- Email: [email protected]
Thermodynamic laws apply to brain function
Medical Hypotheses 74 (2010) 270–274
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Thermodynamic laws apply to brain function Alen J. Salerian * Washington Center for Psychiatry, 5225 Wisconsin Avenue, NW Suite 104, Washington, DC 20015, United States
a r t i c l e
i n f o
Article history: Received 28 August 2009 Accepted 7 September 2009
s u m m a r y Thermodynamic laws and complex system dynamics govern brain function. Thus, any change in brain homeostasis by an alteration in brain temperature, neurotransmission or content may cause region-specific brain dysfunction. This is the premise for the Salerian Theory of Brain built upon a new paradigm for neuropsychiatric disorders: the governing influence of neuroanatomy, neurophysiology, thermodynamic laws. The principles of region-specific brain function thermodynamics are reviewed. The clinical and supporting evidence including the paradoxical effects of various agents that alter brain homeostasis is demonstrated. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction
Region-specific brain function
Thermodynamic laws apply to brain function, thus any change in brain homeostasis by an alteration in brain temperature, neurotransmission or content produces region-specific brain dysfunction. This is the Salerian Theory of Brain (STB), proposed by this review. STB proposes a new paradigm for neuropsychiatric disorders: the governing influence of neuroanatomy, neurophysiology and thermodynamic laws [1,2]. The principles of region-specific brain function, and thermodynamics are already well established [1,2]. What may be a worthy challenge, however, is the need for a careful review of natural laws and their influence in various brain disorders. Thomas Kuhn’s ‘‘The Structure of Scientific Revolutions” is a thoughtful analysis demonstrating that some scientific conclusions may be erroneous and delay important discoveries [3]. Kuhn wisely pointed out that the Ptolemaic assumptions about the celestial movements delayed important discoveries by Copernicus and Galileo for 1500 years. Also, complex events with infinite plasticity may be inaccessible to diagnostic methods that primarily rely on the linearity of evidence.
Wilder Penfield demonstrated that specific brain regions govern motor and sensory function [1]. Paul Broca and Karl Wernicke identified brain regions associated with language and auditory function [1]. Korbinian Brodman described the histological characteristics of cortex that include 52 distinct regions. Evidence suggests amygdala and hippocampus play central roles in memory and learning [1]. The thalamus has been identified as a central switchboard, a filter that blocks out information to perform a specific task [1]. The prefrontal cortex mediates a variety of executive functions such as abstract thought, planning, strategy, creativity, problem-solving [1]. The limbic system monitors emotions and basic survival desires such as thirst, hunger, sex drive and energy [1]. Amygdala plays a key role in our response to threatening stimuli [1]. Collectively, the above-summarized studies suggest, specific brain regions govern specific brain functions.
Outline In this paper, I first review the basic neurobiology of brain function, then offer the supporting data for STB, and finally discuss its implications.
* Tel.: +1 202 244 9000; fax: +1 202 244 6610. E-mail address: [email protected]. 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.09.016
Neurotransmitters and brain function Projections from locus coeruleus activate the entire cortex, the hypothalamus, the cerebral and the brainstem with norepinephrine [1]. Projections from the ventral tegmental area extend to caudate and putamen represents the nigrostriatal pathway with dopamine as the primary neurotransmitter. Mesocortical and mesolimbic tracts project to the prefrontal cortex and the limbic system and projections from the hypothalamus extend to the pituitary with dopamine as the primary neurotransmitter [1]. Serotonergic neurons arise in the raphe nuclei and project to the entire neocortex, the basal ganglia, temporal limbic region, the hypothalamus, the cerebellum and the brainstem [1].
A.J. Salerian / Medical Hypotheses 74 (2010) 270–274
Glutamate is an excitatory amino acid neurotransmitter which is produced by large cells throughout the cerebral cortex and hippocampus [1]. GABA is an inhibitory neurotransmitter with local and longrange systems, in the cerebral cortex and limbic brain [1]. Opioids and endorphins are central nervous inhibitors, and their inhibitory influence plays a major role in brain and pleasure regulation. In general, it is true that neurotransmitters have activating or inhibitory properties. For instance, dopamine, norepinephrine, glutamate and histamine are activators, and serotonin, GABA and endorphins have inhibitory influences [1]. It is also true that multiple chemicals including neurotransmitters and other neuromodulators and chemicals such as brain-derived neurotrophic factor, G-protein, cAMP and others coexist in neurons and synaptic systems and are of great importance for neurotransmission [1]. It is also true that anatomical and functional interactions exist between the noradrenergic neurons originating in the locus coeruleus and the serotonergic nucleus in the raphe nuclei, with each system influencing the other and multiple chemicals coexist and constitute a chemical cocktail with anatomical and functional interactions [1]. Thermodynamic laws Thermodynamic laws are universal and, hence, apply to brain function. For instance, bioengineered, hypothermic, overweight mice outlive normothermic mice on caloric restriction [4] and Salerian–Saleri Temperature Thesis (SSTT) and other evidence suggest core body temperature is a governing force in brain neurodegeneration and longevity [2,5]. Van’t Hoff law suggests an increase in temperature shifts equilibrium in the direction that absorbs heat, and a decrease in temperature shifts equilibrium in the direction that evolves heat [6]. The second law of thermodynamics suggests that all chemical processes have a direction [2]. Neurobiology suggests brain function is region specific [1]. Neurobiology also suggests synaptic transmission is crucial for brain function [1]. Hence, we must conclude: The precise direction of a synaptic system with its unique chemical cocktail is a governing influence for brain function. Any change in brain homeostasis shall activate a cascade of changes with a dynamic homeostasis with a new direction consistent with the second law of thermodynamics and with precise, regionally defined neurobiological consequences. In essence, a single neurotransmitter shall produce a wave of reactions with a new homeostasis and new dynamic state with a new direction and with its unique region-specific brain function. Turbulence, the disordered motion of fluids and its fundamental dynamics will explain certain paradoxical outcomes triggered by a reactant. Thus, a single neurotransmitter will not cause psychosis or depression, although a single transmitter may induce changes in brain homeostasis with catastrophic or minor consequences.
The supporting evidence for STB The supporting evidences for STB are summarized under four headings: (I) Hallucinogenics and psychosis including substances and their paradoxical effects. (II) Changes in brain homeostasis cause terminal effects and withdrawal reactions. (III) Psychosis and negative symptoms. (IV) Antipsychotics for depression.
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Paradoxical effects of hallucinogenic Agents opiates and support STB The hallucinogenic or psychosis-inducing properties of many substances such as lysergic acid diethylamide (LSD), phencyclidine (PCP), ketamine, mescaline, 1-2,5-dimethoxy-40iodophenyl-2aminopropane (DOI), psilocybin and muscimol are well established [7]. Is there a common mechanism or final pathway for their hallucinogenic or psychosis-inducing influence? And if there is, what brain regions and dysfunctions are involved? And what are the crucial alterations in regional brain homeostasis that correspond with brain dysfunction? Aghajanian and Marek demonstrated that increased serotonergic activity by LSD, PCP and mescaline heightens the sensory response of locus coeruleus, a robust noradrenergic center in the limbic system, and activates dopaminergic and glutamatergic transmission in the cortex [7]. The results are heightened and distorted perceptual, cognitive and emotional responses consistent with a psychosis. In essence, Aghajanian’s work suggests that LSD-induced psychosis is produced by a dominant dopaminergic–glutamatergic homeostasis [7]. This may explain similar dynamics in the genesis of hallucinations and psychotic symptoms observed with two N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine and mescaline, that produce a glutamatergic– dopaminergic influence in the prefrontal cortex [7]. The direct post-synaptic effects of serotonin in the cortex are variable: Depolarization, hyperpolarization, or no change, depending upon whether the effects of excitatory 5-HT2 receptors or inhibitory 5-HT1a receptors are predominant in any given layer V pyramidal cell [7]. However, the most striking effect of 5-HT in cortical regions is to increase excitatory post-synaptic potentials [7]. In essence, Aghajanian and Marek propose that a serotoninmediated enhancement of various hallucinogenics induces increased glutamatergic transmission in the cerebral cortex, which is responsible for the high-level cognitive, perceptual and affective distortions caused by prefrontal cortex dysfunction. Of significance is the observation that muscimol, a GABA agonist, and LSD and psilocybin with serotonin-like structures and known serotonin antagonism at the dorsal raphe nuclei cause hallucinations and psychosis consistent with the observation that heightened dopaminergic–glutamatergic influence in the prefrontal cortex may be responsible for the final outcome. Ubiquitous effects of hallucinogenics on such complex brain functions as cognition, perception and mood suggest the involvement of the cerebral cortex [7]. Based upon the collective evidence, all substances with psychosis-inducing or hallucinatory properties cause prefrontal cortex dysfunction with glutamatergic and dopaminergic activation. Thus, because of the thermodynamic and region-specific brain function principles psychosis and hallucinations represent a prefrontal cortex dysfunction directed by a predominant dopamine–glutamate influence. Opiates and their receptors, in general, are central nervous system inhibitors which play a major role in attainment of pleasure an pain control rewarding addictive behavior [8]. The influence of opiates are consistent with STB and support opiate-induced alterations in brain homeostasis with region-specific effects. Opioid receptor subtypes include l, d and j [8]. The l receptors have a high affinity for opiates. Endorphins are endogenous morphines, large peptides in the brain that mimic opiate activity [8]. Through opening of potassium and calcium channels, opiates in general have an inhibitory influence in the central nervous system [8]. Opioid autoreceptors produce inhibitory effects. Somatodendritic autoreceptors hyperpolarize cells in the locus coeruleus by
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enhancing potassium conductants and subsequently reducing cell firing and are ultimately responsible for the analgesic effects [8]. Opioids modulate pain directly in the spinal cord and also by regulating the descending pain inhibitory pathway ending in the spinal cord. Using Position Emission Tomography (PET) studies, Zubieta and colleagues demonstrated that endogenous l opioids modulate both the sensory and emotional components of pain [9–11]. Opioid microinjections into the VTA increase dopaminergic cell firing, with elevated production of dopamine in the nucleus accumbens. Intraventricular b-endorphin produces similar results [9–11]. Ventral tegmental area with mesolimbic dopamine neuron cell bodies that project the nucleus accumbens is known to be crucial for the reinforcing effects of addictive substances, natural rewards of food and water and the reinforcing and rewarding aspects of listening to music [12]. Furthermore, the hedonic aspects of reward is thought to be modulated by endogenous opioid peptide transmission within the nucleus accumbens and is consistent with the observation that musical pleasure can be blocked by naloxone, a non-opioid antagonist [12]. Collectively, the above-summarized Opioid induced paradoxical effects are with the region specific influence of a dynamic brain homeostasis with a new dominant direction – activating or inhibiting – consistent with STB. Changes in brain homeostasis cause terminal effects and withdrawal responses Soon after the discontinuation of morphine-like substances, a constellation of symptoms defined as morphine abstinence syndrome develops. Most of the symptoms slowly emerge in the first 24 h, gradually resolving within 7–10 days from the onset of withdrawal [8,9,11]. The symptoms include increased anxiety, restlessness, irritability, dilated pupils, goose flesh, hot flashes, vomiting, diarrhea, fever, elevated blood pressure, increased heart rate and abdominal and generalized muscle cramps [8,9,11]. Morphine abstinence syndrome seems to represent: 1. Increased noradrenergic parasympathetic and glutamatergic activity and the emergence of withdrawal symptoms coincide with plasma concentration half life and fatal clearance of a morphine-like substance [8,9,11]. Of clinical significance is that the onset of withdrawal does not always coincide with the onset of terminal effects of a substance. For instance, for morphine-like substances, a patient may remain pain free yet at the same time experience withdrawal symptoms. For the analgesic effect is determined by its CNS effect and the withdrawal triggered by the downward shift of the morphine-like substance’s plasma concentration. The data from morphine-like substances and selective serotonin reuptake inhibitors (SSRI) [12], consistent with thermodynamic principles, may suggest that indeed any entry or exit of a substance represents a change in brain homeostasis, hence is associated with physiological fluctuations consistent with withdrawal response. Hence any chemical substance – may produce neurobiological changes upon its entry or exit [8,11,13].
Depletion of dopamine in a circumscribed area of association cortex in rhesus monkeys produces an impairment in spatial-delayed alternation performance nearly as severe as that caused by surgical ablation of the same area [14]. This behavioral deficit can be pharmacologically reversed with dopamine agonists such as Ldopa and apomorphine [14]. These data provide direct evidence that dopamine plays an important role in a specific cortical function. In primates, including humans, the dorsolateral convexity of the frontal lobe plays a selective role in mediating mnemonic, attentional and spatial capacities [15]. In subhuman primates, this region of the cerebral neocortex has high catecholamine levels and syntheses rates, particularly for dopamine, whereas serotonin content and activity in the same cortical tissue is relatively low. The finding that dopamine depletion can be restricted to a circumscribed area of the prefrontal cortex and produce a behavioral deficit in a selective function of that area suggests that dopamine in the prefrontal cortex may function as a neurotransmitter independent of its precursor role. The loss in delayed alternation performance appears to be attributable specifically to substantial depletion of dopamine. Several studies of major depressive disorders and schizophrenia with negative symptoms reveal altered brain responses during functional magnetic resonance imaging in the prefrontal cortex and the pregenual anterior cingulate cortex, a region specifically relevant for expression of anhedonia [15,16]. Of significance is diminished blood oxygenation, hypometabolism at rest and reduced functional responses to stimulation. Because of SSTT, certain brain regions overstressed and exposed to higher metabolic rate and oxidation stress may age faster with faster degeneration and atrophy. Any energy production, i.e., activation, triggers heat production with heat traveling from hot to cold with increases in temperature in surrounding brain regions. Hence, a hot limbic system would activate other parts of brain regions by excitation and activation of glutamatergic and dopaminergic activity consistent with neurological pathways and with biologically predictable routes from the limbic system to the prefrontal cortex. Thus, these biological highways will have more wear and tear and age faster consistent with SSTT and therefore may produce more degeneration in the prefrontal cortex in a biologically predictable way because the prefrontal cortex is the final host of all the input from the rest of the central nervous system. Because the prefrontal cortex is so specifically wired to provide highly sophisticated intellectual and emotional functions even minute shifts in the brain’s prefrontal cortex homeostasis may cause executive dysfunction, anhedonia, apathy, and/or diminished initiative. Goldman et al. showed that reductions of cortical thickness in schizophrenia is heritable, yet cortical thickness, per se, is not a strong intermediate phenotype for schizophrenia [17]. Thickness is reduced most pronouncedly on the lateral surface suggesting a role of schizophrenia risk genes in temporal lobe cortical architecture specifically in amygdala or hippocampus [17]. Although, this observation is in need of further validation, it may have significant implications: The suggestion that not prefrontal but temporal deficits of schizophrenia are genetically inheritable, and hence negative symptoms associated with prefrontal cortex deficits may be attributable to the disease process rather than genetics. The findings summarized above are consistent with STB and the importance of biological connectivity of the brain and thermodynamic laws in the disease process.
Psychosis and negative symptoms support STB Antipsychotics for depression Is it possible that negative symptoms may not represent the core pathophysiology of schizophrenia in a model akin to the degenerative processes that shadow other major medical disorders? The emergence of diabetic retinopathy is such an example.
Two antimanic agents, aripiprazole and quetiapine – both antidopaminergic agents – demonstrate robust efficacy for some people with depression [18,19].
A.J. Salerian / Medical Hypotheses 74 (2010) 270–274
Dopamine is believed to be the workhorse for energy, joy, motivation, initiative and concentration. Precisely because of dopamine’s crucial activating role in the prefrontal cortex, the observation that aripiprazole and Seroquel enjoy antidepressant properties gain significance to support the STB. It seems that their antidepressant efficacy may be due to their dampening influence on the sensory overload of a hyperaroused dopaminergic and glutamatergic limbic system. By quieting down the limbic fire, aripiprazole and quetiapine may offer neuroprotection for the prefrontal cortex and hence assist the prefrontal cortex regain normal function with higher dopamine levels.
Discussion Treatments for neuropsychiatric disorders traditionally target single neurotransmitters and focus on symptom relief based upon the Diagnostic and Statistical Manual For Psychiatric Disorders criteria. There is compelling evidence, however, that the current approach does not often yield satisfactory results in the greater picture of human suffering from neuropsychiatric disorders. This review suggests that thermodynamic laws have profound influence to alter human neurobiology. Or, it can be stated that human neurobiology is governed by thermodynamic laws and hence, the laws of Arrhenius, van’t Hoff, the second thermodynamic law, and the SSTT apply to human brain function. As a consequence of the governing influence of natural laws and the known principles of region-specific brain function, the following statements are correct: 1. Any change in brain homeostasis by an alteration in brain temperature, neurotransmission or content produces region-specific brain dysfunction. 2. Any chemical substance shall cause neurobiological changes upon its entry to the CNS or exit from it. Thus, not only sedatives, hypnotics or narcotics, but all substances have psychotropic influence associated with their entry into and departure from the CNS. 3. Negative symptoms of schizophrenia are consistent with longterm effects of the disease process with ‘‘wear and tear” thermodynamic effects of abnormal neurotransmission on brain neural pathways. 4. A single neurotransmitter can never cause a brain disease, yet may trigger a cascade of chemical reactions that will produce region-specific brain dysfunction. The implications of the crucial impact of thermodynamic laws to alter human neurobiology are, of course, profound, for it logically leads to the necessity of relinquishing the current and universally popular paradigm of the Diagnostic and Statistical Manual of Psychiatric Disorder. Understandably, even the mere consideration of abolishing the DSM paradigm has its own, combustible and inevitably negative consequences. The magnitude of a potential negative response may delay further investigation although scientific advance may necessitate such a change.
Conclusion Collectively, the above data suggests that brain function is region-specific and governed by complex system dynamics and thermodynamic laws, and hence any changes in brain homeostasis – temperature, neurotransmission or content – causes brain dysfunction.
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This article proposes a new paradigm, STB, to study brain function. The new paradigm suggests natural laws apply to brain function. Today DSM-IV navigates neuropsychiatric research [20]. Behavioral and biological research must meet DSM-IV criteria. Yet DSMIV is not built upon neuroscientific evidence consistent with objective measures to evaluate neuroanatomical or neurophysiological abnormalities associated with brain dysfunction. This skewed system is not harmless for it promotes unscientific guidelines to offer solutions for people with brain disorders. STB has several major implications. It introduces the urgent need to replace the DSM-IV system with a scientifically sound system consistent with natural laws and neurobiology; suggests that thermodynamics and complexity apply to brain research; shows that single neurotransmitter theories of brain disorders are inaccurate; proposes that not only narcotics and sedatives but all agents that cross the blood–brain barrier may produce adverse changes in brain homeostasis at the time of their arrival and departure. Like all theories, this particular theory has a variety of limitations. First, it needs to be validated by clinical studies. Another limitation of the theory is the application of principles to issues, concepts, and emotions that fall beyond the ordinary domain of natural laws. The discussion of DSM-IV system is unavoidable in the spirit of helping people with brain disorders.
Conflicts of interest statement None declared.
References [1] Andreasen N. Brave new world. New York: Oxford University Press; 2001. [2] Potter MC. Thermodynamics. McGraw-Hill; 2009. [3] Kuhn T. The structure of scientific revolutions. University of Chicago Press; 1962. [4] Salerian AJ, Saleri NG. Cooler biologically compatible core body temperature may prolong longevity and combat neurodegenerative disorders. Med Hypothesis 2006;66:636–42. [5] Salerian AJ, Saleri NG. Cooling core body temperature may slow down neurodegeneration. CNS Spectr 2008;13:13. [6] Lachish U. Osmosis and thermodynamics. Am J Phys 2007;75(7). [7] Aghajanian GK, Marek GJ. Serotonin and hallucinogenic effects. Neuropsychopharmacology 1999;21:2S. [8] Meyer JS, Quenzer LF. Psychopharmacology. Sunderland, MA: Sinauer Association Inc.; 2005. [9] DiChiara G, North RA. Neurobiology of opiate abuse trends. Pharmacol Sci 1992;13:185–93. [10] Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourne MR, Jewitt DM, et al. Regional l Opioid receptor regulation of sensory and affective dimensions of pain. Science 2001;293:311–5. [11] Basile AS, Fedorova I, Zapata A, Liu X, Shippenberg T. Deletion of the M5 muscarinic acetylcholine receptor accentuates morphine reinforcement and withdrawal effects. In: Proceedings of the national academy of science, USA; 1999. p. 11457. [12] Menon V, Levitin DJ. The rewards of music listening: response and physiological connectivity of the mesolimbic system. Neuroimage 2005;28:175–84. [13] Zajecka J, Tracy KA, Mitchell S. Discontinuation symptoms after treatment with serotonin reuptake inhibitor: a literature review. J Clin Psychiat 1997;58:291–7. [14] Brozoski TJ, Brown RM, Rosvold HE, Goldman PS. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of Rhesus Monkey. Science 1976;205:929–32. [15] Walter M, Henning A, Grimm S, Schulte R, et al. The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Arch Gen Psychiat; 2009; 66 (Hofstadter, 1979). [16] Weinberger DR. Neurodevelopmental perspectives on Schizophrenia. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press; 1995. p. 1171–83.
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[17] Goldman AL, Pezawas L, Mattay VS. Widespread reductions of cortical thickness in schizophrenia and spectrum disorders and evidence of heritability. Arch Gen Psychiat; 2009; 66 (Hofstadter, 1979). [18] Berman MR, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiat 2007;68:6.
[19] Weisler R, Joyce JM, McGill L, et al. Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study. CNS Spectr 2009;14:6. [20] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Press; 1994.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Thermodynamic laws apply to brain function Alen J. Salerian * Washington Center for Psychiatry, 5225 Wisconsin Avenue, NW Suite 104, Washington, DC 20015, United States
a r t i c l e
i n f o
Article history: Received 28 August 2009 Accepted 7 September 2009
s u m m a r y Thermodynamic laws and complex system dynamics govern brain function. Thus, any change in brain homeostasis by an alteration in brain temperature, neurotransmission or content may cause region-specific brain dysfunction. This is the premise for the Salerian Theory of Brain built upon a new paradigm for neuropsychiatric disorders: the governing influence of neuroanatomy, neurophysiology, thermodynamic laws. The principles of region-specific brain function thermodynamics are reviewed. The clinical and supporting evidence including the paradoxical effects of various agents that alter brain homeostasis is demonstrated. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction
Region-specific brain function
Thermodynamic laws apply to brain function, thus any change in brain homeostasis by an alteration in brain temperature, neurotransmission or content produces region-specific brain dysfunction. This is the Salerian Theory of Brain (STB), proposed by this review. STB proposes a new paradigm for neuropsychiatric disorders: the governing influence of neuroanatomy, neurophysiology and thermodynamic laws [1,2]. The principles of region-specific brain function, and thermodynamics are already well established [1,2]. What may be a worthy challenge, however, is the need for a careful review of natural laws and their influence in various brain disorders. Thomas Kuhn’s ‘‘The Structure of Scientific Revolutions” is a thoughtful analysis demonstrating that some scientific conclusions may be erroneous and delay important discoveries [3]. Kuhn wisely pointed out that the Ptolemaic assumptions about the celestial movements delayed important discoveries by Copernicus and Galileo for 1500 years. Also, complex events with infinite plasticity may be inaccessible to diagnostic methods that primarily rely on the linearity of evidence.
Wilder Penfield demonstrated that specific brain regions govern motor and sensory function [1]. Paul Broca and Karl Wernicke identified brain regions associated with language and auditory function [1]. Korbinian Brodman described the histological characteristics of cortex that include 52 distinct regions. Evidence suggests amygdala and hippocampus play central roles in memory and learning [1]. The thalamus has been identified as a central switchboard, a filter that blocks out information to perform a specific task [1]. The prefrontal cortex mediates a variety of executive functions such as abstract thought, planning, strategy, creativity, problem-solving [1]. The limbic system monitors emotions and basic survival desires such as thirst, hunger, sex drive and energy [1]. Amygdala plays a key role in our response to threatening stimuli [1]. Collectively, the above-summarized studies suggest, specific brain regions govern specific brain functions.
Outline In this paper, I first review the basic neurobiology of brain function, then offer the supporting data for STB, and finally discuss its implications.
* Tel.: +1 202 244 9000; fax: +1 202 244 6610. E-mail address: [email protected]. 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.09.016
Neurotransmitters and brain function Projections from locus coeruleus activate the entire cortex, the hypothalamus, the cerebral and the brainstem with norepinephrine [1]. Projections from the ventral tegmental area extend to caudate and putamen represents the nigrostriatal pathway with dopamine as the primary neurotransmitter. Mesocortical and mesolimbic tracts project to the prefrontal cortex and the limbic system and projections from the hypothalamus extend to the pituitary with dopamine as the primary neurotransmitter [1]. Serotonergic neurons arise in the raphe nuclei and project to the entire neocortex, the basal ganglia, temporal limbic region, the hypothalamus, the cerebellum and the brainstem [1].
A.J. Salerian / Medical Hypotheses 74 (2010) 270–274
Glutamate is an excitatory amino acid neurotransmitter which is produced by large cells throughout the cerebral cortex and hippocampus [1]. GABA is an inhibitory neurotransmitter with local and longrange systems, in the cerebral cortex and limbic brain [1]. Opioids and endorphins are central nervous inhibitors, and their inhibitory influence plays a major role in brain and pleasure regulation. In general, it is true that neurotransmitters have activating or inhibitory properties. For instance, dopamine, norepinephrine, glutamate and histamine are activators, and serotonin, GABA and endorphins have inhibitory influences [1]. It is also true that multiple chemicals including neurotransmitters and other neuromodulators and chemicals such as brain-derived neurotrophic factor, G-protein, cAMP and others coexist in neurons and synaptic systems and are of great importance for neurotransmission [1]. It is also true that anatomical and functional interactions exist between the noradrenergic neurons originating in the locus coeruleus and the serotonergic nucleus in the raphe nuclei, with each system influencing the other and multiple chemicals coexist and constitute a chemical cocktail with anatomical and functional interactions [1]. Thermodynamic laws Thermodynamic laws are universal and, hence, apply to brain function. For instance, bioengineered, hypothermic, overweight mice outlive normothermic mice on caloric restriction [4] and Salerian–Saleri Temperature Thesis (SSTT) and other evidence suggest core body temperature is a governing force in brain neurodegeneration and longevity [2,5]. Van’t Hoff law suggests an increase in temperature shifts equilibrium in the direction that absorbs heat, and a decrease in temperature shifts equilibrium in the direction that evolves heat [6]. The second law of thermodynamics suggests that all chemical processes have a direction [2]. Neurobiology suggests brain function is region specific [1]. Neurobiology also suggests synaptic transmission is crucial for brain function [1]. Hence, we must conclude: The precise direction of a synaptic system with its unique chemical cocktail is a governing influence for brain function. Any change in brain homeostasis shall activate a cascade of changes with a dynamic homeostasis with a new direction consistent with the second law of thermodynamics and with precise, regionally defined neurobiological consequences. In essence, a single neurotransmitter shall produce a wave of reactions with a new homeostasis and new dynamic state with a new direction and with its unique region-specific brain function. Turbulence, the disordered motion of fluids and its fundamental dynamics will explain certain paradoxical outcomes triggered by a reactant. Thus, a single neurotransmitter will not cause psychosis or depression, although a single transmitter may induce changes in brain homeostasis with catastrophic or minor consequences.
The supporting evidence for STB The supporting evidences for STB are summarized under four headings: (I) Hallucinogenics and psychosis including substances and their paradoxical effects. (II) Changes in brain homeostasis cause terminal effects and withdrawal reactions. (III) Psychosis and negative symptoms. (IV) Antipsychotics for depression.
271
Paradoxical effects of hallucinogenic Agents opiates and support STB The hallucinogenic or psychosis-inducing properties of many substances such as lysergic acid diethylamide (LSD), phencyclidine (PCP), ketamine, mescaline, 1-2,5-dimethoxy-40iodophenyl-2aminopropane (DOI), psilocybin and muscimol are well established [7]. Is there a common mechanism or final pathway for their hallucinogenic or psychosis-inducing influence? And if there is, what brain regions and dysfunctions are involved? And what are the crucial alterations in regional brain homeostasis that correspond with brain dysfunction? Aghajanian and Marek demonstrated that increased serotonergic activity by LSD, PCP and mescaline heightens the sensory response of locus coeruleus, a robust noradrenergic center in the limbic system, and activates dopaminergic and glutamatergic transmission in the cortex [7]. The results are heightened and distorted perceptual, cognitive and emotional responses consistent with a psychosis. In essence, Aghajanian’s work suggests that LSD-induced psychosis is produced by a dominant dopaminergic–glutamatergic homeostasis [7]. This may explain similar dynamics in the genesis of hallucinations and psychotic symptoms observed with two N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine and mescaline, that produce a glutamatergic– dopaminergic influence in the prefrontal cortex [7]. The direct post-synaptic effects of serotonin in the cortex are variable: Depolarization, hyperpolarization, or no change, depending upon whether the effects of excitatory 5-HT2 receptors or inhibitory 5-HT1a receptors are predominant in any given layer V pyramidal cell [7]. However, the most striking effect of 5-HT in cortical regions is to increase excitatory post-synaptic potentials [7]. In essence, Aghajanian and Marek propose that a serotoninmediated enhancement of various hallucinogenics induces increased glutamatergic transmission in the cerebral cortex, which is responsible for the high-level cognitive, perceptual and affective distortions caused by prefrontal cortex dysfunction. Of significance is the observation that muscimol, a GABA agonist, and LSD and psilocybin with serotonin-like structures and known serotonin antagonism at the dorsal raphe nuclei cause hallucinations and psychosis consistent with the observation that heightened dopaminergic–glutamatergic influence in the prefrontal cortex may be responsible for the final outcome. Ubiquitous effects of hallucinogenics on such complex brain functions as cognition, perception and mood suggest the involvement of the cerebral cortex [7]. Based upon the collective evidence, all substances with psychosis-inducing or hallucinatory properties cause prefrontal cortex dysfunction with glutamatergic and dopaminergic activation. Thus, because of the thermodynamic and region-specific brain function principles psychosis and hallucinations represent a prefrontal cortex dysfunction directed by a predominant dopamine–glutamate influence. Opiates and their receptors, in general, are central nervous system inhibitors which play a major role in attainment of pleasure an pain control rewarding addictive behavior [8]. The influence of opiates are consistent with STB and support opiate-induced alterations in brain homeostasis with region-specific effects. Opioid receptor subtypes include l, d and j [8]. The l receptors have a high affinity for opiates. Endorphins are endogenous morphines, large peptides in the brain that mimic opiate activity [8]. Through opening of potassium and calcium channels, opiates in general have an inhibitory influence in the central nervous system [8]. Opioid autoreceptors produce inhibitory effects. Somatodendritic autoreceptors hyperpolarize cells in the locus coeruleus by
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enhancing potassium conductants and subsequently reducing cell firing and are ultimately responsible for the analgesic effects [8]. Opioids modulate pain directly in the spinal cord and also by regulating the descending pain inhibitory pathway ending in the spinal cord. Using Position Emission Tomography (PET) studies, Zubieta and colleagues demonstrated that endogenous l opioids modulate both the sensory and emotional components of pain [9–11]. Opioid microinjections into the VTA increase dopaminergic cell firing, with elevated production of dopamine in the nucleus accumbens. Intraventricular b-endorphin produces similar results [9–11]. Ventral tegmental area with mesolimbic dopamine neuron cell bodies that project the nucleus accumbens is known to be crucial for the reinforcing effects of addictive substances, natural rewards of food and water and the reinforcing and rewarding aspects of listening to music [12]. Furthermore, the hedonic aspects of reward is thought to be modulated by endogenous opioid peptide transmission within the nucleus accumbens and is consistent with the observation that musical pleasure can be blocked by naloxone, a non-opioid antagonist [12]. Collectively, the above-summarized Opioid induced paradoxical effects are with the region specific influence of a dynamic brain homeostasis with a new dominant direction – activating or inhibiting – consistent with STB. Changes in brain homeostasis cause terminal effects and withdrawal responses Soon after the discontinuation of morphine-like substances, a constellation of symptoms defined as morphine abstinence syndrome develops. Most of the symptoms slowly emerge in the first 24 h, gradually resolving within 7–10 days from the onset of withdrawal [8,9,11]. The symptoms include increased anxiety, restlessness, irritability, dilated pupils, goose flesh, hot flashes, vomiting, diarrhea, fever, elevated blood pressure, increased heart rate and abdominal and generalized muscle cramps [8,9,11]. Morphine abstinence syndrome seems to represent: 1. Increased noradrenergic parasympathetic and glutamatergic activity and the emergence of withdrawal symptoms coincide with plasma concentration half life and fatal clearance of a morphine-like substance [8,9,11]. Of clinical significance is that the onset of withdrawal does not always coincide with the onset of terminal effects of a substance. For instance, for morphine-like substances, a patient may remain pain free yet at the same time experience withdrawal symptoms. For the analgesic effect is determined by its CNS effect and the withdrawal triggered by the downward shift of the morphine-like substance’s plasma concentration. The data from morphine-like substances and selective serotonin reuptake inhibitors (SSRI) [12], consistent with thermodynamic principles, may suggest that indeed any entry or exit of a substance represents a change in brain homeostasis, hence is associated with physiological fluctuations consistent with withdrawal response. Hence any chemical substance – may produce neurobiological changes upon its entry or exit [8,11,13].
Depletion of dopamine in a circumscribed area of association cortex in rhesus monkeys produces an impairment in spatial-delayed alternation performance nearly as severe as that caused by surgical ablation of the same area [14]. This behavioral deficit can be pharmacologically reversed with dopamine agonists such as Ldopa and apomorphine [14]. These data provide direct evidence that dopamine plays an important role in a specific cortical function. In primates, including humans, the dorsolateral convexity of the frontal lobe plays a selective role in mediating mnemonic, attentional and spatial capacities [15]. In subhuman primates, this region of the cerebral neocortex has high catecholamine levels and syntheses rates, particularly for dopamine, whereas serotonin content and activity in the same cortical tissue is relatively low. The finding that dopamine depletion can be restricted to a circumscribed area of the prefrontal cortex and produce a behavioral deficit in a selective function of that area suggests that dopamine in the prefrontal cortex may function as a neurotransmitter independent of its precursor role. The loss in delayed alternation performance appears to be attributable specifically to substantial depletion of dopamine. Several studies of major depressive disorders and schizophrenia with negative symptoms reveal altered brain responses during functional magnetic resonance imaging in the prefrontal cortex and the pregenual anterior cingulate cortex, a region specifically relevant for expression of anhedonia [15,16]. Of significance is diminished blood oxygenation, hypometabolism at rest and reduced functional responses to stimulation. Because of SSTT, certain brain regions overstressed and exposed to higher metabolic rate and oxidation stress may age faster with faster degeneration and atrophy. Any energy production, i.e., activation, triggers heat production with heat traveling from hot to cold with increases in temperature in surrounding brain regions. Hence, a hot limbic system would activate other parts of brain regions by excitation and activation of glutamatergic and dopaminergic activity consistent with neurological pathways and with biologically predictable routes from the limbic system to the prefrontal cortex. Thus, these biological highways will have more wear and tear and age faster consistent with SSTT and therefore may produce more degeneration in the prefrontal cortex in a biologically predictable way because the prefrontal cortex is the final host of all the input from the rest of the central nervous system. Because the prefrontal cortex is so specifically wired to provide highly sophisticated intellectual and emotional functions even minute shifts in the brain’s prefrontal cortex homeostasis may cause executive dysfunction, anhedonia, apathy, and/or diminished initiative. Goldman et al. showed that reductions of cortical thickness in schizophrenia is heritable, yet cortical thickness, per se, is not a strong intermediate phenotype for schizophrenia [17]. Thickness is reduced most pronouncedly on the lateral surface suggesting a role of schizophrenia risk genes in temporal lobe cortical architecture specifically in amygdala or hippocampus [17]. Although, this observation is in need of further validation, it may have significant implications: The suggestion that not prefrontal but temporal deficits of schizophrenia are genetically inheritable, and hence negative symptoms associated with prefrontal cortex deficits may be attributable to the disease process rather than genetics. The findings summarized above are consistent with STB and the importance of biological connectivity of the brain and thermodynamic laws in the disease process.
Psychosis and negative symptoms support STB Antipsychotics for depression Is it possible that negative symptoms may not represent the core pathophysiology of schizophrenia in a model akin to the degenerative processes that shadow other major medical disorders? The emergence of diabetic retinopathy is such an example.
Two antimanic agents, aripiprazole and quetiapine – both antidopaminergic agents – demonstrate robust efficacy for some people with depression [18,19].
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Dopamine is believed to be the workhorse for energy, joy, motivation, initiative and concentration. Precisely because of dopamine’s crucial activating role in the prefrontal cortex, the observation that aripiprazole and Seroquel enjoy antidepressant properties gain significance to support the STB. It seems that their antidepressant efficacy may be due to their dampening influence on the sensory overload of a hyperaroused dopaminergic and glutamatergic limbic system. By quieting down the limbic fire, aripiprazole and quetiapine may offer neuroprotection for the prefrontal cortex and hence assist the prefrontal cortex regain normal function with higher dopamine levels.
Discussion Treatments for neuropsychiatric disorders traditionally target single neurotransmitters and focus on symptom relief based upon the Diagnostic and Statistical Manual For Psychiatric Disorders criteria. There is compelling evidence, however, that the current approach does not often yield satisfactory results in the greater picture of human suffering from neuropsychiatric disorders. This review suggests that thermodynamic laws have profound influence to alter human neurobiology. Or, it can be stated that human neurobiology is governed by thermodynamic laws and hence, the laws of Arrhenius, van’t Hoff, the second thermodynamic law, and the SSTT apply to human brain function. As a consequence of the governing influence of natural laws and the known principles of region-specific brain function, the following statements are correct: 1. Any change in brain homeostasis by an alteration in brain temperature, neurotransmission or content produces region-specific brain dysfunction. 2. Any chemical substance shall cause neurobiological changes upon its entry to the CNS or exit from it. Thus, not only sedatives, hypnotics or narcotics, but all substances have psychotropic influence associated with their entry into and departure from the CNS. 3. Negative symptoms of schizophrenia are consistent with longterm effects of the disease process with ‘‘wear and tear” thermodynamic effects of abnormal neurotransmission on brain neural pathways. 4. A single neurotransmitter can never cause a brain disease, yet may trigger a cascade of chemical reactions that will produce region-specific brain dysfunction. The implications of the crucial impact of thermodynamic laws to alter human neurobiology are, of course, profound, for it logically leads to the necessity of relinquishing the current and universally popular paradigm of the Diagnostic and Statistical Manual of Psychiatric Disorder. Understandably, even the mere consideration of abolishing the DSM paradigm has its own, combustible and inevitably negative consequences. The magnitude of a potential negative response may delay further investigation although scientific advance may necessitate such a change.
Conclusion Collectively, the above data suggests that brain function is region-specific and governed by complex system dynamics and thermodynamic laws, and hence any changes in brain homeostasis – temperature, neurotransmission or content – causes brain dysfunction.
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This article proposes a new paradigm, STB, to study brain function. The new paradigm suggests natural laws apply to brain function. Today DSM-IV navigates neuropsychiatric research [20]. Behavioral and biological research must meet DSM-IV criteria. Yet DSMIV is not built upon neuroscientific evidence consistent with objective measures to evaluate neuroanatomical or neurophysiological abnormalities associated with brain dysfunction. This skewed system is not harmless for it promotes unscientific guidelines to offer solutions for people with brain disorders. STB has several major implications. It introduces the urgent need to replace the DSM-IV system with a scientifically sound system consistent with natural laws and neurobiology; suggests that thermodynamics and complexity apply to brain research; shows that single neurotransmitter theories of brain disorders are inaccurate; proposes that not only narcotics and sedatives but all agents that cross the blood–brain barrier may produce adverse changes in brain homeostasis at the time of their arrival and departure. Like all theories, this particular theory has a variety of limitations. First, it needs to be validated by clinical studies. Another limitation of the theory is the application of principles to issues, concepts, and emotions that fall beyond the ordinary domain of natural laws. The discussion of DSM-IV system is unavoidable in the spirit of helping people with brain disorders.
Conflicts of interest statement None declared.
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