The brain's drugstore: alternative approaches in the treatment of psychopathological states.
Anxiety (Care and treatment)
Neural networks (Physiological aspects)
Neural networks (Research)
Serotonin uptake inhibitors (Health aspects)
Serotonin uptake inhibitors (Research)
Gene expression (Research)
|Publication:||Name: Annals of the American Psychotherapy Association Publisher: American Psychotherapy Association Audience: Academic; Professional Format: Magazine/Journal Subject: Psychology and mental health Copyright: COPYRIGHT 2011 American Psychotherapy Association ISSN: 1535-4075|
|Issue:||Date: Fall-Winter, 2011 Source Volume: 14 Source Issue: 3|
|Topic:||Event Code: 310 Science & research Computer Subject: Neural network|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
The authors intend to examine the relationship between the use of pharmaceutical agents and non-drug alternatives to alter one or more biological processes within the brain. There exist several means, including music therapy, meditation, placebo, or the therapeutic context, and other environmental factors by which therapists may utilize the brain's intrinsic plasticity to influence mental health. This paper contains an exploration of the subjective effects, physiological changes, and specific brain mechanisms involved in music therapy, meditation, and placebo effects. The many neurotransmitter systems involved in neuropathology and the somatization of stress are explored in the context of non-drug therapies. This paper provides a brief introduction to "autointrinsogens"--endogenous chemicals working in synchrony to respond to environmental and mental state adaptations in ways similar to prescription chemical substances. Autointrinsogens have long been a fundamental component of patient response to therapy and recovery but until recently, scientific medicine has focused primarily on exogenous chemical means for treating mental disorders. Promoting further clinical and laboratory research will allow advances in clinically-relevant supplementation of autointrinsogens in patient care.
After studying this article, participants should be better able to do the following:
Identify four means by which therapists may induce an autointrinsogenic response.
Identify the four main subjective effects of meditation practices.
Identify neurotransmitters involved in creating subjective effects of meditation and music.
Incorporate non-drug techniques into existing therapeutic regimens.
Define epigenetics and outline its applicability in the context of patient health.
KEYWORDS: drugs, autointrinsogens, placebo-effect, meditation, music, epigeneticso.
PROGRAM LEVEL: Intermediate
DISCLOSURES: The authors have nothing to disclose
"Up to six prescriptions per second, around the clock and around the year, are said to be written for SSRIs [Serotonin selective reuptake inhibitors]" (Stahl, 2008, p, 522) Nevertheless, clinicians have yet to derive a single cure for depression, anxiety, and other psychological disorders. Traditional routes of treatment for depression in the West consist of multi-drug therapies. While effective in relieving symptoms, standard antidepressant therapy has many side effects, including sexual dysfunction, xerotemia, sleep disruption, and weight gain (Stahl, 2008). Just as the Western world has approached imbalances in brain chemistry through exogenous means, the Eastern world has long benefited from techniques whereby individuals exploit the brain's intrinsic plasticity to influence mental health. If is only recently that researchers have begun to comprehend the sophisticated processes intrinsic to the brain that will, in the right environment, allow it to adapt to imbalances and in a sense treat itself. This paper will introduce several instances where drug-responses have been observed without the introduction of exogenous chemical substances capable of altering one or more biological processes within the brain. While this is hardly an exhaustive exploration of the brain's magnificent intrinsic plasticity, it provides a brief introduction to what this paper will term "autointrinsogens"--endogenous chemicals working in synchrony to respond to environmental and mental state adaptations in ways similar to prescription chemical substances.
Meditation, or "a group of practices that cultivate focused attention and moment-to-moment awareness of one's experience in order to heighten the capacity to bring conscious choice to response and reactions," first entered the Western psyche in the 1800s through cultural influences from India, China, and Japan (Kristeller, 2007), Recently, clinicians have begun to incorporate meditative practices into the therapeutic approach to treat and combat depression, anxiety, compulsive overeating, and drug addiction. Today, one of the most clinically relevant approaches drawing on meditation techniques is the Mindfulness+Based Stress Reduction Program developed at the University of Massachusetts Medical Center (Kristeller, 2007), Success in the use of meditation as an adjunctive treatment approach for mental illness and as a primary means for maintaining mental health has spurred a great deal of research exploring meditation's physiological and neuropsychological effects and mechanisms of action (Rubia, 2009).
Subjective effects of meditation
Subjects report considerable cognitive and affective benefits from meditation. Individuals having engaged in long-term meditation, the result of years of training, report the following physical, cognitive, emotional and psychological effects: (1) a penetrating relaxation and relief from stress, (2) enhancement in self-control and improved concentration, (3) detachment from exogenous stressors, positive mood, emotional resilience, and (4) personality equilibration (Rubia, 2009). Grossman, Niemann, Schmidt, and Walach (2003) reviewed 64 studies analyzing the therapeutic effects of the Mindfulness-Based Stress Reduction Program on subjects with a wide spectrum of medical histories, as well as non-diseased subjects who reported elevated stress levels. Although results were derived from a limited number of studies, there was significant evidence supporting the efficacy of therapeutic use of meditation to relieve suffering associated with a wide range of psychiatric, physical, and psychosomatic disorders.
Physiological changes resulting from meditation
More interesting than perceived relaxing and equilibrating effects of meditation are the physiological changes in the body's response to stress for those who practice meditation. Subjects undergoing meditation exhibit what researchers have termed the "relaxation response," an increase in parasympathetic autonomic nervous system function accompanied by a decrease of sympathetic functioning (Benson & Klipper, 1975). Several studies relate primary physiological changes, such as decreased body temperature, lower blood pressure, and lower salivary cortisol levels to subjective reports of calmness during the relaxation response.
A recent study compared physiological responses of healthy Chinese undergraduates randomly assigned to participate in five 20-minute sessions of either a form of meditation known as integrative body-mind training, or simple relaxation, which serves as a control (Tang, Ma, Fan, Feng, Wang et al., 2009). During each meditation session, researchers measured blood pressure, respiratory rate, and heart rate variability, and took single photon emission tomography and electroencephalogram recordings of brain activity (Tang et al., 2009). After five days and five sessions, both groups showed positive changes in physiological indexes. However, those undergoing integrative body-mind training showed lower heart rate, increased belly respiratory amplitude, lower respiratory rate, and lower heart rate variability than the simple relaxation group (Tang et al., 2009). The Integrative body-mind training group showed lower brain activity in general, but greater regional blood flow in several brain sites including the right anterior cingulate cortex, right posterior cingulate cortex and the basal ganglia (Tang et al., 2009). This finding is of interest because schizophrenic patients tend to have decreased gray and white matter density and decreased activity in the anterior cingulate gyrus (Costain, Ho, Crawley, Mikulis, Brzustowicz, et al., 2010). More importantly, there were no similar patterns of brain activation in the simple relaxation group (Tang et al., 2009). Together, these findings indicate meditation has promising neuropsychological effects that are distinct from those experienced during periods of relaxation.
Researchers suggest the increased activity of the putamen and caudate nucleus in the integrative body-mind training group could indicate increased dopamine (DA) release (Tang et al., 2009). DA is involved in pathways for reward and reinforcement within the brain. It follows that release of DA from the putamen and caudate nuclei encourages meditators to maintain a longer meditative state (Tang et al., 2009). Although the results of this study in Eastern society do not generalize to populations in the West, its findings are consistent with numerous other studies of populations in the U.S. which report an autonomic physiological response in meditation distinct from physiological changes resulting from simple relaxation (Rubia, 2009).
In addition to activating brain regions involved in stress prevention and reinforcement, meditation appears to improve capacity for concentration. Functional magnetic resonance imaging studies, designed to observe differences in activation in brain regions during meditation, suggest meditation-associated functional upregulation in brain regions responsible for attention control, namely the inferior prefrontal cortex, inferior parietal lobe and the insula (Farb, Segal, Mayberg, Bean, McKeon, et al., 2007). Meditation activates paralimbic areas, fronto-limbic affective networks, and fronto-parietal attention networks in a unique pattern that may explain the sustained attention and emotional leveling resulting from meditative states (Cahn & Polich, 2006). Combined, the physiological changes resulting from meditation suggest it may be useful in patients experiencing chronic stress and pathological anxiety.
Neurotransmitters involved in meditation
Given interesting behavioral and brain-mapping findings, it is worth exploring specific neurotransmitter changes resulting from meditation. Meditation communicates its effects through four key neurotransmitters: dopamine (DA), serotonin, norepinephrine (NE), and cortisol. Several studies have observed DA release in limbic brain regions during meditation as well as increased blood plasma levels of serotonin and melatonin (Lou, Kjaer, Friberg, Wildschiodtz, Holm, et al., 1999; Walton, Pugh, Gelderloos, & Macrae, 1995; Harinath, Malhotra, Pal, Prasad, Kumar, et al., 2004). Walton, Pugh, Gelderloos, and Macrae (1995) observed neurotransmitter levels in a group of healthy students with no history of meditation practices and a similar group of healthy students matched for age and area of study who had practiced meditation for more than eight years. Researchers analyzed urine samples from the two groups for neurotransmitter metabolites and found differences on most measures (Walton et al., 1995). The meditating group was lower in cortisol and aldosterone, higher in dehydroepiandrosterone sulfate, a cortisol antagonist, and 5-hydroxyindoleacetic acid, a serotonin metabolite, and lower in excretion of vanillylmandelic acid, a metabolite of DA and peripheral NE (Walton et al. 1995). Interestingly, cortisol levels were inversely correlated with number of months of meditation practice in females who practiced meditation (Walton et al., 1995).
In summary, meditation appears to decrease cortisol and NE release while increasing serotonin and DA activity in the brain. As cortisol and NE are known to be involved in stress response, lower levels of cortisol and NE metabolites are pharmacological indications that endogenous activity in response to meditation practice might parallel activity of NE beta-receptor antagonists used to treat anxiety disorders (Meyer & Quenzer, 2005; Walton et al. 1995). Additionally, increased 5-hydroxyindoleacetic acid likely indicates high release and processing of serotonin. Among other effects, partial serotonin 1A receptor agonists, such as buspirone and ipsapirone, reduce anxiety (Meyer & Quenzer, 2005). It is possible that one of the many endogenous mechanisms in response to meditative practices produces lower subjective appraisal of stress levels through increasing serotonin release and thus increasing serotonin binding at presynaptic and postsynaptic 1A receptor sites (Meyer & Quenzer, 2005).
Dose-Dependence in Meditation
Not only does meditation demonstrate clinically-relevant stress relief, reinforcement, and attentional control, but there also exists a physiological difference in response between short-term and long-term meditators (Cahn & Polich, 2006). Moreover, long-term meditation can induce long-term changes in brain structure and functioning such that subsequent meditation sessions result in enhanced activation in fronto-parietal regions implicated in attentional control compared to earlier sessions (Cahn & Polich, 2006). Furthermore, Aftanas and Golosneykin (2005) demonstrated that long-term meditators show reduced stress response when researchers played a stressful video-clip for them. Meditators showed reduced skin potential levels, indicating lower stress levels, and reduced gamma activity in frontal brain regions in response to the stressful stimuli (Aftanas & Golosneykin, 2005). Rubia analyzed several results similar to these, supporting the claim that long-term meditation results in stress reduction and greater emotional resilience (Rubia, 2009).
The "experience-dependent 'dose'-effects" with meditation are not the only dose-dependency researchers have observed (Rubia, 2009). Lazar, Bush, Gollub, Fricchione, Khalsa, et al. (2000), found fronto-limbic brain activation to be more intense within individuals in deeper compared to lighter meditative states. Other studies further support these dose-effects. Activation and structural modifications in fronto-parietal networks are correlated with lifetime hours of meditation practice (Brefczynski-Lewis, Lutz, Schaefer, Levinson, & Davidson, 2007; Aftanas & Golocheikine, 2001) Furthermore, there is a direct correlation between the variation in subjective quality of meditation for individuals and the degree of resulting brain activation (Brefczynski-Lewis et al., 2007; Aftanas & Golocheikine, 2001).
There is reason to approach dose dependency findings with caution. Although there have been robust findings supporting the effect of meditation to increase parasympathetic activity, reduce perceived stress, and increase endogenous DA, serotonin, and melatonin levels, many of the studies were based on comparison of two different groups of subjects--those who had been long term meditators and those who were novices (Farb et al., 2007; Rubia, 2009). There are likely confounders between the two subject groups that would predispose individuals to choose to incorporate the practice of meditation into daily life for long periods of time.
MUSIC AND THE BRAIN
While meditation involves an active orientation of the mind and focused concentration, there are other, more passive non-drug alternatives through which individuals may induce an autointrinsogenic response. One such alternative, music therapy, is "the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music therapy program" (American Music Therapy Association, 1999). The therapeutic use of music dates back to Ancient Egypt; however, music therapy was not formally introduced into the United States healthcare setting until caregivers noted improved physical and psychological health in World War l veterans exposed to live music in the 20th century (American Music Therapy Association, 1999).
Researchers have since explored the efficacy of music therapy in the treatment of psychiatric disorders, such as depression and schizophrenia, post-operative inflammatory response, dementia, and chronic pain (Kejr, Gigante, Hames, Krieg, Mages, et al., 2009; Tang & Vezeau, 2010). Although music therapy is often administered as receptive music therapy, through a headset, some studies have explored "active music therapy," which involves group sessions during which participants actively create music or participate in music selection (Kejr et al., 2009; Tang & Vezeau, 2010; Bittman, Berk, Felten, Westengard, Simonton, et al., 2001). Both "passive" and "active" music therapies serve as "positive interventions known to maintain robust cell-mediated responses, reduce perceived stress and heightened activation of the hypothalamic-pituitary-adrenal axis (HPA) and sympathetic nervous system" (Bittman et al., 2001. p. 39). Figure 1 shows the hypothalamic-pituitary-adrenal axis, which is essentially the body's communication circuit for stress. Upon appraising a stimulus as stressful, the hypothalamus signals the anterior pituitary gland to stimulate glucocorticoid and NE release from the adrenal glands. While adaptive for short periods of stress, overactivation of the HPA axis from chronic stress suppresses immune functioning and leads to neuronal death (Meyer & Quenzer, 2005).
[FIGURE 1 OMITTED]
Excessive neuron death is involved in depression, schizophrenia, and Parkinson's disease (Stahl, 2008). The HPA axis is vital in maintaining the body's homeostasis as it regulates the stress response and directs much of immune system activity (Meyer & Quenzer, 2005; Angelucci et al., 2007).
Music affects multiple brain structures. The nucleus accumbens, ventral tegmental area, hypothalamus, and insula are activated in response to music (Angelucci, Ricci, Padua, Sabino, & Tonali, 2007; Boso, Politi, Barale, & Enzo, 2006). These areas are implicated in reinforcement, reward processing, and processing of emotional and rewarding stimuli (Meyer & Quenzer, 2005) as illustrated in Figure 2.
Given music's observable activation of the hypothalamus, it is possible that music therapy may interact with the HPA axis to achieve its anxiolytic effect (Angelucci et al., 2007; Boso et al., 2006).
Further research supports music's rewarding effects. Ten university students with more than eight years of music training were allowed to self-select music that produced a pleasurable response accompanied by measurable physiological changes including chills and increased heart rate (Blood & Zatorre, 2001). Researchers then performed positron emission tomography (PET) scans as subjects listened to their music of choice and observed increased regional cerebral blood flow in the ventral striatum, midbrain, amygdala, orbitofrontal cortex, and ventral medial prefrontal cortex (Blood & Zatorre, 2001). These brain regions are important in neural mechanisms of reward (Meyer & Quenzer, 2005).
Environmental factors, such as ambient noise, lighting, wall color, and social context, can easily act as confounding variables, limiting the validity of results in studies examining music research. While most of the studies cited above effectively controlled environmental factors, several failed to control for time of day (Bittman et al., 2001; Tang & Vezeau, 2010). Since cortisol levels vary with time of day, being highest in early morning hours, failing to control for time of day could compromise the ecological validity of findings (Stahl, 2008).
[FIGURE 2 OMITTED]
Music affects neurotrophin transcription. Neurotrophic factors, proteins that regulate neuron development and survival, are vital to brain health (Stahl, 2008). The brain varies transcription of over twelve different neurotrophins to permit some neurons to flourish and sentence others to death (Stahl, 2008). Imbalances in two important neurotrophins: nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are implicated in neuronal death that results in major depressive disorders and schizophrenia (Stahl, 2008). Angelucci et al. investigated the effect of daily exposure to slow wave music on brain biology of adult mice, using immunoassays to measure hypothalamic concentrations of BDNF and NGF (2007). Music caused notable up-regulation of BDNF and a down regulation of NGF in the hypothalamus (Angelucci et al., 2007). Other studies have demonstrated that mice subjected to chronic stress by immobilization following administration of exogenous glucocorticoids show hippocampal nerve damage correlated with decreased expression of BDNF compared to control mice (Smith, Makino, Kvetnansky, & Post, 1995). While these two studies were limited to animal subjects, the findings are nonetheless important as they suggest music could counter BDNF depletion associated with depressive and anxiety disorders (Stahl, 2008).
Music affects histamines. Histamines bind to peripheral receptors to produce an inflammatory response and stimulate the central nervous system when bound to H1 receptors in the brain. Music reduces the body's histamine response to allergens. Kejr et al. (2009), measured salivary histamine levels in two similar groups of Swiss individuals aged 21-31 known to have food allergies when exposed to the "adverse food" during receptive music therapy, and in the absence of music therapy. Researchers controlled for type of allergic response, separating subject groups into those who exhibited typical allergic responses and those who simply rejected the adverse food (Kejr et al., 2009). Listening to 10 minutes of classical music suppressed salivary histamine levels in individuals experiencing either type of inflammatory response to adverse food and also lowered pulse rate (Kejr et al., 2009). In addition to modulating inflammation, listening to music may have a sedative effect as its activity parallels antihistamine medications which produce drowsiness (Stahl, 2008).
Neurotransmitters and Neuromodulators
Imaging data suggests endogenous neurotransmitters and neuromodulators play a role in the brain's response to passive music listening. Menon and Levitin (2005) acquired fMRI data of 13 subjects with no formal music training as they listened to segments of either Beethoven's Fifth Symphony and Mozart's Eline Kleine Nachtmusik or scrambled cacophonous versions of the originals. Data revealed significant activation in both the nucleus accumbens and ventral tegmental area during the normal music listening period as compared to unpleasant musical stimuli and interactions with the orbito-frontal cortex and insular frontal cortex (Menon & Levitin, 2005). Based on neuroimaging data, Menon and Levitin concluded that DA, endorphins, and endocannabinoids communicate music's effects on the brain. This result is consistent with research that has demonstrated an association between musical stimuli and increased release of endorphins and endocannabinoids into the bloodstream (Blood & Zatorre, 2001; Boso et al., 2006). It is also possible that music induces peripheral synthesis and release of nitric oxide (NO), a gaseous neuromodulator known to induce vasodilation, warm skin, and lower blood pressure, and serve an immunoenhancing function (Boso et al., 2006; Meyer & Quenzer, 2005).
While data on neurotransmitter and neuromodulator release in response to music is fascinating, the reader should take caution in generalizing from these results. The three studies referenced are based on small sample sizes and conclude neurotransmitter activity indirectly based on imaging data (Boso et al., 2006; Blood & Zatorre, 2001; Menon & Levitin, 2005).
Perhaps one of the most confounding aspects of the brain's plasticity for scientists has been the placebo effect (Finniss, Kaptchuk, Miller, & Benedetti, 2010). While the word "placebo," which is Latin for "I will please," has many connotations and usages, this paper will adopt a definition in the context of patient care (Finniss et al., 2010). Within the context of pharmacological research, the placebo effect describes an observable or otherwise measurable therapeutic effect on an individual in response to a pharmacologically inert treatment, often attributed to favorable treatment expectations (Finniss et al., 2010; Sandier, 2005).
Researchers have used placebos to control for the influence of confounding factors in medical research since 1784, but only recently have studies explored the mechanisms by which placebos generate changes in the course of disease (Finniss et al., 2010). Not only have researchers measured chemical changes in the brain in response to placebos, but findings indicate that the same "sugar pill" applied to different physiological conditions in different settings will effect change via separate pathways (Finniss et al., 2010).
Neurobiological Mechanisms of Action
Placebo effects have been shown to reduce pain, slow heart rate, decrease anxiety, change brain metabolism, alter behavior, and increase physical performance through clinically-relevant means (Finniss et al., 2010, Snadler, 2005). Like synthetic drugs, placebo effects can be graded and gradually increased--a form of dosing (Finniss et al., 2010). Depending on the condition for which a patient is being treated, a placebo can impact a variety of physiological systems (Finniss et al., 2010). In all cases, placebos appear to activate autointrinsogens in a disease-specific process, sometimes mimicking pathways of existing drug treatments and often following a neurobiological pathway not replicated by exogenous chemicals (Finniss et al., 2010).
Placebo analgesia. Mechanisms of placebo action on pain, an often debilitating condition, interestingly follow pathways similar to those targeted by exogenous analgesics (Finniss et al., 2010). Pain researchers have documented activation of endogenous DA and opioids following administration of placebos to treat pain (Finniss et al., 2010; Amanzio & Benedetti, 1999). PET scanning techniques measuring changes in binding potential of a radioactively labeled DA antagonist, raclopride, and a radioactively labeled opioid analogue, carfentaril, demonstrated opioid activation in the nucleus accumbens, amygdala, anterior cingulate cortex, oribitofrontal cortex, and periaqueductal gray matter following placebo administration. Concurrent DA activation was observed in the nucleus accumbens, ventral putamen, and right ventral caudate nucleus (Scott, Stohler, Egnatuk, Wang, Koeppe, & Zubieta, 2008).
Other researchers have revealed similar findings (Finniss et al, 2010; Howland, 2008). A systematic review of 12 studies exploring mechanisms of placebo analgesia in subjects experiencing either post-operative or experimentally-induced pain demonstrated that concealed administration of an opioid antagonist, naloxone, will inhibit the analgesic effects of placebo in subjects experiencing pain (Sauro & Greenberg, 2005). Similar research has successfully subtracted the placebo effect from administration of routine analgesics pharmacologically by administering naloxone to inhibit the non-specific activation of endogenous opioid systems by the psychosocial context of clinical treatment (Amanzio, Pollo, Maggi, & Benedetti, 2001).
Although there are consistent findings regarding the regions of activation following placebo administration for pain, researchers have observed individual variations in magnitude of response that vary with type of pain, level of expectation, and different social conditioning (Finniss et al., 2010). It is also worth noting that the placebo effect complements widely used painkillers, such as morphine and tramadol, enhancing their effectiveness (Finniss et al., 2010). Using the "open-hidden study design," wherein two similar patient groups are treated with the same medication either by clinician administration in full view of the patient (open treatment) or through infusion by a computer pump without the presence of a clinician or any other therapeutic cues (hidden treatment), researchers investigated placebo interactions with widely effective painkillers (Amanzio et al., 2001). Amanzio et al. (2001) discovered that the ED50, the dose required to reduce postoperative pain by 50% in patients, was significantly higher in the hidden treatment groups than in the context of open treatment.
Placebo as treatment for Parkinson's disease. Another area in which there is a prominent placebo effect is in the treatment of Parkinson's disease (de la Fuente-Fernandez, Ruth, Sossi, Schulzer, Calne, & Stoessl, 2001). Recently, researchers have taken advantage of refinements in neurobiological methods of analysis to discover the neural mechanisms of action through which placebos improve motor symptoms in Parkinson's disease (de la Fuente-Fernandez et al., 2001; Benedetti, Colloca, Torre, Lanotte, Melcarne, et al., 2004; Benedetti, Lanotte, Calloca, Ducati, Zibetti, et al., 2009). In a double-blinded study, comparing an active treatment for Parkinson's to placebo, researchers gave radioactive raclopride, known to compete with endogenous DA for a binding site on its D2 and D3 receptors, to patients and used PET to estimate levels of endogenous DA release (de la Fuente-Fernandez et al., 2001). Patients in the placebo group demonstrated increased DA release, as compared to baseline release, in the striatum region of the midbrain (de la Fuente-Fernandez et al., 2001). Furthermore, level of expectation in patients was directly related to the magnitude of increased DA release, which suggests that expectation or mindset determines the "dose" of placebo in patients with Parkinson's disease (de la Fuente-Fernandez et al., 2001).
[FIGURE 3 OMITTED]
Other studies assessing DA release and neuronal activity confirm these findings through different techniques (Benedetti et al., 2004; Benedetti et al., 2009). Benedetti et al. (2004) surgically implanted electrodes in order to carry out single-neuron recordings in the subthalamic nucleus of the basal ganglia system, a site of particular interest for treatment of Parkinson's disease. Patients with Parkinson's disease who received placebo in the form of verbal suggestion of improvement in body rigidity along with subcutaneous saline injection, showed reduced subthalamic activity (Benedetti et al., 2004). This finding is consistent with the theory that hyperactivity in the sub-thalamic nucleus, due to DA depletion, causes rigidity in patients with Parkinson's patients and suggests that placebos increase DA release to reduce activity in the subthalamic nucleus (Stahl, 2008). Further research expanded knowledge of neural circuits involved in the Parkinsonian placebo response, applying the same neuron recording methods to other thalamic regions of the brain (Benedetti et al., 2009). Data confirms reduced activity in the subthalamic nucleus, as well as demonstrates clinically important increase in activity of the thalamus in Parkinson's patients who responded to placebo (Benedetti et al., 2009).
Analgesia and Parkinson's disease therapy exemplify disease-specific variations in autointrinsogenic responses to psychosocial aspects of treatment in a formal setting, but it is important to consider psychosocial factors that contribute to heterogeneity in placebo responders within treatment of a single symptom or disease. The more suggestible an individual, the higher the dose of his or her placebo effect (Finniss, 2010). Physiological indicators of placebo response consistently reveal that subjects whose expectations match therapist suggestions experience greater biological changes as a result of placebos (Finniss et al., 2010). Furthermore, placebo responses can be conditioned. An individual who experiences a positive change in symptoms shortly following stimulation of the placebo response will experience more intense symptom relief and demonstrate an enhanced physiological response after subsequent placebo treatments (Benedetti et al., 2009; de la Fuente-Fernandez et al., 2001; Amanzio et al., 2001).
Not only do expectations, conditioned responses, and individual mindsets evoke the brain's autointrinsogenic response, the environment itself is capable of altering brain circuits both transiently, through differential activation of brain regions, and permanently, by altering gene expression, without the input of any exogenous pharmacodynamic substances (Caspi & Moffitt, 2006). While early genetic research assumed a direct linear relationship between individual genetic content and illness, including psychiatric disorders, research revealed this approach to be too simplistic to describe even the most common psychiatric conditions such as depression, schizophrenia, and addiction (Caspi & Moffitt, 2006; Meyer & Quenzer, 2005). At the beginning of the 21st Century, researchers discovered that environmental factors such as emotions, social signals, and nutrition can produce heritable modifications in genes without altering their DNA sequences, silencing some and overexpressing others (Lipton, 2008). The "transmission of non-DNA sequence information through either meiosis or mitosis" is termed "epigenetics" (Pray, 2004). While epigenetics can explain many deviations from what was expected to be a linear gene-to-disease path, the fact that similar individuals may respond differently to the same environ mental cue suggests there is more to explore in the gene-environment-disease relationship (Caspi & Moffitt, 2006).
In order to account for apparent environmental causes to mental disorders and individual differences in response to environmental causes, researchers have developed a model accounting for gene-environment interactions termed, "the Biopsychosocial Model" (Meyer & Quenzer, 2005). Even more recently, researchers are finding increasing evidence that endogenous chemical mechanisms in the brain are implicated in all aspects, biological, psychological, and social, that influence disease and disorder (Caspi & Moffitt, 2006). Based on recent findings related to the distinct, direct relationship between environmental cues and neuroplasticity, Caspi and Moffitt (2006) expect that neurobiological processes are the point of convergence between the paths of genes, environment, and disease. Moreover, Caspi and Moffitt (2006), would suggest that through the brain, genes affect response to environment, while environment differentially alters expression of genes through neural mechanisms. In addition, mind state affects appraisal of environment, and thus moderates the influence of environmental factors on brain functioning and eventually gene expression (Meyer & Quenzer; Caspi & Moffitt, 2006). This data would suggest a four-fold, bidirectional relationship between environment, genetics, and psychopathology, with the brain as the point of functional mediation between the three factors as illustrated in Figure 3.
GENES HODULATE EFFECT OF EHVIROHHEHT VIA BRAIH CHAH6ES
Monoamine oxidase and aggression. Researchers attempting to understand the heterogeneity in child responses to abusive environments explored a functional polymorphism in the gene encoding monoamine oxidase A, the enzyme known to metabolize and thus deactivate monoamine transmitters (Caspi, McClay, Moffitt, Mill, Martin, et al., 2002). Caspi et al. (2002), followed over 1,000 male children through adulthood, investigating the relationship between adolescent and adult conduct disorder, measured according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, and genetic propensity for monoamine oxidase A expression. Caspi et al., 2002, found that abused subjects genetically predisposed to low monoamine oxidase activity were more likely to exhibit increasing antisocial behavior throughout adolescence and early adulthood. This is consistent with earlier findings that suggest lower monoamine oxidase levels increase hyperactivity in response to stress (Morell, 1993). Functionally, this association is likely due to the role of monamine oxidase in breaking down the neurotransmitters associated with the fight-or-flight response to stress (Meyer & Quenzer, 2005; Morell, 1993). The monoamine oxidase gene on the X chromosome is incriminated in many mental illnesses, including depression and generalized anxiety disorder (Morell, 1993; Caspi et al., 2002).
Serotonin transporter and depression. In a similar attempt to connect differing responses to environmental stressors to genetic factors by way of brain mechanisms, researchers explored factors causing certain individuals to develop depression in response to a given stressful experience while others do not (Caspi, Sugden, Moffitt, Taylor, Craig, et al,, 2003). Caspi et al. (2003) performed a prospective-longitudinal study of a representative birth cohort to explore whether variations in the gene encoding the serotonin transporter (5-HTT) could explain varying influence of life-stress on depression. Individuals with two copies of an allele with a shorter promoter region for the 5-HTT gene have lower efficiency in transcription of the transporter, and thus show decreased expression of the 5-HTT gene relative to those with a normal allele (Lesch, Bengel, Hells, Sabol, Greenberg, et al., 1996). Caspi et al. (2003) effectively demonstrated that individuals with shorter promoter regions for the 5-HTT gene had more symptoms of depression, including suicidality, and higher diagnosis of depression in response to life-stress.
Other research on human subjects confirms the findings of this study and offers additional insight into the brain mechanisms involved (Canli & Lesch, 2007). Canili and Lesch (2007) observed that even those who were heterozygous for the short promoter region for 5-HTT demonstrated increased activation in the amygdala in response to negative photo cues. This study further supports the link between genes, environment, and autointrinsogens.
Environment dictates gene expression through changes in neural networks
Adverse experiences early in life can cause individuals to be hypersensitive to stress and more vulnerable to psychiatric disease, including depression, schizophrenia, and anxiety disorders later in life (McEwen, 2007; Cirulli, Francia, Berry, Aloe, Alleva, et al., 2009). Quality of maternal affection and care early in life determines the development of brain circuits mediating mood and stress response, including the HPA axis (Prieve, Romeo, Francis, Sisti, Mueller, et al., 2006). Animals that are held early in life show increased glucocorticoid receptor expression in the hippocampus, decreased corticotrophin-releasing hormone mRNA levels, and greater overall hippocampus volume than animals that are neglected early in life (Cirulli et al., 2009). Alterations in neurotrophin expression in response to maternal care may contribute to HPA axis development in animals (Cirulli et al., 2009). Rats subjected to several 3-hour periods of maternal separation demonstrate an immediate, transient increase in BDNF gene expression in the hippocampus and prefrontal cortex, followed by a chronic reduction of BDNF expression in limbic and prefrontal regions of the brain (Roceri, Cirulli, Pessina, Peretto, Racagni, et al., 2004).
BDNF has profound effects on animal development (Cirulli et al., 2009). As mentioned above, low BDNF levels are known to be implicated in depression and hyper-anxiety (Shimizu, Hashimoto, Okamura, Koike, Komatsu, et al., 2003). BDNF also indirectly controls development and adaptability of the visual system through regulation of the GABAergic inhibitory system and activation of the CREB (cyclicAMP response element binding) protein, a transcription factor for BDNF known to enhance and mediate development of the visual system (Cancedda, Putignano, Sale, Viegi, Berardi, et al., 2004). Mice pups exposed to higher levels of licking from adult females show accelerated development of the visual system, as measured through their performance on a visual water task, testing visual acuity, and through in vitro measurements of white matter-induced long-term potentiation (Cancedda et al., 2004).
The brain possesses endogenous chemicals capable of acting as drugs. The mind can synchronize the production and subsequent release of endogenous chemicals to prevent pathology and treat symptoms. Words, music, concentrated state of mind, and maternal contact are themselves drugs. The idea that the brain has the capacity to treat itself may have profound impacts on therapeutic techniques in the West. Already, clinical researchers have explored non-drug alternatives to treating a variety of disorders, many of them mental illnesses (Harrison, Manocha, & Rubia, 2004; Silverman, 2009). This paper suggests means by which clinicians may supplement standard therapy to incorporate a more holistic approach to patient health.
There are many cases of biological imbalance that require exogenous pharmacological treatment. Specifically, disorders resulting in degeneration or loss of organs that would produce endogenous hormones or signal transmitters necessary for regulation of the body's homeostasis. Type 1 diabetes mellitus, for example, results from the rapid autoimmune destruction of the insulin-producing beta cells of the pancreas (Hanas, & Brink, 2004). Patients suffering from this condition must rely on an external source of insulin hormone (Hanas, & Brink, 2004). It would be unrealistic to expect the brain to correct any imbalance for which it does not possess an intrinsic chemical treatment.
Research has effectively mapped out many neural mechanisms for the brain's therapeutic effect on itself. This paper has explored only a handful of the available studies that reveal the brain's intrinsic pharmacological capacities. While some studies are better-controlled than others, the majority lead to the same conclusion: the brain possesses the capacity to heal itself.
Much research has explored synergism with placebos and medications, yet there is a paucity of research exploring drug-autointrinsogen interactions for therapeutic purposes (Finniss et al., 2010). How effective are non-drug alternatives in complementing existing exogenous treatment? How might clinicians tailor treatment plans in such a way that would foster self-rehabilitation of the brain rather than developing chronic dependencies on pharmaceutical substances? Research in these areas is scarce. A handful of studies have explored the efficacy of meditation as a treatment for ADHD, but results were largely inconclusive due to poor controls (Krisanaprakornkit, Ngamiarus, Witoonchart, & Piyavhatkul, 2010).
How does the autointrinsogenic response compare to existing medications? What are the differences in magnitude of response? Ethical limitations are likely the reason direct comparisons between the brain itself and standard medications have not been explored in sufficient depth. As Finniss et al. (2010) emphasized, researchers cannot withhold a known effective treatment from an ill individual for the sake of expanding knowledge. For this reason, little research is available that compares meditation, music, environmental manipulations, or any other of the breadth of factors capable of eliciting an autointrinsogenic response. However, placebo treatment is one exception to this limitation, as researchers have utilized many techniques, including functional imaging, to compare placebo mechanisms for the treatment of many conditions to existing drugs (Finniss et al., 2010).
The placebo effect operates through different pathways depending on the disease it addresses. The mechanisms for placebo treatment of pain appear to be analogous to those affected by morphine or hydrocodone (Finniss, et al., 2010). Similarly, placebo effects for treating Parkinson's disease, are achieved through modulation of D2 and D3 receptors in the striatum; the same receptors through which existing antiparkinsonian medications, such as apomorphine, bromocriptine, pramipexole, ropinirole, and rotigotine, agonize the dopaminergic system (Finniss, et al., 2010). Placebo antidepressant effects, on the other hand, are not functionally equivalent to any one anti-depressant medication (Leuchter, Cook, Witte, Morgan, Abrams, 2002). Effective placebo treatment of depression induces changes in brain functioning that are distinct from those resulting from treatment with fluoxetine (Prozac) or venlafaxine (Effexor) (Leuchter et al., 2002). More interesting is the finding that studies conducted to investigate placebo mechanisms, rather than to substantiate medications by distinguishing them from placebos, demonstrate larger and sustained placebo effects (Finniss, et al., 2010; Leuchter, et al., 2002; Vase, Riley, Price, et al., 2002).
A hallmark of placebo antidepressants in clinical trials has been an abrupt, short- term response, or reduction in at least 50% of negative symptoms, followed by eventual symptom relapse (Stahl, 2008). However, recent studies assessing the efficacy of placebo antidepressant treatment reveal medication responders and placebo responders both showed well sustained symptom improvement (Leuchter, et al., 2002; Finniss, et al., 2010). This apparent discrepancy may be attributed to context differences between normal clinical practice, mimicked in studies exploring placebo as treatment, and the clinical trial setting (Finniss, et al., 2010). Nevertheless, such an interesting finding warrants further exploration.
While many studies have examined dosage and dose-dependency in the context of neuroplasticity, methods to grade and attune the brain's use of neurotransmitters deserve further exploration (Aftanas & Golosneykin, 2005; Cahn & Polich, 2006; Rubia, 2009 Brefczynski-Lewis et al., 2007; Aftanas & Golocheikine, 2001). Is it possible, or even relevant, to determine the half-life of various autointrinsogenic effects? How do personality differences influence individual responses to placebo, music, meditation, and other treatments?
The question that follows is: Can the brain, alone, cure itself?. There is likely no simple answer to this question. Given the complicated connection between environment, lifestyle, mindset, genes, and the brain, researchers might explore a cohesive approach for many major psychiatric illnesses, including depression, schizophrenia, and generalized anxiety disorder (Zgourides, 2010; Caspi & Moffitt, 2006).
Arguably more valuable than learning how to take advantage of neuroplasticity to treat disease, however, would be to learn how human beings can cater habits and thinking patterns to augment their own autointrinsogenic responses in order to prevent disease. Research might explore the most efficient means by which clinicians and educators can collaborate to enable individuals to make changes in daily habits and environmental factors that would prevent mental and physical pathologies.
This article is approved by the following for 1.5 continuing education credits:
The American Psychotherapy Association[R] provides this continuing education credit(s) for Diplomates and certified members, who we recommend obtain 15 credits per year to maintain their status.
"Special thanks to Dr. Amy Harkins (Soint Louis University) for comments on the manuscript."
POST CE TEST QUESTIONS
(Answer the following questions after reading the article)
1. Epigenetics refers to:
a. The study of relationship between stress and genetic makeup.
b. The transmission of non-DNA sequence information through either meiosis or mitosis.
c. The study of the influence of ontogenetic aspects of behavior.
d. Study of the relationship between cell structure and behavior.
2. Which of the following most accurately describes autointrlnsogens:
a. Effects of chemical events in the environment on brain behavior.
b. The random effects of the internal milieu on brain and behavior.
c. Endogenous chemicals coordinating responses to environmental and mental state adaptations in ways similar to prescription drugs.
d. Homeostatic influences on brain, behavior and pathophysiology.
3. Which of the following most accurately describes the relationship between the Placebo Effect and the brain's response to medications:
a. The placebo effect may operate through many different mechanisms, sometimes acting in ways analogous to drugs.
b. The brain does not respond to medications without expectations related to treatment.
c. Medication responses are qualitatively and quantitatively distinct from the placebo effect, with no obvious parallels in mechanisms or effects.
d. The placebo effect serves as a control to isolate for genuine drug-responses and thus has no relevance to prescription medications.
4. According to this article, which of the following factors would have the most significant effect on brain and behavior:
a. Receptive Music Therapy
b. Regular Meditation sessions
c. Placebo treatment for chronic pain
d. It cannot be determined from the given information.
5. Pathways in the brain that mediate a therapeutic effect for placebo verses drug:
a. Are the same
b. Are different
c. Change with age
d. Depend on the disorder
6. The major point of this article is:
a. Placebos are as effective as drugs
b. All medications should be replaced with non-drug alternatives
c. There is significant research that would suggest therapeutic relevance of the exploration of the brain's intrinsic plasticity.
d. There is an overabundance of information indicating that the brain is capable of acting in a self-healing capacity
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by Sara Rendell and Michael Anch
ST. LOUIS UNIVERSITY
SARA RENDELL is a neuroscience student at Saint Louis University researching neuronal communication and regeneration. She has had clinical experiences in Hopitale Bon Samaritan, Haiti, including treatment of acute trauma injuries and maternity care. She continues to volunteer in a free clinic serving the population of North Saint Louis.
MICHAEL ANCH, Ph.D., Associate Professor of Psychology at Saint Louis University, mentors students in the undergraduate and graduate psychology programs as well as being a mentor in the neuroscience program. In addition, Dr. Anch has been involved with the Students and Teachers as Research Scientists (or STARS) program while also teaching full time. His primary interests are sleep disorders and nutrition, and how they affect your health. A lifelong learner and teacher, Dr. Anch published a book titled: Sleep: A Scientific Perspective.
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