by Grace E. Jackson, MD
November 10, 2006
Author E. Van Winkle presents an intriguing hypothesis about the consequences of emotional suppression. Specifically, she suggests that the inhibition of emotions “during fight or flight reactions” leads to a toxic process in the human brain (“endogenous toxicosis”) which is characterized by shrinkage of the neurons which produce norepinephrine (NE). The author advances the view that low levels of NE are a cause of depression, while high levels lead to mania, anxiety, and/or aggression.
On a neurochemical level, Van Winkle contends that there are only two kinds of neurons in the central nervous system: noradrenergic neurons, which make and use norepinephrine; and cholinergic neurons, which make and use acetylcholine (ACH). While the author recognizes the existence of other chemicals in the brain – such as glutamate, GABA, serotonin – she describes these other substances as “false neurotransmitters” which represent toxic metabolites.
The “toxic mind” refers to the neurochemical consequences of suppressing emotion during times of stress. According to Van Winkle, NE neurons become damaged by emotional suppression. This subsequently causes the NE neurons to accumulate “toxic metabolites.” During periods of “detoxification crisis,” Van Winkle states that these so-called false neurotransmitters, combined with NE, burst out of swollen lysosomes (storage sacs) resulting in the over-stimulation of post-synaptic neurons. The “over-stimulation” of these cells is responsible for all forms of mental illness.
Van Winkle’s paper is interesting but convoluted. Several anachronistic and inaccurate statements demand a corrective analysis. The present evaluation will focus upon eight essential claims which constitute the foundation of Van Winkle’s Toxic Mind hypothesis.
Claim #1: Abnormal levels of catecholamines are the cause of all mental illnesses
The author (a self-described retired neuroscientist) presents the “catecholamine” hypothesis of depression as though it is an incontrovertible fact. In reality, the catecholamine theory of depression – which states that abnormal levels of dopamine, NE, and/or epinephrine are the cause of depression – has not been validated in the world of clinical medicine. Due to problems involving low sensitivity and low specificity, blood and brain levels of catecholamines have never been perfectly predictive of mood, anxiety, or psychotic disorders.
Claim #2: “Toxic metabolites” can be measured in the urine of psychotic patients
Van Winkle claims that “urine levels of methylated compounds” can be recovered from psychotic patients, demonstrating the existence of a neuropathological process within their brains. This is an antiquated and fallacious assumption. In fact, catecholamine levels — recovered from anywhere BUT the brain tissue itself — are largely irrelevant to the prediction of mental state and behavior. The reason for this is that the brain makes and regulates its own levels of catecholamine neurotransmitters. Urine levels of catecholamine metabolites are not accurate reflections of the primary metabolic pathways within the brain, because urine reflects the metabolic breakdown of catecholamines that have been made primarily outside the brain (in the medulla of the adrenal gland).
Furthermore, the primary metabolic pathway for norepinephrine WITHIN the human brain is neither via degradation by COMT (catechol-o-methyl-transferase) nor via degradation by MAO (monoamine oxidase). Rather, catecholamines are primarily “metabolized” by reuptake into the nerve terminals in which they are synthesized or stored, and from which they are released.
Claim #3: There are only two kinds of neurons in the human brain
The conjecture that there are only two kinds of neurons inside the human brain is an outdated view of brain function dating from the early 1930s, when the work of neurochemist Henry Dale was predominant. Seventy years of research have subsequently revealed that neurons commonly make use of specific combinations of chemical messengers at all of their synapses. These combinations are unique to the neurons which migrate to specific regions of the brain during embryonic development.
While there exist a limited number of small molecular weight neurotransmitter substances (ACH, dopamine, norepinephrine, epinephrine, serotonin, histamine), there are now thought to be dozens more neurotransmitters in the form of amino acids (GABA, glycine, glutamate), peptides (e.g., vasoactive intestinal peptide, gastrin, substance P, neurokinin, prolactin, LH, growth hormone, thyrotropin, neuropeptide Y, galanin, secretin), hormones (TRH, gonadotropin releasing hormone, corticotrophin releasing hormone, growth hormone releasing hormone), and gases (e.g., nitric oxide). Far from representing “false” neurotransmitters which pile up in norepinephrine or ACH neurons only during times of “endogenous toxicosis,” these major neurotransmitters are present from the earliest moments of fetal life, and they represent non-toxic means of sustaining vital life functions.
Claim #4: All neurotransmitters are “false” unless they are NE or ACH
False neurotransmitters are currently recognized by neuroscientists, but not in the manner used by Van Winkle. The process of synthesizing neurotransmitters within the central nervous system (brain and spinal cord) is a tightly regulated process. The formation of neurotransmitters depends upon the precise activation of genes which are located in the nucleus of each neuronal cell body. In other words, norepinephrine neurons are genetically programmed to make norepinephrine. Serotonin neurons are genetically programmed to make serotonin. There is nothing “false” about this arrangement, since neurons begin to “specialize” during the process of cell differentiation in the embryo.
Neuronal endings (called “boutons” or nerve terminals) contain special units on their cell membranes called “reuptake pumps” (aka, neurotransmitter transporters). These pumps are the primary means of neurotransmitter metabolism, in terms of removing chemicals from the gaps between cells (i.e., the nerve synapses) and returning them to the pre-synaptic neurons for storage, breakdown, or re-release. Neurotransmitter reuptake pumps function to prevent the kind of “toxic” over-stimulation which Van Winkle believes to be responsible for all forms of mental illness.
In some cases, these reuptake pumps act “promiscuously,” in the sense that they transport look-alike chemicals back into the nerve ending. For example, norepinephrine-containing neurons can transport dopamine back into the nerve terminal, and vice versa. When this happens, neuroscientists refer to the “intruder” chemical as a “false” neurotransmitter, since it has taken up temporary residence in a foreign host. Thus, while it is true that neuroscientists speak about “false” neurotransmitters in the human brain, the phenomenon is entirely different from the process which Van Winkle describes.
Claim #5: False neurotransmitters spill out of lysosomes during a detoxification crisis
Van Winkle contends that “false neurotransmitters” and norepinephrine are the cause of all mental illness, because they fill up storage sacs called lysosomes to the point of bursting. Following the rupture of these lysosomes, Van Winkle contends that these false neurotransmitters cause a host of abnormal thoughts and behaviors by spilling out of the pre-synaptic cell and over-stimulating post-synaptic neurons.
In reality, neurotransmitters are warehoused in specialized organelles called “storage vesicles” which bear specific proteins on their membranes (e.g. VMAT = vesicular monoamine transporter). These cell components are believed to be far more complex than lysosomes (the latter which function as non-specific trash disposals).
Van Winkle is only partly correct when she suggests that neurotransmitters are released from lysosomes. During the process of normal neurotransmission, non-peptide neurotransmitters are released from storage vesicles under the influence of electrical and chemical stimuli (generally, via the process of exocytosis). While it is technically possible for neurotransmitters to accumulate – along with other cellular debris – inside lysosomes, these chemicals would not “burst” out of the lysosomes unless and until the entire neuron or nerve ending had undergone a catastrophic event (such as cell death). At that time, the neurotransmitters (possibly degraded) would be released in a chaotic fashion and would not be capable of the organized or predictable type of post-synaptic stimulation to which Van Winkle refers.
Claim #6: False neurotransmitters result from toxic “atrophy” in NE neurons of the brain
According to Van Winkle: “so-called dopaminergic, serotonergic, GABAergic neurons are NE neurons that, as a result of atrophy and abnormal metabolism, have accumulated these substances.”
In the past 15 years, neuroscientists and molecular biologists have demonstrated a number of mechanisms which effect neuronal shrinkage (atrophy) and cell death. These mechanisms include the disruption of energy production in the mitochondria of each cell (by inhibiting the electron transport chain, or by uncoupling the process of oxidative phosphorylation from the generation of ATP); and the generation of free radical species which subsequently cause cell death by necrosis or apoptosis (programmed cell death). In none of these cases has neuronal damage been shown to induce the accumulation of neurotransmitters that were not originally synthesized or stored in the damaged or dying cell.
Van Winkle is surely correct in suggesting that toxic processes are harmful to the human brain. However, noradrenergic neurons do not accumulate other transmitters following a process of involution (shrinkage). Equally untrue is Van Winkle’s claim that the release of these “false neurotransmitters” leads predictably to the symptoms of mental illness.
Claim #7: Different neuronal receptors exist for different kinds of memory
One facet of Van Winkle’s paper implies that “endogenous toxicosis” results in the formation of harmful memories. According to Van Winkle, there are many different kinds of cell membrane receptors for the “false” neurotransmitters in the brain. She asserts that variations in receptor structure are responsible for different qualitative experiences of memory (e.g., for different shades of blue). Furthermore, she then suggests that short-term memory is based upon changes in the superficial layers of a cell receptor. Long-term memory is based upon changes in deeper regions of the cell receptor.
It is true that there are dozens of different receptor subtypes in the brain. However, there is no research evidence to support the hypothesis that memory is “housed” in discrete locations or segments of cell membrane receptors. In light of the fact that cell membranes and their components are highly fluid structures which undergo constant dynamic change, it is highly unlikely that specific memories would be encoded by such vulnerable structures with transient lifespans.
Based upon the longstanding observation that “neurons which fire together, wire together,” neuroscientists now believe that memories are formed, retained, and retrieved due to specific patterns (distributed networks) of neuronal activity. Thus, it is a distributed network of neuronal circuitry which must undergo frequent training and re-activation in order to establish memory. It is the regional variation of these processes which determine the temporal and qualitative features of specific kinds of memory (episodic, motor, implicit, semantic, autonoetic).
Claim #8: When negative emotions are suppressed, toxic chemicals clog up neurons
Van Winkle contends that the “suppression of emotion leads to toxic chemicals which clog up (noradrenergic) neurons.” She offers no evidence from neuroscience to support this claim. Interestingly, large numbers of studies have been conducted over the past 20 years, in an effort to establish the physiological consequences of both emotional experience (mood states) and emotional activity (expression vs. repression or inhibition).
Van Winkle is partly correct when she states that emotional suppression has demonstrable physiological effects, but it is far from clear that the effects are in the direction which she purports. According to Van Winkle, the intentional inhibition of emotions results in an accumulation of toxic metabolites within the noradrenergic neurons of the brain. To date, there is no research evidence to support this claim.
In contrast to Van Winkle’s assertion, several studies of method-trained actors have revealed strong associations between the expression of emotion, regardless of the valence (positive or negative), and heightened activity in the immune system, autonomic nervous system (increased heart rate and blood pressure), and hypothalamus-pituitary-adrenal axis (e.g., elevation in cortisol). With the exception of the first finding (immuno-activation) these findings suggest that it is the expression of emotion, rather than its suppression, which leads to a change in biological markers consistent with an acute stress response.
On the other hand, when the suppression of emotional expression has been studied in breast cancer survivors, emotional inhibition has been linked to greater levels of subjective distress (anxiety, dysphoria). In at least one study of cardiac patients, the suppression of a specific emotion (hostility) predicted the development of hypertension. Other cardiac researchers have found that emotional suppression, in general, predicts the severity of stenotic disease (i.e., more severe blockage of arteries). In the context of these findings, Van Winkle is partly correct when she suggests that the suppression of emotion may have important health effects. However, it would be a mistake to accept this claim uncritically or without qualification.
First, the capacity to inhibit impulsivity and emotionality can be a highly adaptive and health-promoting response for the human organism, based upon research investigations of individuals skilled in auto-hypnosis and transcendental meditation.
Second, it is essential to distinguish between the act of suppressing emotional experience or perception, on the one hand, and suppressing emotional activity (expression) on the other. Several research teams have found that the suppression of emotional expression creates subjective distress. In contrast, the suppression of emotional perception – via the act of “reappraising” or reframing one’s interpretation of stressors or situations – can create greater well-being.
Third, there is no research evidence at this time to corroborate a link between emotional suppression and the atrophy of noradrenergic neurons in the brain. On the other hand, there is strong evidence connecting the expression of intensely felt emotions (sad or happy) with short-term elevations in blood cortisol, and strong independent research linking prolonged elevations in cortisol with shrinkage of non-adrenergic neurons in the memory center of the brain (e.g., hippocampus of the temporal lobe).
Van Winkle argues that the suppression of negative emotion during times of stress leads to an “exogenous crisis” characterized by the shrinkage of NE neurons. These damaged neurons then accumulate “false transmitters” which – along with NE – leak out of swollen lysosomes during episodes of “detoxification crisis.” The leaked transmitters then over-stimulate post-synaptic neurons, resulting in mental illness.
This brief critique has presented eight arguments, mostly opposing Van Winkle’s conjectures. The field of neuropsychiatry remains largely ignorant about the consequences of emotionality. Although toxic effects have been well studied and well replicated in relation to the human perception of chronic stress, it remains far less clear that the same processes are associated with chronic patterns of emotional expression or inhibition. Van Winkle’s Toxic Mind hypothesis offers an intriguing but overly simplistic view of the causes of mental illness (i.e., over-stimulation of cells by norepinephrine), and an overly pessimistic view of the consequences of self-regulation (e.g., emotional suppression is not necessarily hazardous to the human brain).
- Brown, W.A., Sirota, A.D., Niaura, R., and Engebretson, T.O. (1993). Endocrine Correlates of Sadness and Elation. Psychosomatic Medicine 55, 459-467.
- Cooper, J.R., Bloom, F.E., and Roth, R.H. (2003). The Biochemical Basis of Neuropharmacology, (8th edition). New York: Oxford University Press.
- Futterman, A.D., Kemeny, M.E., Shapiro, D., Polonsky, W., and Fahey, J.L. (1992). Immunological variability associated with experimentally-induced positive and negative affective states. Psychological Medicine 22, 231-238.
- Futterman, A.D., Kemeny, M.E., Shapiro, D., and Fahey, J.L. (1994). Immunological and Physiological Changes Associated With Induced Positive and Negative Mood. Psychosomatic Medicine 56, 499-511.
- Gordon, E. (Ed), (2000). Integrative Neuroscience. Amsterdam: Harwood Academic Publishers.
- Iwamitsu, Y., Shimoda, K., Abe, H., Tani, T., Okawa, M., and Buck, R. (2005). The relation between negative emotional suppression and emotional distress in breast cancer diagnosis and treatment [Abstract]. Health Communication 18 (3), 201-215.
- John, O.P., Gross, J.J. (2004). Healthy and unhealthy emotion regulation: personality processes, individual differences, and life span development [Abstract]. Journal of Personality 72 (6), 1301-1333.
- Kandel, E.R., Schwartz, J.H., and Jessell, T.M. (1991). Principles of Neural Science (3rd edition). Norwalk, CT: Appleton & Lange.
- Koh, K.B., Cho, S.Y., Kim, J.W., Rho, K.S., Lee, S.H., and Park, I.H. (2004). The relationship of anger expression and alexithymia with coronary artery stenosis in patients with coronary artery diseases [Abstract]. Yonsei Medical Journal 45 (2), 181-186.
- Nestler, E.J., Hyman, S.E., and Malenka, R.C. (2001). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. New York: McGraw-Hill Companies, Inc.
- Van Winkle, E. (2000). The toxic mind: the biology of mental illness and violence. Medical Hypotheses 54 (1), 146-156.
- Zhang, J., Niaura, R., Todaro, J.F., McCaffery, J.M., Shen, B.J., Spiro, A. 3rd, and Ward, K.D. (2005). Suppressed hostility predicted hypertension incidence among middle-aged men: the normative aging study [Abstract]. Journal of Behavior Modification 28 (5), 443-454.