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Targeting abnormal neural circuits
in mood and anxiety disorders:
from the laboratory to the clinic
Kerry J Ressler & Helen S Mayberg
VOLUME 10 NUMBER 9
SEPTEMBER 2007
1116-1124
NATURE NEUROSCIENCE 14.805, for 2006; 4th of 341 neuroscience journals
http://www.nature.com.libaccess.lib.mcmaster.ca/neuro/index.html
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Kerry J. Ressler MD, Ph.D
Assistant Professor of Psychiatry and Behavioral
Sciences
1- Department of Psychiatry and Behavioral Sciences, Emory University, School
of Medicine, Atlanta, Georgia
2- Yerkes National Primate Research Center
http://userwww.service.emory.edu/~kressle/
http://userwww.service.emory.edu/~kressle/kerry.htm
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B.S. in molecular biology@ M.I.T.
PhD (1995) Department of Neurobiology, Harvard University
M.D. (1997) Harvard School of Medicine
Residency in Psychiatry at Emory University School of Medicine
Research fellow with Dr. Michael Davis at Emory
studying behavioral neuroscience
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Dr. Ressler's lab at Yerkes Research Center is focused onthe molecular and cellular mechanisms of fear learning
and the process of extinction of fear in mouse models. He
hopes that by understanding how fear works in the brain,
it will improve our understanding of and advancetreatments for fear-based disorders, such as PTSD and
Panic Disorder.
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The goal of my laboratory is to create a program whichutilizes the enormous power of molecular biology to
approach difficult and important questions in systems
neuroscience.
I use genes known to be involved in synaptic plasticity to
examine plasticity in the amygdala and regions whichconnect with it during the consolidation phase of fear
memory formation.
http://www.emory.edu/NEUROSCIENCE/facultyprofiles_Z.html
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I am also initiating a program to create transgenic animal
models for visualizing the amygdala neurons, some of its
sensory inputs and the neuromodulatory projections which
together mediate some of the important behavioralresponses of fear and stress.
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During his clinical time, Dr. Ressler is co-director
with Dr. Ann Schwartz of the newly created Post-traumatic Stress Disorders Clinic at the Adult
Outpatient Psychiatry Clinic at Grady Memorial
Hospital.
Dr. Ressler was recently nominated as an Investigatorwith the Howard Hughes Medical Institute.
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Helen S Mayberg M.D., FRCPC
Professor of Psychiatry & Neurology
http://en.wikipedia.org/wiki/Helen_S._Mayberg
http://neurology.emory.edu/Faculty/Mayberg.htm
1- Department of Psychiatry and Behavioral Sciences, Emory University,School of Medicine, Atlanta, Georgia
2- Department of Neurology, Emory University, School of Medicine, Atlanta,
Georgia
She is also affiliated with Rotman Research Institute at Baycrest Centre and the
Departments of Psychiatry and Neurology, University of Toronto
http://en.wikipedia.org/wiki/Helen_S._Mayberghttp://neurology.emory.edu/Faculty/Mayberg.htmhttp://neurology.emory.edu/Faculty/Mayberg.htmhttp://en.wikipedia.org/wiki/Helen_S._Mayberg8/14/2019 Ressler KJ, et al. PPT.ppt
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Born in 1956 in California
B.A. (1976) Psychobiology @ UCLA
M.D. (1981) University of Southern California
University of California, Irvine Graduate studies: Departmentof Radiological Sciences
Residency (1985) @ Columbia Universitys Neurological
Institute in New York City
Research fellowship (1987) at Johns Hopkins Universitys PET
facility from
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Research Focus
My research concerns the characterization of neural
systems mediating mood and emotions in health anddisease using functional neuroimaging.
Defining brain mechanisms underlying major
depression is the primary goal, with an emphasis on
development of algorithms that will discriminatepatient subgroups, optimize treatment selection, and
provide markers of disease vulnerability.
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INTRODUCTIONMajor depressive disorder (MDD) is the most common of allpsychiatric disorders.
MDD ranks among the top causes of worldwide diseaseburden and disability, with lifetime risk of 712% in menand 2025% in women.
20% completely fail to SSRIs, 60% may not achieveadequate response.
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The different anxiety disorders, including panic disorder,
post-traumatic stress disorder (PTSD) and phobias, are
also extremely common, with a combined lifetimeprevalence of over 28%, and with a similar societal cost-
burden with similar rates of failure to respond to
treatment with that in MDD.
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In this review, MDD and anxiety disorders will be
considered together:
1- comorbidity
2- a significant problem of diagnostic classificationwith highly overlapping symptom criteria
3- similar involved brain circuits
4- similar treatments (e.g., SSRIs, CBT)
Current clinical descriptions are probably not
identifying the phenotypic clusters of disorders
that may be most useful from a neurobiological
and treatment perspective.
Problem in current clinical descriptions!
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There are several circuits within the limbic-cortical
system that mediate
-Stress responsiveness
- Mood and emotional regulation.
Disorders of mood and anxiety represent brain-baseddisorders that lead to dysregulation of these circuits.
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New neurostimulatory therapiesbased on progress inunderstanding emotion circuitryand new
pharmacological therapiesbased on understandingemotional learningare likely to provide more rapid androbust methodologies for treating MDD and anxietydisorders.
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1- Abnormal circuit modulation in mood and
anxiety disorders
PET and fMRI studies have examined differences in
brain regional activation in depressed and anxious
subjects relative to controls and in patients before
and after treatment.
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Many brain areas may underlie some of the differentsymptom clusters of depression.
nucleus accumbensalong with other areasinvolved in reward processing, are also likely to beinvolved in the anhedonic components ofdepression.
http://en.wikipedia.org/wiki/Nucleus_accumbens
http://www.biopsychiatry.com/nucleus-accumbens.htm
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The areas most reproducibly found to be dysregulated in
common emotional disorders are the prefrontal cortex(PFC) and subgenual cingulate cortex (Cg25), whichseem to be involved in emotion experience andprocessing,
as well as
the hippocampusandamygdala, which are involved inemotional memory formationand memory retrieval.
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Review focuses on:
role of Cg25 in emotion regulation and processing, therole of the amygdala in emotional memory formation and
expression.
1 = BA25 (subcallosal gyrus),
2 = BA24sg (SGPFC)
3 = BA32 (paracingulate gyrus)
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Cg25 is involved in the production of sad
emotions and in antidepressant treatment
response.
activated during transient sadness
Decreased activity in Cg25 after treatment, even after
placebo. Also in social phobia.
Activity in Cg25 before treatment predicts treatment
response with CBT.
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A- Transient sadness in healthy
volunteers increases activity in Cg25
measured by PET
B- Decreased Cg25 activity with chronic
fluoxetine treatment for MDD.
C- Cg25 decrease in recovery with chronic
fluoxetine from Parkinsons disease
related depression.
D- Natural recovery with decreased Cg25
activity in patients treated with placebo.
E- Predictors of response in subjects
responding to CBT for depression included
low pretreatment Cg25 activity.
F- Subgenual cortical decreased activity
was common in responders compared with
nonresponders for those responding both
to citalopram and CBT for social phobia.
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Overactivation of the amygdala is also implicated indepression and anxiety.
Amygdala activation decreases with recovery frommood symptoms.
Studies that implicate Cg25 also find significantamygdala decreases with response to CBT treatment forsocial phobia.
http://www.psycheducation.org/emotion/amygdala.htm
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A genetic polymorphism has repeatedly beenimplicated in gene by environment interactions fordisorders of emotional dysregulation: the serotonin
promoter polymorphism 5-HTTLPR.
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Takahashi T, Suzuki M, Kawasaki Y, Hagino H, Yamashita I, Nohara S, Nakamura K, Seto H, Kurachi M.Biol Psychiatry.
Perigenual cingulate gyrus volume in patients with schizophrenia: a magnetic resonance imaging study. 2003;53:593-600.
Carriers of the risk-conferring 5-HTTLPR
polymorphism have reduced gray matter volume
in the perigenulate regionsurrounding Cg25 aswell as in the amygdala.
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prefrontal-limbic circuits, the Cg25 and amygdala
areas in particular, may be critically involved in
emotional processing and regulation in mood and
anxiety disorders.
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2- Neurostimulation therapies modulate
dysregulated circuits
Several somatic therapies, available or under
investigation, may modulate the disrupted circuit activity.Vagus nerve stimulation therapy(VNS)
Transcranial magnetic stimulation(TMS)
Magnetic seizure therapy (MST)
Deep brain stimulation (DBS)
Deep Brain Stimulation for Treatment-Resistant Depression: An ExpertInterview With Helen S. Mayberg, MD@http://www.medscape.com/viewarticle/520659
Posted 01/05/2006
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VNSapproved by the FDA for treatment of medication-resistant
depression and was approved earlier for the treatment ofepilepsy.
Promising but long-term efficacy in refractory patients stillremains to be demonstrated.
Mechanism: may help correct dysfunctionalneurotransmitter modulatory circuits in patients withdepression.
the nucleus of the tractus solitarius
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Functional imaging suggests that VNS leads to acute
changes in hypothalamus, orbitofrontal cortex,amygdala,hippocampus, insula, medial prefrontalcortexand cingulate cortex.
Chronic VNS treatment leads to significant
ventromedial prefrontal cortex deactivation, similarlyto other approaches to depression treatment.
Low rates of relapse, well-tolerated
VNS may be an important adjunct for
refractory depression.
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TMS
Repetitive transcranial magnetic stimulation (rTMS) andelectroconvulsive therapy (ECT) are both somatic
treatments relying upon altering local and distant neural
circuits within the brain.
rTMS is also potentially useful as a probe for
understanding brain activity changes with response to
treatment with rTMS and ECT.
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When PET and TMS combined it was seen that,
Baseline hypometabolism responds better to high-
frequency stimulation that seems to enhance excitability,
Baseline hypermetabolism responds better to low-
frequency stimulation that seems to dampen excitability.
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In preclinical studies, rTMS modulates neuralcircuits and neurotransmitter systems thought to beinvolved with mood regulation.
rTMS modulates cortical -adrenergic receptors,
serotonergic receptors in frontal cortex, and increasesNMDA receptors in hypothalamus and basolateral
amygdala.
Furthermore, rTMS at 10 Hz in a rat model of depressionleads to enhanced hippocampal plasticity after stress.
rTMS acutely modulates dopamine and serotonin levels.
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MST
involves the induction of relatively focal seizureactivityusing focused magnetic stimulation.
MST seems to offer greater control of intracerebralcurrent intensity than is possible with ECT and thus
may result in fewer cognitive side effects.
.
Relatively new May 2000. in Switzerland. But yetpromising as it has the ability to focally stimulate
cortical areas. It will provide a new tool to dissectthe critical circuitry involved in recovery fromdepression.
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DBS
Parkinsons disease
DBS may also modulate disorders of emotion, in
addition to its known role in treating disorders of
motion.
DBS targeting the left caudate may lead to recovery
from depressive symptoms.
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BA25 has been investigated in treatment-resistant
depressive patients more extensively.
DBS can reduce elevated BA25 activity. Distal effects on
remote cortical and brainstem areas might arise from
indirectly from BA25 or directly from the WM tractspassing through the field of stimulation.
Early data on DBS suggest that it might be a
powerful tool to specifically target dysregulatedneural circuits.
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3- Pharmacological therapies to modulate
emotional learning
3a-Enhancing extinction of fear
3b- Preventing consolidation of traumatic
memories
3c-Preventing reconsolidation of traumatic
memories
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3a- Enhancing extinction of fear
From an operational perspective,
Extinction may thus be defined as
a reduction in the strength or probability of a
conditioned fear response as a consequence ofrepeated presentation of the conditioned stimulusin the absence of the UCS.
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Extinction is a form of learning and not unlearning or
the forgetting of a conditioned association so why not
enhance the neurotranmission of NMDA receptors
the D-Cycloserine(DCS) partial NMDA agonist, used in
the treatment of tuberculosis, potential use in facilitating
extinction-based therapies for human anxiety disorders.
Subjects receiving DCS (one dose) showed greater decreases
in physiological measure of anxiety. Placebo-compared
trials also showed promising results in favor of DCS in
patients with anxiety.
Seromycin
http://www.coccyx.org/treatmen/cycloser.htm
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3b- Preventing consolidation of traumatic
memories
With certain disorders, notably PTSD, the time of the
insult that created the disorder is knownit is when
the initiating trauma occurred.
Memories do not immediately become permanent atthe time of the initial experience.
Instead they exist in a labile state for at least hours
and possibly days, during which they becomeconsolidated into a more permanent memory.
There is a host of in vitro and in vivo data in
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There is a host of in vitro and in vivo data in
animals outlining the molecular, synaptic,
neurotransmitter and systems-level changes that
may occur during this consolidation process.
TraumaLabile memoriesConsolidation of memories (after
hours/days)Labile again when recalled = Reconsolidation
(following retrieval)
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Differential memory systems are encoding differentaspects of a memory in parallel.
Declarative memory systems [hippocampal-corticalpathways]
are likely to be encoding the what, when and where ofan event,
in parallel
amygdala-cortical pathways are encoding the emotional
salience and aversiveness of the memory.
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Therefore, agents that block the emotionaloverconsolidation of a traumatic memory perhaps
could preserve the declarative aspects of the samememory. This idealized approach would not render thepatient fully amnestic, but would potentially preventPTSD.
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Fear consolidation is blocked after training by anantagonist of noradrenergic activation.
Propranolol, a common -blocker used for
hypertensioncan block central 1 and 2 adrenergic
receptors.
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Patients after a trauma (motorcyle accident) tookpropranolol and placebo for 10 days.
After 1 month; patients who were on propranolol
PTSD measures trended lower, as well as
physiological symptoms of PTSD.
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Another consolidation-blockade approach is basedon the findings that lower cortisol levels after
trauma predict subsequent PTSD.
Glucocorticoids are involved in emotional memoryencoding and retrieval and high doses ofglucocorticoids decrease the catecholamine.
Early data with small # of subjects support thatwhen cortisol given after the trauma it decreasesthe number of subjects with PTSD.
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Every memory recall event is accompanied by
competition between molecular events that strengthen
the original memory (reconsolidation) and those thatinhibit that memory (extinction).
By differentially enhancing or inhibiting these
processes, opposing effects on the state of the existingfear memories may be obtained.
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Other neuromodulators including dopamine andglutamate-NMDA receptor activation are
implicated in the consolidation of fear memories.This work remains in its early stages, but there isroom for optimism.
In emergency rooms, in the future, on the battlefield orafter a disaster the early routine medical interventionsin later PTSD prevention may be as important as theones we do after stroke and MI today.
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3c- Preventing reconsolidation of traumatic
memories
Memories remain labile and associative when they arerecalled.
Reactivated memories are also sensitive to
pharmacological disruption.
Local infusion of protein synthesis inhibitors into discretebrain regions prevents the reconsolidation of the memory,but do not cross the blood-brain barrier easily, so unlikely
to be used in humans.
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More benign drugs, given in animals acutely with
recall of fear memories, may also act to reduce
later memory expression, possibly through
inhibiting reconsolidation mechanisms.
NMDA receptor agonists
-adrenergic antagonists timolol or propranolol
block reconsolidation, and thus may serve as
useful agents in future human studies of
reconsolidation.
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Reconsolidation occurs for recently learned memories
but not distant memories.
Propranololhas not been reported to block
reconsolidation in humans, as the initial report about
animals was a decade ago but it is safe to try in humans
as well.
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Disrupting the remote memories from chronic PTSD maynot be possible using reconsolidation-impairing
approaches.
Extinction of fearmay eventually be optimal in more
chronic cases.
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Conclusions
This is a very exciting time in the fields of learningand memory and psychiatry, because the growingliterature on the differential processes involved inmemory formation are now increasingly amenable to
translational human studies.
This review has focused on recent developments in
understanding the neural circuit processes
underlying mood and anxiety disorders.
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It is hoped that recent progress in understanding theneurobiology of emotional regulation anddysregulationwill lead to powerful and exciting new
treatments for mood and anxiety disorders.
New experimental treatments may alleviate symptomsthrough the correction of dysregulated circuitactivityas well as prevent overlearning or enhance
extinction learningin circuits mediating negativeemotional memories.
CREDITS
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Casting
Margaret
McKinnon
PhD
Title
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Margaret
McKinnon
PhD
Cathy
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