snow fall sets in. The hamsters are crepuscular, that is they are most active during the twilight hours of the day. As the light grows more orange and the days grow shorter, the hamsters forage more intensely for food, almost double their body weight, and their physiology changes. Come Winter, the hamsters can resist deep freezer temperatures as low as -70 °C for many hours without any harm, using their brown body fat to maintain body temperature. When the brown fat is depleted, they begin to shiver and die in short time. By contrast, animals unconditioned during the autumn would perish already at -30 °C.

The hormone melatonin is thought to play a crucial role in the hamsters' seasonal behavioral and physiological changes. Nerve cells in the brain's pineal gland secrete this hormone into the blood stream. The cells are light sensitive and increase hormone production, when the animals are more exposed to long wavelength-rich autumn light and extended nights. Heldmaier and others (1981) observed that hamsters that were artificially maintained at long daylight hours in the autumn, developed only mild cold resistance. However, their sensitivity to melatonin was enhanced. Chronic administration of melatonin increased cold resistance in these animals. By contrast, short daylight-adapted hamsters showed the anticipated increase in cold resistance and no sensitivity to melatonin treatment. Summer- and winter-adapted hamsters are shown in the video below.


Melatonin does not only govern the Siberian hamster's life. It plays a crucial role in the bouts of depression that people living above the polar circle confront during the long and dark winters. The control of nerve cell function through a substance that nerve cells produce in response to environmental changes constitutes a powerful demonstration of experience-dependent brain self-administration.

Normally, the nerve cells in our brain are well poised to maintain control over the diverse processes that keep our brain's biochemistry in balance. However, genetic predisposition, developmental mishaps, and traumatic experience may sway that balance toward extremes beyond control. We may be able to bounce back by just taking time out, re-balancing our brain and calming our mind. If our own coping mechanisms do not suffice, we need professional help.

Psychotherapies have proven effective for some. Yet, success seems subtle. Time is needed to produce measurable results. By contrast, drugs targeting specific neurotransmitters are known to restore functionality quickly and robustly. An overwhelming number of comments from affected people sent to The New York Times supports this contention. But, there is no reason to believe that substances purified from natural products should be a priori more beneficial than pharmaceuticals synthesized in laboratories, solely because the former originate in nature. Only thorough research and experience will tell which drugs produce positive results regardless of provenance.

Drug therapies entail one drawback. The substances are administered systemically. That is, they are injected or ingested and absorbed by the whole body, although their intended targets may only consist of small regions of the brain. Other organs may be susceptible to the drugs. notably, the walls of the intestines contain more nerve cells than the brain. The intestinal nerve cells possess receptors similar to those found on brain nerve cells and may respond to the drugs with adverse effects on digestive function.

Moreover, drugs accumulate in the liver. Foreign chemical compounds are made water-soluble by oxidative liver enzymes. The increased concentration of the drugs may induce detrimental hyperactivity of these enzymes. The load that the metabolites add to the kidneys, where they are excreted with the urine, may damage kidney tissue. The risks mount, when medication begins early in life. But as Dr. Friedman so validly pointed out in his article, we simply do not know at present what the precise consequences of the life-long exposure to psychotherapeutics will be.

Therapies that are targeted only to the brain regions involved in the disorder would reduce the risk of adverse effects. Psychotherapeutic drugs are designed to target specific receptors on nerve cells and modify the molecular pathways that are particularly involved in a specific disorder. However, their action could be directed to specific brain regions only, if they were infused directly into the tissue, requiring a craniotomy.

By contrast, biofeedback-based therapies may improve nerve cell function locally without invasive intervention. Cognitive therapies can be considered as providing biofeedback, if they concentrate on the behavioral manifestations of the disorder and address specific symptoms. Conscientious modification of behavior may re-adjust the biochemical balance of the involved brain regions and this re-adjustment may conversely improve the behavior. Other therapies involving biofeedback consist of learning to play a musical instrument or a sport. These methods challenge sensory and motor skills. They demand focus and render immediate sensory feedback. With practice, brain function and skill improve concomitantly.

Neurofeedback, e.g. BrainMaster, is a technologically more sophisticated extension of the behavioral interventions described above. Electrical brain waves are recorded from the scalp with button electrodes. The power of these brain waves is used to inform the participants whether they are making progress in the desired direction. The measurements can be displayed in dynamic graphs on computer screens or integrated into computer games. I have written about such electroencephalographic techniques and the experience I had with equipment manufactured by J&J Engineering in my post published on this site on May 24, 2008. The brain waves of interest are known as alpha waves. Their profound role in mental focus can be explored with Mind ball popular in science museums.

Neurofeedback is an emerging technology and several comments to Parker-Pope's article lament its shortcomings with frustration. The applications using this technology must be sufficiently flexible to accommodate the very specific needs of the participants. Costly, time-consuming experimentation may be needed to find effective parameters in each instance. Moreover, the recordings of the minuscule surface potentials from the scalp are sensitive and easily compromised. Thick hair diminishes conductance and attenuates the strength of the recordings. Firm contact between the electrodes and the scalp needs to be established with sufficient amounts of conductance paste that must not dry out during the session. The impedance of the electrodes needs to be held stable to produce accurate and reproducible measurements of brain wave power. Thus, participants need to be fully cooperative and must be careful not to pull on the recording wires. Failing at any step may render the whole session useless.

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Revised: 01/30/2012

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