Salerian Brain Laws #1 and #2 (SBL1 and SBL2):

Frontal Cortex Function and Dopamine Govern Mood and Executive Function

By Alen J. Salerian, MD

I am excited to share two of my discoveries of brain function and dysfunction, two novel theories I advance about the essence of all neuropsychiatric disorders.  Region specific dysfunction and abnormal neurotransmission regulated by thermoregulation laws govern all neuropsychiatric disorders.

The precise scientific details of my theories are going to be published in peer-reviewed journals by the end of 2009, yet my wish to help people with serious neuropsychiatric disorders prompted me to immediately reveal my findings.

Salerian Brain Law #1 suggests two factors govern all neuropsychiatric disorders:  region-specific brain dysfunction and abnormal neurotransmission mediated by thermodynamic laws.  In essence, Salerian Brain Law #1 proposes that the laws which govern neurological disorders also govern neuropsychiatric illnesses as diverse as schizophrenia, bipolar disorder, depression, post-traumatic stress disorder, addictions.  Thus, Salerian Brain Law suggests the majority of neuropsychiatric disorders are biological in origin, the presenting symptoms, the severity and the course of the disorder defined by a specific region of the brain influenced by the specific neurotransmitters responsible in regulating the neuropsychiatric function of that particular brain region.

The second Salerian Law of the Brain suggests that the prefrontal cortex dictates human mood and executive function, consistent with its evolutionary neurobiological supremacy over the rest of the brain.  Thus, only when the prefrontal cortex function is less than perfect or only when the prefrontal cortex function is dysfunctional that a Homo sapien brain exhibits any mood or executive dysfunction.

In essence, the prefrontal cortex is the king with full authority over a chemical cocktail of complex neurobiological homeostasis, and hence, no mood or executive dysfunction can develop in the presence of a robust and functional prefrontal cortex.

The above-mentioned interactions frequent occur in lower species, yet they are not as profound for the extraordinary superiority of the prefrontal cortex to perceive, process, mediate and master the sensory input from other parts of the brain as they are in Homo sapien brain function.  This is precisely why, for any clinical entity with diminished executive function, compromised initiative and lowered energy, motivation, mood and self-confidence to develop, there must always be some disturbance or dysfunction of prefrontal cortex function.

As to the notion of complexity of brain function, mental state and the countless factors that may influence neurobiology, hence the prefrontal cortex, one can merely state that the final outcome remains the same; to use a common if not so scientific language that the bottom line does not change the evolutionary superiority of the prefrontal cortex over the rest of the brain.

The use of the Salerian Laws or any section of this paper without the written consent of Alen J. Salerian, MD and Washington Center for Psychiatry is prohibited.

GABA (GABA-GAMMA-AMNIOBUTYRIC ACID)
GABA is an elegant force of your calm and inner peace.  For example, a brain with sickly GABA has recurrent seizures and is almost always irritable, edgy, and combative.  In less traumatic cases, sickly GABA may make you fearful, easily reactive, and may cause insomnia.

DOPAMINE
Dopamine gives you energy, concentration, alertness, initiative, and perhaps most importantly the ability to enjoy life.  When your dopamine is out of sorts, so is your joy.

NOREPINEPHRINE
Norepinephrine is a good friend of dopamine and offers you energy, alertness, and concentration.

ACETYLCHOLINE
Acetylcholine is the champion defender of your memory.  For example, a brain with Alzheimer’s disease has lost its acetylcholine.  However, there are lesser degrees.  Perhaps acetylcholine is just getting tired with age.  Maybe you lose your keys more often, can’t always remember what you just said, forget phone numbers you always knew by heart or annoy your daughter by calling her husband George when his name is Bill.

SEROTONIN
So what do you say to a woman who is irritable, easily frustrated, and highly moody for a week before her menstrual cycle?  Your serotonin is low!  Serotonin is a brain fuel which helps you cope with anger, irritability and fear.  If you are phobic about flying or public speaking, feel plagued with unnecessary worry, get mad at red lights, fight road rage, or become overly agitated at every little thing your partner does, any pill that normalizes your serotonin will help relieve your symptoms.

The influence of these brain fuels does not negate the impact of life events or behavior.  These angels, however, often play a defining role in all areas of your behavior.  In a genetically predetermined manner, your angels often function in concert with one another and silently relay messages back and forth in response to input from the outside world.  In other words, like our height, skin, or eye color, the general traits of your particular angels are programmed at birth. In essence, the brain fuels are the genetic color of your brain and have a profound impact on you and your environment.

No one would challenge the fact that an individual’s sensitivity to sunlight depends upon skin color.  People with fair skin are more susceptible to sunburn and skin cancer than people of darker complexion.  In a similar manner, the brain’s chemistry determines sensitivity to rejection, mood, fear, irritability, and concentration.  It is critical to understand the specific functions of each chemical fuel.

Rats Have Angels (Every Living Creature Does!)
Your brain fuels are highly sensitive to external and internal events:  they expand or shrink, grow stronger or weaker, depending on your overall health, diet, exercise, sunlight exposure, and conflicts or tension in your life.

What are your brain fuel’s greatest friends and worst foes?  Exercise, sunlight, and good health are the angels’ best friends.  Their enemies include chronic unresolved anger, frustration, and any circumstances that trigger real or imagined feelings of being entrapped.  No other human dynamic is as universally toxic and potentially deadly to the human spirit and your angels as the perception of entrapment.  This dynamic, with its multiple faces – such as people in miserable marriages or financial desperation, or hostile job environments, people living in poverty, or children of abusive homes – directly and mercilessly assault your angels.

The collapse of hope is a serious injury to your angels and depletes their power and functionality.

Let me share a study about rats.  Rats are great teachers if we learn from them.

Put some rats in a cage and separate them from their food source.  Create a path to the food source but make sure there is an obstacle such as a glass gate which keeps them from their food. Watch the rats: observe how many times and for how long they will try to get to the food before giving up.

The rats have two challenges:  physical stamina and mental determination (potentially including willpower, drive, confidence, and mood).  Age is a factor as well:  if you give them a temporary break and let them dine even once, they will renew their efforts.

The main lesson: the majority of rats stop trying after a predictable number of times, well before they are physically incapable.

Simple enough. So, where are their angels?

Evidence suggests that after repeated failures, the angels shut down.  They collapse. Their magical powers suddenly disappear.  The angels stop flying, communicating or showing any signs of life.

The Similarities Between Rats and Humans

Entrapment equals hopelessness.  Hopelessness equals death.

People who haven’t experienced clinical depression may not easily appreciate the fact that severely depressed people, unable to see their way out of psychological torture, will seriously consider suicide.  It’s not hard to find thousands of examples of suicide where the act was an expression of entrapment and hopelessness rather than depresion.

Rats, humans, and your angels are all controlled by life, emotions, chemicals, and our perceptions.  When you feel trapped, your angels are injured; when they are sick you end up feeling trapped even if you aren’t.  Your brain is you; your angels are you; and your life affects your angels.

Pills, Angels, and Rats
What if you gave a rat a pill to replenish his brain fuels?  He would try harder and longer and not give up as his unmedicated counterparts do.  It’s as if the medicated rats have thicker skin against frustration, disappointment, and early resignation because the now healthier angels can provide them with extra protection.

We know that what occurs in the human brain is similar to actions and reactions in rat brains. It should not surprise you that the majority of newly introduced medications for sleep, mood, anxiety, and energy disorders were first studied and discovered in pre-clinical rat studies.

By Alen J. Salerian, MD, Nansen G. Saleri, PhD, Justin Salerian

Summary
Lowering core body and brain temperature has been shown to be beneficial for multiple sclerosis, cardiovascular accidents, traumatic brain injuries and myocardial infarction. Svante Arrhenius’ rate law – governs human thermoregulation and all biochemical reactions including complex chemical processes involved in mood disorders.

We reviewed the studies on core body and brain temperature’s influence on mood, mood disorders and their treatment. Our review suggests the majority of therapeutic strategies against mania are hypothermic while thermogenic strategies are used to combat depressive disorders.

We hypothesize that therapeutic manipulation of brain temperature may represent a key mechanism in the treatment of mood disorders possibly because of brain temperature’s profound influence on human biology governed by Svante Arrhenius’ rate law. We postulate that brain temperature may rise with mania and fall with depression

Introduction
The influence of temperature in the physiopathology of various neurodegenerative and psychiatric disorders has been of increasing scientific interest in the last decade. Two areas in which brain and body temperature may have a crucial impact are neurodegenerative and mood disorders. Salerian and Saleri have proposed a temperature-dependent biochemical system in humans governed by the Arrhenius rate law. We postulated that due to the exponential relationship between temperature and biochemical reactions, a relatively minor alteration in core body or brain temperature may be of significant therapeutic benefit in combating neurodegenerative disorders and prolonging lifespan (1). We further speculated that this small alteration may be as little as a drop of 1°C in core body temperature.

Many failures in temperature control have been observed in psychiatric disorders. It has been reported that patients with schizophrenia exhibit dysregulation of body temperature, including different baseline temperatures, abnormal daily range of temperatures and diurnal variation showing an early peak, an impaired ability to compensate to heat stress and compensating more effectively to cold stress (2).

”Wehr, et al (1989) suggested that chronic treatment with antidepressants decreased hypothalamic temperature in Syrian hamsters resulting in a cold defense reaction (thermogenesis) that may contribute to the behavior-activating properties of antidepressant drugs (3). Evidence suggests the antidepressant effect of sleep deprivation can be influenced by psychotropic medications (antidepressants or neuroleptics) and by ambient temperatures (3). Wehr hypothesized that the antidepressant effect of these diverse factors may be because of their common thermoregulatory influence.
In this review, we examine the brain temperature’s influence on mood, mood disorders and their treatments. The premise of our review is stated in the form of a hypothesis, hereafter referred to as the Salerian Mood Hypothesis (SMH), is that: The therapeutic manipulation of brain temperature may represent a key modality in the treatment of mood disorders as brain temperature may rise with mania and fall with depression.

Lithium is Hypothermic
1. Studies with rats suggest that lithium increases heat shock proteins that are hypothermic (4).
2. Studies with rats suggest that lithium increases brain cholinergic activity that is
hypothermic (5).
3. Lithium toxicity in mice is associated with severe hypothermia prior to death (6).

Neuroleptics are Hypothermic
Experimental studies with cats, mice and rats have shown that various neuroleptics are hypothermic and that clozapine, olanzapine and Risperdal produce a dose-dependent drop of colonic temperature in adult male Wistar rats (7). Similarly, it has been demonstrated that chlorpromazine induces a drop in colonic temperature in monkeys (8).

Neuroleptics, with a few exceptions, seem to be hypothermic in humans (9). Haloperidol, olanzapine and risperdal reduce axillary temperature of psychotic patients (9). It has been show that neuroleptic-induced hypothermia is associated with amelioration of psychosis in schizophrenic patients (9). Clozapine decreases core body temperature, improves BPRS and displays a linear but weak relationship between the degree of hypothermia and improvement of psychosis (9).

Antidepressants are Hyperthermic
Sibutramine, duloxetine and bupropion increase colonic temperature in female Wistar rats (10). In support of the thermogenic effects of antidepressants, it has been demonstrated that 12 antidepressant drugs including butriptyline, protriptyline and nortriptyline were highly thermogenic in rats (11). It has also been shown that bupropion, a dopamine/norepinephrine reuptake inhibitor, increases brain and colonic temperature in rats (12). Similarly, studies indicate that many antidepressants currently in clinical use have marked thermogenic properties and could therefore cause reduction in body weight without altering the food intake in mice (11). Soubri, et al, 1989, demonstrated that food restriction decreases responsiveness to antidepressant drugs in rats (13). This study may explain the findings of Duncan, Johnson and Wehr (1995) that fluoxetine and clorgyline reduced hypothalamic and body temperature in hamsters (14). The fluoxetine-induced hypothermia may be caused by the caloric restriction and not its direct neurochemical effect.

The studies on the effects of antidepressants on humans have been contradictory; yet there is one study that suggests chronic administration of antidepressants elevates tympanic membrane temperature (15).

Single Electroconvulsive Shock is Hypothermic Whereas Chronic Electroconvulsive Shock is Hyperthermic
Investigations of the effect of electroconvulsive shock (ECS) on body temperature have been contradictory. A single ECS has been demonstrated to reduce colonic temperature in mice. However, repeated ECS attenuates the hypothermia produced by single ECS (16).

Nicotine-Induced Hypothermia, Antidepressants and Bright Artificial Light
Is there any evidence to suggest that a nicotinic mechanism is involved in the regulation
of core body temperature and mood? Although not all the interactions between nicotine, body temperature and various antidepressants are fully understood, nicotine has been demonstrated to induce hypothermia following intracerebral nicotine administration in cats, monkeys and rats (17). Further, chronic administration of nicotine induces tolerance supporting a receptor mediated process (17). Other studies suggest that nicotine-induced alterations in body temperature are influenced by genetic factors. Differential sensitivity towards dependent nicotine-induced hypothermia is identified as the key factor for different strains of inbred mice (18). A recent study in mice deficient in beta-2 and in AChR subunit reduced hypothermic response to low doses of nicotine suggesting that this subunit partially mediates nicotine-induced hypothermia (18).

Fluoxetine, phenelzine sulfate, desipramine and bright artificial light have been shown to produce reduced sensitivity to the hypothermic effects of nicotine (17). Mendelsohn, et al, in 2005, speculated that the capacity of three chemically distant classes of antidepressants and bright artificial light (a treatment for seasonal depression) to produce this result suggests that nicotine’s thermoregulatory influence may be involved in the mechanism of action in these treatments.

Clinical Manifestations Associated With Hypothermia and Hyperthermia
Transient and reversible psychosis with auditory and visual hallucinations that appear when core body temperature rises above 39°C and disappear after core body temperature normalizes and has been documented (19).

Patients with moderate (34-30°C) hypothermia experience brady cardia and hypotension (following early and brief tachycardia and hypertension) as well as progressive depression of mental functions starting with apathy, psychomotor retardation, and silence (20).

Synopsis
Body and brain temperature’s influence on mood can be summarized as follows:
1. Most neuroleptics, lithium and single ECT are hypothermic and they improve mania.
2. Chronic ECT and chronic administration of antidepressants are thermogenic and they improve depression.

Successful treatment strategies with biologically opposing influence and opposing thermal properties suggest that temperature change may represent a critical mechanism in the pathophysiology of mood disorders and may promise an avenue for therapeutic exploitation. Therefore, it is logical to induce hypothermia for mania and thermogenesis for depression.

Further studies are necessary to confirm SMH. Of importance will be studies to measure core body and brain temperature during and after treatment for various mood disorders. If clinical studies validate SMH, there could be novel approaches in the treatment of mood disorders specifically designed with temperature-altering prowess.

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