How Neurosciences help us to understand some (psycho)therapeutic processes { Bernadette Grosjean. MD. Psychotherapy Seminar Harbor UCLA 2013-2014 “We must recollect that all our provisional ideas in psychology will presumably one day be based on an organic substructure” Sigmund Freud “On Narcissism” 1914. In 1936 Rosenzweig wondered:  Whether the factors alleged to be operating in a given therapy are identical with the factors that actually are operating  Whether the factors that actually are operating in several different therapies may not have much more in common than have the factors alleged to be operating Several Meta-analyses report no differences among different types of therapies, although all are superior to no treatment. Luborsky,L. 1975,1993,1999,2002; Smith & Glass 1977;Grissom 1996; Wampold et al 1997; Ahn and Wampold 2001; Prochaska and Norcross 2003. Common factors  Operation of implicit, non verbal factors  Formal consistency of the therapeutic ideology as a basis for reintegration.  Alternative formulation of psychological events Rosenzweig 1936. Time travel { From neuron to mirror neuron “SOUL IS DISTINCT FROM THE BODY” Hippocrates (460-377 B.C.) Plato Athenes (427-347 B.C.) René Descartes Saint Augustin ( 354 -430) St Thomas Aquinas (1225-1274) (1596-1650) Santiago Ramon Y Cajal 1852-1934 “The nervous system is made up of billions of separate nerve cells”. Nerve cells are polarized, receiving information on their cell bodies and dendrites, and conducting information to distant locations through axons. "... mental exercise facilitates a greater development of the protoplasmic apparatus and of the nervous collaterals in the part of the brain in use. In this way, pre-existing connections between groups of cells could be reinforced by multiplication of the terminal branches of protoplasmic appendices and nervous collaterals". CAJAL. Royal Society. London 1894 Donald Hebb (1904-1985) The Organization of Behavior “ Cells that fire together wire together” Hebb was fascinated by the way people learned and the way they retained information. In 1949, he suggested that the nervous system was encoding information by strengthening activated neuronal connections. Terje Lomo- Timothy Bliss Long Term Potentiation “The stimulation of certain neuronal fibers by high frequency waves creates a significant and measurable increase in the inter-synaptic strength, insofar as it increases the ability to initiate post-synaptic potentials. Terje Lomo Norway 1966. Timothy Bliss.London, 1973. LTP Long-Term Potentiation This phenomenon, which may persist for weeks, is labeled long term potentiation (LTP).” Eric Kandel Nobel Prize in 2000. In 1965 proposed that a form of post- synaptic potentiation may correspond to a simple form of learning. Psychotherapy, like medication, is ultimately mediated by neuro-anatomical structures “Successful psychotherapy is correlated with discrete brain changes” Etkin, Kandel et al. 2005; Roffman et al. 2005. NEUROPLASTICITY • • 100 billion neurons Each develops between 1,000 to 10,000 connections with other neurons Timeline… Brain growth spurt in humans between the last 3 months of pregnancy and extends into the first 3 years of life.  Around 18 month dente gyrus (hippocampus) starts to “create” episodic memory.  Around 4 y/o starts developing autobiographic memory.  Major Pruning end around the end of puberty.  Adult brain remains plastic during the entire life.  NEUROPLASTICITY Development shapes the brain by altering the strength of synaptic connections within the brain.  New synapses can be formed in response to experience.  Genetic information, toxic substance, and stressful or absent experience can lead to elimination of synapses.  N-methyl-D-aspartate subtype glutamate receptors { NMDARs Glutamate  Glutamate is recognized as a neurotransmitter in 1972 (Watkins).  Primary excitatory neurotransmitter in the mammalian brain (60%).  Receptors for Glutamate are divided into NMDA and non NMDAr (AMPA, Kainate). NMDA-receptor Hippocampus, forebrain, amygdala, caudate, putamen and thalamus (rodents). NMDAR, can “detect” the coincidence of 2 events, so called “associativity”. LTP is dependent on the presence NMDA receptors (NMDAR) (Collingridge & al 1983).  Glutamate and NMDAR are involved in many CNS mechanisms of plasticity including those contributing to learning and memory.   The period when NMDAR function is critical for neuronal survival in rats encompasses a period that in humans extends form the third trimester of pregnancy to several years after birth. Balâazs et al 2006 Brain Human: genes around 35,000  We share about 97% of our genes with chimpanzees. Our closest relative, the bonobo, has about 98.4 % of the same genes that we do. (just 500 genes #)  Human brains differ from those of other primates in three main areas- the frontal lobes, the hippocampus, and the cerebellum.  Those three highly developed brain structures allow humans to do all sorts of amazing things.  We can manipulate symbols and create realities in our heads that can stand quite apart from the external reality that all other animals share.  The advanced processors that allow us to remember, imagine, plan, and create are still basically wired up to emotional systems that are not too different from those of our primate ancestors.   We continue to be driven by the same instincts and emotions. It is as though we have a super-fast computer hooked up to a chimpanzee emotional system. Hippocampus “Puzzle Assembler”. Facilitate the storage of spatial, non verbal and semantic or verbal memories that involve the encoding of experience into powerful symbolic representation facilitated by language Rich in NMDA receptors Hippocampus / Dente Gyrus The dentate gyrus is a site of active neurogenesis . I has been hypothesized that it ensure that new learned patterns do not interfere with the old ones and remain separable (Viamontes 2008) Amygdala “EMOTIONAL BRAIN”   Key role in the emotions (fear, pleasure). Key role in implicit, emotional memories: interprets the emotional significance of the experience. Rich in glucocorticoid and NMDA receptors Anterior Cingulate Cortex “Conflict monitoring” Vital to cognitive functions, such as reward anticipation, decision-making, empathy, and emotion.  ACC is involved in the processing of the affective dimension of pain  responsible for rendering new memories permanent.  NMDA receptor in the prefrontal cortex are critically involved in both LTP and contextual memory (Zhao et al. 2005). Cerebellum  There is increasing recognition that the cerebellum contributes to cognitive processing and emotional control in addition to its role in motor coordination The cerebellum, along with our frontal lobes and hippocampus, is much larger in humans than our physical stature would predict. In fact this mysterious structure contains over half of the brain's neurons.  The commonly recognized function of the cerebellum is the coordination and balance of muscle movements. Our talents in that area certainly would not explain the need for such enlarged cerebellums.  Ventral Pre-motor Cortex ...And MIRROR NEURONS Illustration © Marco Iacoboni Mirror Neurons A class of neurons that discharge not only when a monkey executes goal-related hand action, but also when observing other individuals executing similar actions. Gallese, Rizzolatti et al. 1996. Mirror Neurons Empathy “Einfühlung”  To empathize, we need to invoke the representation of the actions associated with the emotions we are witnessing.  In human, fMRI study showed that the same brain region are activated while observing an emotion or during the imitation of the emotional face expression “Neural mechanisms of empathy in human: a relay from neural systems for imitation in limbic area” Carr, Iacoboni et al 2003. Environment – NMDA neurotransmission { Stress... Continuation of, or re-exposure to, stress results in unregulated excitation of glutamate neurons (Farb et al 1992), and a growing body of data have implicated glutamatergic neurotransmission in stress-induced hippocampal atrophy and death (Mc Ewen 1999). Neglect...  Early maternal separation appeared to exert a dramatic suppressive effect on synaptic overproduction in the early development of hippocampus. De Bellis et al.2001.  Neonatal isolation impairs hippocampal-dependent context conditioned fear in adult rats. Kosten et al 2007 Fear...  It is impossible to cancel some memories related to fear once those have been “written” at the amygdala level (rodents). Ledoux 1996  Neocortex is indispensable for the extinction of the reflex associated to fear once it has been created through conditioning.  Animal studies show that important forms of learning in both the conditioning and extinction of fear are dependent upon proper function of NMDA neurotransmission in the amygdala (Miserendino et al. 1990; Rodriguez et al. 2001; Pietersen et al. 2006). MAIN POINTS NMDA neurotransmission: influences and is influenced by experience. has a clear impact on cognition (specifically emotion, affect, motivation, appraisal and evaluation of environmental stimuli). Neuronal damage mediated by NMDA neurotransmission may vary depending on the timing and the intensity, duration and type of stress. Appropriate NMDA stimulation may enhance learning abilities Changing fear…. http://www.nature.com/nature/videoar chive/memory/index.html Recent research on changing fears has examined targeting reconsolidation. (2010)  During reconsolidation, stored information is rendered labile after being retrieved. Pharmacological manipulations at this stage result in an inability to retrieve the memories at later times, suggesting that they are erased or persistently inhibited. Unfortunately, the use of these pharmacological manipulations in humans can be problematic.  Changing fear…. http://www.nature.com/nature/videoar chive/memory/index.html  Through a non-invasive technique to target the reconsolidation of fear memories in humans, Schiller et al provide evidence that old fear memories can be updated with non-fearful information provided during the reconsolidation window. Changing fear….  As a consequence, fear responses are no longer expressed, an effect that lasted at least a year and was selective only to reactivated memories without affecting others.  These findings demonstrate the adaptive role of reconsolidation as a window of opportunity to rewrite emotional memories, and suggest a non-invasive technique that can be used safely in humans to prevent the return of fear.  Schiller D, Monfils M, Raio CM, Johnson D, LeDoux JE, Phelps EA (2010) Blocking the return of fear in humans using reconsolidation update mechanisms. Nature 463:49-53 . Nature AND Nurture In rodents, in comparison with animals reared by low licking ⁄ grooming mothers, the offspring of “good” (high licking) mothers showed: - increased hippocampal NMDA subunit mRNA expression, - enhanced synaptogenesis and improved hippocampal-dependent spatial learning. Bredy et al 2004 About the good enough environment... Reduced maternal care effect on cognitive function can be reversed with peripubertal environmental enrichment. Bredy et al 2003, 2004. Human Studies Nurse-visited children born to mothers with low psychological resources compared with controlgroup counterparts had : -at 6 months of age were less likely to exhibit emotional vulnerability in response to fear stimuli -at 9y/o have better grade-point averages and achievement test scores in math and reading in grades 1 through 3 -as a trend, were less likely to die from birth through age 9, an effect accounted for by deaths that were attributable to potentially preventable causes. Home Visiting by Paraprofessionals and by Nurses: a Randomized, controlled Trial. Olds et al; Pediatrics 2002,2004,2007, 2010. www.nursefamilypartnership.org  Long-term effects of prenatal and infancy nurse home visitation on the life course of youths: 19-year follow-up of a randomized trial.Eckenrode J, Campa M et al. Arch Pediatr Adolesc Med. 2010 EPIGENETICS  It is now common knowledge that humans share the majority (97%)of their genes with monkeys and apes, even worms and mice  The sequencing of the human genome, completed in 2003.  However, the genome itself turns out to have limited value for understanding disease and human characteristics. The real boss?  Scientists are now pinpointing exactly how nurture affects nature.  Life experiences — from toxin exposure to physical affection — can alter gene expression in dynamic and sometimes reversible ways.  http://www.youtube.com/watch?v=ehwFVgQ82ZY  http://kacv.pbslearningmedia.org/resource/biot09.sci .life.gen.epigenetics/epigenetics/ EPIGENETICS The real boss    Epigenome literally means "above the genome." It is a molecular marking system that controls gene expression without altering the DNA sequence. In a sense, the epigenome is the genome's boss.   In the initial weeks after an egg is fertilized — when its cells are rapidly multiplying and developing into something like a full-fledged body — the epigenome acts as an overbearing micro-manager. Each new cell has identical DNA, but the epigenome orders some cells to work as, say, skin cells and others to become neurons. …so how does neuroscience apply to psychotherapy work? ( to relationship…to life…) { Background… Brain circuitry (via synapses and eventually epigenome) is the final (?) common pathway for the ever-expanding set of methods that can be used to alleviate psychological distress. One of them, psychotherapy, can be describe as an interpersonal process designed to bring about modifications of feelings, cognitions, attitudes and behavior which have proved troublesome.” Strupp 1978. Background… Neuronal plasticity is affected by environment not only at the initial establishment of neuronal circuitries of a developing brain, but during our entire life through memory retrieval, (re)- consolidation and rewiring connections. Background… This potential of neuroplasticity has considerable implications when it comes to rehabilitation processes such as psychotherapy. During psychotherapy the “attachment quality” of the therapeutic relationship is critical. Experimental evidence suggests that secure attachment, is associated with reduction in amygdala firing (lessening anxiety) and increases in nucleus accumbens activity (possibly related to enhanced reward representations). Bartels and Zeki 2000,2004. Within the secure attachment achieved through basic psychotherapeutic engagement The new learning is verbal (symbolic) and non verbal (emotional). There is activation of circuits involving explicit and implicit memory & (past) learning (priming, reflex). Mirror Neurons maybe crucial player in -our ability for empathy -our emotional learning and mentalization processes In a secure, coherent therapeutic context: Reactivated schemes are given new implicit (mostly emotional) and explicit (mostly semantic) valences and a new recording of new associations (circuits activation) may take place in a new context. Experiences turns on the (epi)genetic machinery and through the synthesis of new proteins, change and create new brain internal connections. Common factors ? Rosenzweig 1936.  Operation of implicit, non verbal factors?  Formal consistency of the therapeutic ideology as a basis for reintegration?  Alternative formulation of psychological events Neuroplasticity, quality of attachment, mirror neurons qualities, ability to “teach” new emotional and cognitive (symbolic learning)...  “From the perspective of neuroscience, psychotherapy can be understood as a specific kind of enriched environment designed to enhance the growth of neurons and the integration of neural networks” Cozolino, 2010 1. 2. 3. 4. 5. Establishment of a safe and trusting relationship Gaining new information and experiences across the domains of cognition, emotion, sensation, behaviour Simultaneous or alternating activation of neural networks, that are inadequately integrated Moderate levels of stress or emotional arousal alternating with periods of calm and safety. Integration of conceptual knowledge with emotional and bodily experience. “A fragile ego left alone remains fragile. Medication or superficial support alone is not a substitute for the feeling that one is understood by another human being.” Anonymous Thank you ! www.bgrosjean.com "... mental exercise facilitates a greater development of the protoplasmic apparatus and of the nervous collaterals in the part of the brain in use. In this way, pre-existing connections between groups of cells could be reinforced by multiplication of the terminal branches of protoplasmic appendices and nervous collaterals". CAJAL. Royal Society. London 1894.