11/13/2011 1 AAPB Virtual Learning Series 2011 Fred Shaffer, PhD, BCB Truman State University and Saybrook University [email protected]Clinical Update on Brain Anatomy and Physiology Attendees will be able to: 1. explain the significance of neurogenesis and the impact of depression on this process. 2. identify the mirror neuron system’s location, possible function, and possible role in autism. 3. describe the cingulate cortex and insula's locations and hypothesized roles in addiction. 4. explain how injury can result in neuropathic pain.
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Clinical Update Brain Anatomy and Physiology 2011...and Physiology Attendees will be able to: 1. explain the significance of neurogenesis and the impact of depression on this process.
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AAPB Virtual Learning Series 2011
Fred Shaffer, PhD, BCBTruman State University and Saybrook [email protected]
Clinical Update on Brain Anatomy and Physiology
Attendees will be able to:
1. explain the significance of neurogenesis and the impact of depression on this process.
2. identify the mirror neuron system’s location, possible function, and possible role in autism.
3. describe the cingulate cortex and insula's locations and hypothesized roles in addiction.
4. explain how injury can result in neuropathic pain.
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Topic 1: Neurogenesis and depression
Researchers have known for several decades that olfactory receptor neurons are constantly replaced due to their degeneration after several weeks (Costanzo, 1991).
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The “no new neurons” doctrine has been further challenged by the discovery of embryonic stem cells that can differentiate into neurons or glial cells.
Researchers have demonstrated the growth of new neurons in the human hippocampus and olfactory bulb, but not definitively in the neocortex.
If neurogenesis occurs in the adult neocortex, the new neurons may possess the features of interneurons instead of pyramidal neurons (Cameron & Dayer, 2008).
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Depression appears to involve both immune and glucocorticoid responses.
The genesis of depression involves the production of increased pro‐inflammatory cytokines like tumor necrosis factor (TNF) and interleukins (IL‐1 and IL‐6).
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These cytokines suppress neurogenesis, reduce serotonin transmission, and increase production of damaging neurochemicals like glucocorticoids (Hennessy et al., 2009).
Most antidepressants exert anti‐inflammatory effects (Maes et al., 2009).
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High chronic levels of cortisol may suppress neurogenesis in the hippocampus.
Antidepressants may trigger the release of trophic factors like BDNF that promote cellular repair and restore neurogenesis (Julien, Advokat, & Comaty, 2011).
Antidepressants may require neurogenesis to produce behavioral changes (Crupi et al., 2011).
Source: Julien et al. (2011)
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Source: Stahl (2008)
Source: Stahl (2008)
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Hanson et al. (2011) have challenged the neurogenesis hypothesis of depression.
Petrik et al. (2012) have qualified it by proposing that suppression of neurogenesis does not occur in all cases of psychological distress and depression, and that antidepressants do not always promote it.
1. Neurogenesis definitely occurs in the olfactory epithelium, olfactory bulb, and hippocampus, and may occur in the neocortex.
2. Increased production of pro‐inflammatory cytokines and neurotoxic neurochemicals in depression may damage neurons and glial cells,interfere with repair, and suppress neurogenesis.
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3. Effective behavioral and pharmaceutical treatments for depression reduce threatsto neurons and glial cells and reinstate repair via neurotrophins and neurogenesis.
Topic 2: Mirror neuron system and autism
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Researchers have proposed that the human neocortex contains a mirror neuron system that is selectively activated when we perform movements or observe the actions of others.
In humans, this system may encompass Broca’s area, the inferior frontal gyrus, inferior parietal cortex, insular cortex, occipital cortex, premotor cortex, and superior temporal sulcus.
An analysis of 125 published papers by Molenberghs et al. (2011) unexpectedly found neurons with mirroring properties in the cerebellum, limbic system, and primary visual cortex.
The authors proposed that a core network is responsible for the observation and execution of movements.
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The nervous system recruits additional areas to perform non‐motor affective, auditory, and somatosensory functions.
Source: Wikimedia Commons
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Mirror neurons look like other neurons when examined using a microscope. Their mirror properties emerge from their connections among sensory, motor, and emotional systems (Nash, 2011).
Some, perhaps the majority, of our mirror neurons may be tuned by experience (Catmur, Walsh, & Heyes, 2007).
The mirror neuron system appears to encode the goal of a motor act and its component movements, whether a model manipulates an object or mimes the action.
The mirror neuron system encodes actions of others and stores them to predict their future actions (Rajmohan & Mohandas, 2007).
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An immature mirror neuron system may allow babies to imitate their parents’ mouth movements, like thrusting out the tongue, soon after birth.
Modeling of tongue thrustingSource: Wikimedia Commons
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Ramachandran (2010) has called the mirror neurons that are activated when they observe others’ movements, “monkey see—monkey do neurons.”
He calls mirror neurons that are activated by others’ emotional displays, “Gandhi neurons.”
Rizzolatti and Sinigaglia (2006) hypothesized that the primary role of the mirror neuron system is to help us understand others’ intentions, which allows us to achieve empathy.
When we observe others’ facial expressions of emotion, visual information may be directly transmitted to mirror neurons in the insular cortex, producing the visceral changes that color our emotions.
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Empathy emerges from an interaction of the prefrontal cortex, mirror neuron system, and the limbic system.
Empathy involves activation of the amygdala, somatosensory cortex, precuneus, insula, posterior cingulate, ventromedial prefrontal cortex, inferior frontal gyrus, superior temporal sulcus, right inferior parietal lobe, and the anterior cingulate cortex.
In autism, mirror neurons may not fire when observing other individuals performing actions. This may help explain deficits in empathy, social skills, language, and the development of a theory of mind (Enticott et al., 2011).
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However, Dinstein et al. (2010) reported normal mirror neuron responses using an fMRI in their sample of autistic subjects.
Andari and colleagues (2010) recently reported that oxytocin inhalation increased the strength of interaction of 13 high‐functioning subjects in a simulated ball toss game and reported feelings of trust and preference with the most cooperative partner, and lengthened gazing time on the eyes when viewing pictures of faces.
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Brang and Ramachandran (2010) have proposed that the core symptoms of autism may be due to deficient numbers of mirror neurons, congenital olfactory bulb aplasia/dysplasia that reduces oxytocin and vasopressin binding, and temporal lobe epilepsy that disrupts autonomic feedback.
These deficits may impair emotional empathy and introspection.
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1. The mirror neuron system may play a crucial role in observational learning, development of a theory of mind, and empathy.
2. Mirror properties appear to arise from these neurons’ interconnections and not from their structure.
3. The mirror neuron system may be configured by experience.
4. The core symptoms of autism may be due to abnormal development of mirror neuron systems and olfactory bulbs, and temporal lobe epilepsy, that collectively disrupt autonomic feedback.
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Topic 3: The role of the cingulate cortex and insula in addiction
The cingulate cortex (cingulate gyrus) is located in the medial cerebral cortex above the corpus callosum.
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The anterior cingulate cortex plays an important role in attention and is activated during working memory.
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The amygdala, prefrontal cortex, and cingulate cortex are activated when we contemplate moral dilemmas (Green et al., 2001; Pfaff, 2007).
In the footbridge dilemma, would you push a heavy person off a footbridge to stop a runaway trolley that will otherwise kill five people on the track?
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In the lifeboat dilemma, would you push one of six other people on a lifeboat into the icy waters to stop its sinking?
The anterior cingulate cortex mediates emotional and physical pain, and has cognitive (dorsal anterior cingulate) and affective (ventral anterior cingulate) conflict‐monitoring components.
Damage to the anterior cingulate cortex may deprive addicts of warning signals and result in repeated poor decisions that cost them their jobs, marriages, and friendships (Kennerley et al., 2011).
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Garavan (2009) proposed that the posterior cingulate cortex mediates our reactivity to drug cues (sight of drug paraphernalia) and drug cravings.
The orbitofrontal cortex is an area of the prefrontal cortex that lies immediately above the orbits that house the eyes.
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The orbitofrontal cortex may aid planning by evaluating the consequences (rewards and punishments) of our actions and helping to generate the motivation to ingest drugs.
Phineas Gage's profound personality changes were produced by damage to this subdivision and to the ventromedial prefrontal cortex.
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The orbitofrontal cortex appears to adjust decision‐making based on the stakes involved and enables us to switch between important (investments) and trivial (snacks) choices.
The orbitofrontal cortex compares our current choices with recent ones, while the anterior cingulate cortex registers both our predictions and prediction errors (Kennerley et al., 2011).
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These are the four lobes of the brain that can be observed from the brain’s surface.
In contrast, the insular cortex lies deep within the lateral sulcus that divides the temporal and parietal lobes.
Source: Wikimedia Commons
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It is the primary taste cortex and it is activated when you see something that disgusts you (a fraternity bathroom) or when you view another person’s expression of disgust (literally, bad taste).
The insular cortex has been implicated in the experience of pain and basic emotions, including anger, disgust, fear, happiness, and sadness.
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The insular cortex is activated by frightening pictures (Schienle et al., 2002) and angry faces Fusar‐Poli et al., 2009).
The anterior insula is activated by pictures of lovers as opposed to friends.
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Damasio (2010) proposed that this region helps map visceral states associated with emotional experience and generates conscious feelings.
This could provide the basis of somatic markerslike the discomfort produced by a risky decision.
The insular cortex receives reports of internal states, like hunger and drug craving, and motivates individuals to engage in consummatory behavior.
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In studies of gambling, subjects took fewer chances after taking a risk (independent of the odds of winning or losing).
fMRI data showed that the insula was more active after subjects gambled than when they passed on a gamble (Xue et al., 2010).
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In neuroeconomic studies, when the anterior insula was activated, subjects chose risk‐avoidant financial strategies (choosing bonds instead of stocks).
In the Prisoner’s Dilemma game, mutually cooperative decisions also resulted in activation of this region.
The insular cortex is stimulated by drug‐related cues. It may produce conscious awareness of the aversive feelings produced by drug withdrawal and may activate memories of pleasurable drug‐related experiences.
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The insular cortex is activated by urges for alcohol, cocaine, heroin, marijuana, and nicotine (Garavan, 2009).
Stroke damage to the insular cortex can eliminate nicotine addiction (Naqvi et al., 2007).
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1. The cingulate cortex is located within the medialcerebral cortex and provides feedback regardingwhether the outcomes of our decisions matchedour expectations.
2. The insular cortex lies deep within the lateral sulcus and helps to generate our consciousemotions, somatic markers, and cravingto acquire and ingest addictive drugs.
Topic 4: Injury and neuropathic pain
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Nociceptors are peripheral receptors that respond to painful stimuli.
Free nerve endings in the dermis have specialized receptor proteins that respond to temperature changes, chemicals, and pain.
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A‐δ and C fibers transmit pain information to the dorsal horn of the spinal cord and comprise the anterolateral (spinothalamic system).
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Pain information crosses the midline in the spinal cord and ascends to the thalamus.
Peripheral fibers release glutamate to excite spinal cells in the dorsal horn.
They also release substance P (peptide) to postsynaptic neurons, resulting in dendritic remodeling, possibly influencing pain perception (Li & Tator, 2000).
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After peripheral nerve injury (amputation or back trauma), microglial cells that enclose the synapse between pain afferents and dorsal horn neurons release brain derived neurotrophic factor (BDNF).
BDNF excites the dorsal horn neurons and reverses their response to GABA and glycine (causing both to activate them), amplifying their response to pain signals (Coull et al., 2005; Milligan & Watson, 2009).
This results in allodynia, a neuropathic pain syndrome where nonpainful stimuli, like light touch, elicit severe pain.
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Dorsal horn neurons now overwhelm the thalamus with pain messages.
Chronic pain may structurally reroute neuronal connections in the dorsal horn of the spinal cord.
Both structural reorganization of the dorsal horn and volume transmission (extrasynapticrelease) of neurotransmitters may contribute to the spread of pain beyond the site of injury.
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Flor et al. (2006) proposed that some of the pain amplification also takes place in the cortex and can be reduced through behavioral interventions.
Chronic pain can accelerate the loss of gray matter. Low back pain patients show 1.3 mm3
more dorsolateral prefrontal cortex shrinkage a year than normal.
This is comparable to 10‐20 years of ordinary aging (Apkarian et al., 2004).
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1. Neuropathic pain involves sensitization of dorsal horn neurons and cortical remodeling.
2. Untreated neuropathic pain can greatly accelerate shrinkage of the dorsolateral prefrontal cortex.
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3. Effective treatment of neuropathic pain should emphasize prevention of sensitization through biofeedback, neurofeedback, physical therapy, and pharmaceutical interventions.
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