+

PTSD and Abnormal N-acetylaspartate Levels in

Hippocampus and Anterior Cingulate Cortex

Kimberly Sitter

+What is PTSD? (DSM-V)

Criterion A: stressor

Criterion B: intrusive symptoms

Criterion C: avoidance

Criterion D: negative alterations in cognitions and mood

Criterion E: alterations in arousal and reactivity

Criterion F: Persistence (in Criteria B, C, D, E) for >1 month

Criterion G: functional significance

+Who has PTSD?

Veterans

Children (extended in DSM-V)

Rape Victims

Survivors of Natural Disasters

+Effects of PTSD

Society:

$42.3 billion to anxiety disorders annually

Effects on individuals (CVD, Depression)

7.7 million Americans age 18+

Individual:

Substance Abuse

Depression and Anxiety

Eating Disorders

Self-harm/Suicide

Other Mental Health Issues

+Treatment Options

Cognitive Therapy, Exposure Therapy, Eye movement

desensitization and reprocessing (EMDR)

Medications (for symptoms of the disorder)

Depression: Antidepressants (SSRIs), Zoloft, Paxil

Anxiety: Anti-anxiety meds (short term)

Insomnia: Prazosin

Further research on biopsychological underpinnings of the

disorder help to elucidate effectiveness of treatments and better

treatment options

+Brain Abnormalities of PTSD

Volumetric reduction of brain structures (hippocampus,

amygdala, anterior cingulate cortex)

Effects: Working Memory, Fear condition/extinction

Higher Glucocorticoids (BDNF) and increased cell sensitization

Effects: deficits in short-term memory loss

Decreased levels NAA

+Role of Anterior Cingulate Cortex

and Hippocampus in PTSD

Anterior Cingulate Cortex:

ACC and medial prefrontal cortex postulated to modulate amygdala

during anxiety

Abnormal relay of information to hippocampus, amygdala, and

sensory cortex plays a role in failure of extinction

Hippocampus:

vital in declarative memory and organizes episodic memories

Low Hippocampal volume associated with severe re-experience

symptoms in PTSD subjects

+N-Acetylasparte(or N-acetylaspartic acid) (abbrev. NAA)

Derived from aspartic acid

C6H9NO5

Molecular weight: 175.139

Synthesized from aspartic acid and acetyl-CoA

NAA second most concentrated molecule in the brain

Many functions in the brain

*NAA a neuronal marker in cell bodies *(MRS)

Levels in hippocampus related to WM performance

Possible neurotransmitter on glutamate receptors

+Magnetic Resonance Spectroscopy

(MRS)

An in vivo non-invasive and radioactive free procedure

Used to study metabolic changes in the brain due to damage or

disease

Related to Magnetic Resonance Imaging (MRI)

both techniques use signals from hydrogen protons

MRI creates 2-D image of brain

MRS uses H1 signals to determine relative concentrations of

target brain metabolites (i.e. NAA)

Other names: MRSI (Magnetic Resonance Spectroscopic

Imaging) or Proton Magnetic Resonance Spectroscopy

+Study 1: Decreased N-acetyl-aspartate levels in anterior

cingulate and hippocampus in subjects with post-traumatic stress

disorder: a proton magnetic resonance spectroscopy study

Authors: Ham, B., Chey, J., Yoon, S.J., Sung, Y., Jeong, D.,

Kim, S.J., Sim, M.E., Choi, N., Choi, I., Renshaw, P.F., Lyoo,

I.K.

Purpose: study relationship of NAA levels in the brain with

clinical presentations of PTSD in subjects

Hypothesis: find decreased NAA levels in ACC and

hippocampus in PTSD subjects, and level of NAA decrease

would correlate with severity of symptoms

+Study 1: Methods

Participants:

N=26; survivors of a subway fire in Taegu, South Korea

N=25; sex-matched healthy comparison subjects

Requirements:

Uniform trauma: initially trapped inside two burning trains

PTSD Diagnosis: Structured Clinical Interview for DSM-IV

Symptom Severity: Structured Clinician Administered PTSD scale (CAPS) for DSM-IV, Hamilton Depression Rating Scale (1960), Hamilton Anxiety Rating Scale (1959)

(9) Exclusion Criteria: illness; injury resulting from trauma; loss of consciousness; axis I psychiatric disorders; antisocial or borderline personality disorders; lifetime exposure to any substances other than nicotine, caffeine, or social drinking; childhood ADHD; IQ <80; “contraindictions” to MR scanning

+Study 1: Subject Demographics

PTSD Subject Demographics:

All subjects right-handed

Met criteria for PTSD at time of brain scans

No significant difference in level childhood traumatic experiences between PTSD and comparison groups

Life Stressor Checklist—Revised (LSC-R, 1997)

Comorbidities: (axis I disorders)

Major Depressive Disorder (n=10)

Panic Disorder (n=3)

Social Phobia (n=2)

Somatoform disorder (n=2)

Generalized Anxiety Disorder (n=2)

+Study 1: Placement of ACC and

Bilateral Hippocampus

All scans performed 15.0 ± 1.1 months post fire accident

MRI: 3-Tesla whole-body imaging system (GE VH/1, USA)

Brain voxels of interest (VOIs)

+Study 1: Results

Significantly decreased NAA concentration in ACC and

hippocampus in PTSD subjects

NAA levels of ACC and hippocampus negatively correlated with

re-experience symptom scores in PTSD subjects

+Study 2: Abnormal N-acetylaspartate in hippocampus and

anterior cingulate in posttraumatic stress disorder

Authors: Schuff, N., Neylan, T.C., Fox-Bosetti, S., Lenoci, M.,

Samuelson, K.W., Studholme, C., Kornak, J., Marmar, C.R.,

Weiner, M.W.

Purpose: inconsistencies in hippocampal volume and metabolic

functions in studies may be due to comorbidity of alcohol abuse

Hypothesis: not stated

interest in correlations/interactions of PTSD and alcohol on

hippocampal NAA and hippcampal volume

Metabolic function in ACC of PTSD subjects regardless of

alcoholism

+Study 2: Method

Participants:

N=55; subjects with PTSD

N=49; subjects without PTSD

4 Groups:

N=28; PTSD with alcohol abuse

N=27; PTSD without alcohol abuse

N=23; No PTSD with alcohol abuse

N=26; No PTSD without alcohol

Subject recruitment:

From outpatient mental health clinic of San Francisco Veterans Affairs Center and from the community by advertisement

+Study 2: Criteria

PTSD Measures (interviews):

Clinician Administered PTSD Scale (CAPS)

Tested for inter-rater reliability

Structured Clinical Interview for DSM-IV Diagnosis (SCID) (Diagnose alcohol or drug abuse, or dependence)

Interview of Life Stressor Checklist—Revised (LSC-R, 1996)

Alcohol Abuse Measures:

PTSD with alcohol: Veterans with alcohol abuse in past 5 years

PTSD without alcohol: Veterans with no history alcohol abuse

Operational definition alcohol consumption:

Total cumulate drinks/year over past 5 years

Current alcohol consumption as cumulate drinks month prior study

+Study 2: Exclusion Criteria

Exclusions:

Veterans with past but not current PTSD or subsyndromal PTSD

Psychotic disorder or bipolar disorder

Drug abuse or Dependence

Neurological Illness, head trauma with loss of consciousness,

medical disorders affecting brain function

MRI scanning exclusion criteria

MRIs reviewed for exclusionary neuropathological conditions

(brain tumors, lesions, vessel disease)

+Study 2: MRI and MRS Acquisition

1.5 T Vision MR system (Siemens Inc., Iselin, NJ)

+Study 2: Volume Measurements of

the Hippocampus

Use MPRAGE images and semi-automatic brain-mapping tool

(Medtronic, Lousville, CO)

Guided by 22 manually placed landmarks in hippocampus

Landmarks have been independently validated

Correlations of manual and semi-automated measures: >90%

Volume Measurement Validity

Two readers with Inter-rater Reliability: 96%

Double-blind reader reviewed and corrected all manual and

automated measurements

+Study 2: Results

Brain Volumes:

PTSD alone not significantly associated smaller volumes of left or right hippocampus

Strong association increasing age and smaller hippocampal volume (left and right)

Trend of smaller hippocampi with childhood trauma

Still no significant effect on hippocampal volume when adjusting for the most severe symptoms in subjects or just comparing men

No significant effect of PTSD with long-term alcohol-drinking behavior on hippocampal volume

However, trend for smaller frontal lobe white matter in PTSD

+Study 2: Results (cont.d)

Brain Metabolites:

PTSD associated with reduced NAA concentration in hippocampus

PTSD associated with reduced NAA concentration in ACC

Long-term alcohol consumption did not alter these results

No significant effect of childhood trauma or lifetime or current

depression on metabolite concentrations

No significant effect of psychiatric medications on metabolites

No other significant metabolite abnormalities found in PTSD outside

of ACC

+Discussion

Study 1:

Strengths:

Large sample size (26 survivors with PTSD and 25 controls)

Uniform traumatic experiences

Limitations:

Did not compare subway fire survivors who did not develop PTSD

with survivors tested who are PTSD positive

Comorbid diagnoses of depression, anxiety, and substance abuse

Future Studies:

Longitudinal follow-up: Do NAA differences recover over time or with

treatment?

+Discussion

Study 2:

Strengths:

Scans were semi-automatically traced and then manually adjusted and checked

Went further to analyze subjects with most severe symptoms and did not find smaller hippocampal volumes

Limitations:

Alcohol consumption only account for a 5-year window prior to study

Did not collect data on nicotine use

Future Studies:

Small hippocampus may be tied more closely to childhood trauma than for adult PTSD

+Discussion

Findings in BOTH studies:

PTSD associated with reduced NAA in hippocampus in absence of

reduced hippocampal volume

PTSD associated with reduced NAA concentration in ACC

PTSD associated reduced NAA/Cr ratio in hippocampus

Explains PTSD symptoms: abnormalities in cognition, emotion

regulation, fear conditioning and fear extinction (hyper-active

response to trauma cues), re-experience

Metabolite measures are a more sensitive marker for neuronal

abnormality in PTSD than volumetric measures of the brain