Targeting abnormal neural circuitsTargeting abnormal neural circuits in mood and anxiety disorders: in mood and anxiety disorders: from the laboratory to the clinicfrom the laboratory to the clinic

Kerry J Ressler & Helen S MaybergKerry 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

Kerry J. Ressler MD, Ph.DKerry J. Ressler MD, Ph.D

Assistant Professor of Psychiatry and Behavioral Assistant Professor of Psychiatry and Behavioral SciencesSciences

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

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 Emorystudying behavioral neuroscience

Dr. Ressler's lab at Yerkes Research Center is focused on the 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 advance treatments for fear-based disorders, such as PTSD and Panic Disorder.

The goal of my laboratory is to create a program which utilizes 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 which connect with it during the consolidation phase of fear memory formation.

http://www.emory.edu/NEUROSCIENCE/facultyprofiles_Z.html

I am also initiating a program to create transgenic animal I am also initiating a program to create transgenic animal models for visualizing the amygdala neurons, some of its models for visualizing the amygdala neurons, some of its sensory inputs and the neuromodulatory projections sensory inputs and the neuromodulatory projections which together mediate some of the important behavioral which together mediate some of the important behavioral responses of fear and stress. responses of fear and stress.

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 Dr. Ressler was recently nominated as an Investigator with the Howard Hughes Medical Investigator with the Howard Hughes Medical InstituteInstitute..

Helen S Mayberg M.D., FRCPC Helen S Mayberg M.D., FRCPC

Professor of Psychiatry & NeurologyProfessor of Psychiatry & Neurologyhttp://en.wikipedia.org/wiki/Helen_S._Mayberghttp://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

Born in 1956 in CaliforniaBorn in 1956 in California

B.A. (1976) Psychobiology @ UCLAB.A. (1976) Psychobiology @ UCLA M.D. (1981) University of Southern California M.D. (1981) University of Southern California

University of California, Irvine Graduate studies: University of California, Irvine Graduate studies: Department of Radiological SciencesDepartment of Radiological Sciences

Residency (1985) @ Columbia University’s Neurological Residency (1985) @ Columbia University’s Neurological Institute in New York CityInstitute in New York City

Research fellowship (1987) at Johns Hopkins University’s Research fellowship (1987) at Johns Hopkins University’s PET facility from PET facility from

Research FocusResearch FocusMy research concerns the characterization of neural systems mediating mood and emotions in health and disease using functional neuroimaging.  Defining brain mechanisms underlying major brain mechanisms underlying major depressiondepression is the primary goal, with an emphasis on development of algorithms that will discriminate patient subgroups, optimize treatment selection, and provide markers of disease vulnerability. 

INTRODUCTIONMajor depressive disorder (MDD) is the most common of all psychiatric disorders.

MDD ranks among the top causes of worldwide disease burden and disability, with lifetime risk of 7–12% in men and 20–25% in women.

20% completely fail to SSRIs, 60% may not achieve adequate response.

The different anxiety disorders, including panic disorder, post-traumatic stress disorder (PTSD) and phobias, are also extremely common, with a combined lifetime prevalence of over 28%, and with a similar societal cost-burden with similar rates of failure to respond to treatment with that in MDD.

In this review, MDD and anxiety disorders will be considered together:1- comorbidity2- a significant problem of diagnostic classification with highly overlapping symptom criteria3- similar involved brain circuits4- 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!Problem in current clinical descriptions!

There are several circuits within the limbic-cortical system that mediate-Stress responsiveness- Mood and emotional regulation.

Disorders of mood and anxiety represent brain-based disorders that lead to dysregulation of these circuits.

New neurostimulatory therapiesNew neurostimulatory therapies based on progress in understanding emotion circuitryemotion circuitry and new new pharmacological therapiespharmacological therapies based on understanding emotional learningemotional learning are likely to provide more rapid and robust methodologies for treating MDD and methodologies for treating MDD and anxiety disordersanxiety disorders.

1- Abnormal circuit modulation in mood 1- Abnormal circuit modulation in mood and anxiety disordersand 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.

Many brain areas may underlie some of the different symptom clusters of depression.

nucleus accumbens along with other areas involved in reward processing, are also likely to be involved in the anhedonic components of depression.

http://en.wikipedia.org/wiki/Nucleus_accumbenshttp://www.biopsychiatry.com/nucleus-accumbens.htm

The areas most reproducibly found to be dysregulated in common emotional disorders are the prefrontal cortex (PFC) and subgenual cingulate cortex (Cg25),, which seem to be involved in emotion emotion experience and processingexperience and processing, as well as the hippocampushippocampus and amygdalaamygdala, which are involved in emotional memory formationemotional memory formation and memory memory retrievalretrieval.

Review focuses on:role of Cg25 in emotion regulation and processing, the role of the amygdala in emotional memory formation andexpression.

1 = BA25 (subcallosal gyrus),

2 = BA24sg (SGPFC)

3 = BA32 (paracingulate gyrus)

Cg25 is involved in the production of sad Cg25 is involved in the production of sad emotions and in antidepressant treatment emotions and in antidepressant treatment response.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.

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 Parkinson’s 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.

Overactivation of the amygdala is also implicated in depression and anxiety.

Amygdala activation decreases with recovery from mood symptoms.

Studies that implicate Cg25 also find significant amygdala decreases with response to CBT treatment for social phobia.

http://www.psycheducation.org/emotion/amygdala.htm

A genetic polymorphism has repeatedly been implicated in gene by environment interactions for disorders of emotional dysregulation: the the serotonin promoter polymorphism 5-HTTLPRserotonin promoter polymorphism 5-HTTLPR.

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-HTTLPRpolymorphism have reduced gray matter volume in the perigenulate regionperigenulate region surrounding Cg25 as well as in the amygdalaamygdala.

prefrontal-limbic circuits, the Cg25 and amygdala areas in particular, may be critically involved in emotional processing and regulation in mood and anxiety disorders.

2- Neurostimulation therapies modulate 2- Neurostimulation therapies modulate dysregulated circuitsdysregulated circuits

Several Several somatic therapiessomatic therapies, available or under , available or under investigation, may modulate the disrupted circuit investigation, may modulate the disrupted circuit

activity.activity. Vagus nerve stimulation therapyVagus nerve stimulation therapy (VNS)

Transcranial magnetic stimulationTranscranial magnetic stimulation (TMS)

Magnetic seizure therapyMagnetic seizure therapy (MST)

Deep brain stimulationDeep brain stimulation (DBS)

Deep Brain Stimulation for Treatment-Resistant Depression: An Expert Interview With Helen S. Mayberg, MD @http://www.medscape.com/viewarticle/520659Posted 01/05/2006

VNSVNSapproved by the FDA for treatment of medication-resistantdepression and was approved earlier for the treatment of epilepsy.Promising but long-term efficacy in refractory patients still remains to be demonstrated.Mechanism: may help correct dysfunctional neurotransmitter modulatory circuits in patients with depression.

the nucleus of the tractus solitarius

Functional imaging suggests that VNS leads to acute changes in hypothalamus, orbitofrontal cortex, amygdala, hippocampus, insula, medial prefrontal cortex and cingulate cortex.

Chronic VNS treatment leads to significant ventromedial prefrontal cortex deactivation, similarly to other approaches to depression treatment.

Low rates of relapse, well-tolerated

VNS may be an important adjunct for VNS may be an important adjunct for

refractory depression.refractory depression.

TMSTMSRepetitive transcranial magnetic stimulation (rTMS) and electroconvulsive 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.

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.

In preclinical studies, rTMS modulates neural circuits and neurotransmitter systems thought to be involved with mood regulation.

rTMS modulates cortical β-adrenergic receptors, serotonergic receptors in frontal cortex, and increases NMDA receptors in hypothalamus and basolateral amygdala.

Furthermore, rTMS at 10 Hz in a rat model of depression leads to enhanced hippocampal plasticity after stress.

rTMS acutely modulates dopamine and serotonin levels.

MSTMSTinvolves the induction of relatively focal seizure activity using focused magnetic stimulation.

MST seems to offer greater control of intracerebral current intensity than is possible with ECT and thus may result in fewer cognitive side effects.

.

Relatively new May 2000. in Switzerland. But yet promising as it has the ability to focally stimulate cortical areas. It will provide a new tool to dissect the critical circuitry involved in recovery from depression.

DBSParkinson’s disease

DBS may also modulate disorders of emotion, DBS may also modulate disorders of emotion, in addition to its known role in treating in addition to its known role in treating disorders of motiondisorders of motion.

DBS targeting the left caudate may lead to recovery from depressive symptoms.

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 tracts passing through the field of stimulation.

Early data on DBS suggest that it might be a powerful tool to specifically target dysregulated neural circuits.

3- Pharmacological therapies to 3- Pharmacological therapies to modulate emotional learningmodulate emotional learning

3a-3a-Enhancing extinction of fear

3b- Preventing consolidation of traumatic Preventing consolidation of traumatic memoriesmemories

3c-Preventing reconsolidation of traumatic Preventing reconsolidation of traumatic memoriesmemories

3a- Enhancing extinction of fear3a- 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 of repeated presentation of the conditioned stimulus in the absence of the UCS”.

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

3b- Preventing consolidation of traumatic 3b- Preventing consolidation of traumatic memoriesmemories

With certain disorders, notably PTSD, the time of the insult that created the disorder is known—it is when the initiating trauma occurred.

Memories do not immediately become permanent at the time of the initial experience.

Instead they exist in a labile state for at least hours and possibly days, during which they become consolidated into a more permanent memory.

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.

Trauma Labile memories Consolidation of memories (after hours/days) Labile again when recalled = Reconsolidation (following retrieval)

Differential memory systems are encoding different aspects of a memory in parallel.

Declarative memory systems [hippocampal-cortical pathways]are likely to be encoding the ‘what, when and where’ of an event,in parallelamygdala-cortical pathways are encoding the emotionalsalience and aversiveness of the memory.

Therefore, agents that block the ‘emotional overconsolidation’ of a traumatic memory perhapscould preserve the declarative aspects of the same memory. This idealized approach would not render the patient fully amnestic, but would potentially prevent PTSD.

Fear consolidation is blocked after training by an antagonist of noradrenergic activation.

Propranolol, a common β-blocker used for hypertensioncan block central β 1 and β 2 adrenergic receptors.

Patients after a trauma (motorcyle accident) took propranolol and placebo for 10 days.After 1 month; patients who were on propranolol PTSD measures trended lower, as well as physiological symptoms of PTSD.

Another consolidation-blockade approach is based on the findings that lower cortisol levels after trauma predict subsequent PTSD.

Glucocorticoids are involved in emotional memory encoding and retrieval and high doses of glucocorticoids decrease the catecholamine.

Early data with small # of subjects support that when cortisol given after the trauma it decreases the number of subjects with PTSD.

Every memory recall event is accompanied by competition between molecular events that strengthen the original memory (reconsolidation) and those that inhibit that memory (extinction).

By differentially enhancing or inhibiting these processes, opposing effects on the state of the existing fear memories may be obtained.

Other neuromodulators including dopamine and glutamate-NMDA receptor activation are implicated in the consolidation of fear memories. This work remains in its early stages, but there is room for optimism.

In emergency rooms, in the future, on the battlefield or after a disaster the early routine medical interventions in later PTSD prevention may be as important as the ones we do after stroke and MI today.

3c- Preventing reconsolidation of 3c- Preventing reconsolidation of traumatic memoriestraumatic memories

Memories remain labile and associative when they are recalled.

Reactivated memories are also sensitive to pharmacological disruption.

Local infusion of protein synthesis inhibitors into discrete brain regions prevents the reconsolidation of the memory, but do not cross the blood-brain barrier easily, so unlikely to be used in humans.

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 agonistsβ-adrenergic antagonists timolol or propranolol

block reconsolidation, and thus may serve as useful agents in future human studies of reconsolidation.

Reconsolidation occurs for recently learned memories but not distant memories.

Propranolol has 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.

Disrupting the remote memories from chronic PTSD may not be possible using reconsolidation-impairing approaches.

Extinction of fear may eventually be optimal in more chronic cases.

ConclusionsThis is a very exciting time in the fields of learning and memory and psychiatry, because the growing literature on the differential processes involved in memory formation are now increasingly amenable totranslational human studies.

This review has focused on recent developments in understanding the neural circuit processes underlying mood and anxiety disorders.

It is hoped that recent progress in understanding understanding the neurobiology of emotional regulation and the neurobiology of emotional regulation and dysregulationdysregulation will lead to powerful and exciting new treatments for mood and anxiety disorders.

New experimental treatments may alleviate symptoms through the correction of dysregulated correction of dysregulated circuit activitycircuit activity as well as prevent overlearning or prevent overlearning or enhance extinction learningenhance extinction learning in circuits mediating negative emotional memories.

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