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Reductions in Occipital Cortex GABA Levels in Panic Disorder Detected With 1H-Magnetic Resonance Spectroscopy
Andrew W. Goddard, MD;
Graeme F. Mason, PhD;
Ahmad Almai, MD;
Douglas L. Rothman, PhD;
Kevin L. Behar, PhD;
Ognen A. C. Petroff, MD;
Dennis S. Charney, MD;
John H. Krystal, MD
Arch Gen Psychiatry. 2001;58:556-561.
ABSTRACT
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Background There is preclinical evidence and indirect clinical evidence implicating  -aminobutyric
acid (GABA) in the pathophysiology and treatment of human panic disorder.
Specifically, deficits in GABA neuronal function have been associated with
anxiogenesis, whereas enhancement of GABA function tends to be anxiolytic.
Although reported peripheral GABA levels (eg, in cerebrospinal fluid and plasma)
have been within reference limits in panic disorder, thus far there has been
no direct assessment of brain GABA levels in this disorder. The purpose of
the present work was to determine whether cortical GABA levels are abnormally
low in patients with panic disorder.
Methods Total occipital cortical GABA levels (GABA plus homocarnosine) were
assessed in 14 unmedicated patients with panic disorder who did not have major
depression and 14 retrospectively age- and sex-matched control subjects using
spatially localized 1H-magnetic resonance spectroscopy. All patients
met DSM-IV criteria for a principal current
diagnosis of panic disorder with or without agoraphobia.
Results Patients with panic disorder had a 22% reduction in total occipital
cortex GABA concentration (GABA plus homocarnosine) compared with controls.
This finding was present in 12 of 14 patient-control pairs and was not solely
accounted for by medication history. There were no significant correlations
between occipital cortex GABA levels and measures of illness or state anxiety.
Conclusions Panic disorder is associated with reductions in total occipital cortex
GABA levels. This abnormality might contribute to the pathophysiology of panic
disorder.
INTRODUCTION
DYSREGULATION in brain -aminobutyric acid (GABA) neuronal function
might contribute to the pathophysiology of human panic disorder. For example,
lowered brain GABA levels are associated with anxietylike behaviors in animals,1, 2 and elevated brain GABA levels tend
to be associated with anxiolysis.2, 3
Although clinical studies of GABA levels in patients with panic disorder have
shown normal plasma4, 5 and cerebrospinal
fluid GABA levels,6 to date there have been
no in vivo studies, to our knowledge, evaluating brain GABA levels in this
patient population. Other components of the GABA system, such as the benzodiazepine
(BZD) receptor, have been implicated in the pathophysiology of panic. For
instance, impaired brain GABAA/BZD receptor functioning has been
directly linked to neophobic behaviors in mice,7, 8
behaviors that resemble human agoraphobia. Furthermore, a generalized cortical
reduction in BZD receptor binding in patients with panic disorder was recently
observed using a positron emission tomographic technique, with effects being
most pronounced in the right orbitofrontal and insular cortices,9
although, subsequently, other groups10, 11
also using positron emission tomography did not detect these abnormalities.
In addition, regional cortical reductions in BZD receptor binding have been
identified with single-photon emission computed tomographic techniques in
frontal,12, 13, 14
temporal,12, 13 left hippocampal,
precuneus,15 and occipital12
areas of patients with panic disorder.
We hypothesized, based on the previously mentioned observations, that
there are deficits in GABA neuronal functioning in panic disorder. We therefore
executed a study using a novel 1H-magnetic resonance spectroscopic
(MRS) technique16 to test whether total occipital
cortex GABA levels (GABA plus homocarnosine) are abnormally reduced in panic
disorder. In this study, we chose to evaluate GABA levels in an occipital
cortex region of interest (ROI) because researchers17, 18, 19
have developed a reliable method to measure GABA in this location and have
used it successfully to detect GABA abnormalities in other neuropsychiatric
illnesses.17, 18, 19
Also, when we began the study, our ability to reliably examine other ROIs
more traditionally related to anxiety (eg, the frontal cortex) was limited
because of technical issues (patient immobilization, shimming adjacent to
the sinuses, and variable head shape in the frontal regions). Finally, the
imaging literature, although consistently implicating frontal areas in panic,
also suggests that more generalized cortical GABA abnormalities could be present.
PARTICIPANTS AND METHODS
PARTICIPANTS
This study was conducted at the Yale Anxiety Clinic and the Yale Magnetic
Resonance Center, New Haven, Conn. Most patients (12 of 14) responded to paid
advertisements in local newspapers and on television; patient 3 was self-referred
and patient 9 was a clinic referral (Table
1). After a psychiatric evaluation performed by a research psychiatrist
(A.W.G. or A.A.), patients were informed of the study rationale and procedures.
All patients gave their written informed consent to participate and received
their own copy of the Yale institutional review board–approved informed
consent document.
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Occipital Cortex -Aminobutyric Acid (GABA) Levels in Patients
With Panic Disorder and Control Subjects
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We studied 14 outpatients with panic disorder (8 women and 6 men; mean
± SD age, 37 ± 10 years) who were moderately ill judging by
their mean ± SD total prescan Panic Disorder Severity Scale (PDSS)20 score (13 ± 4; n = 13). The PDSS samples 7
symptom domains (each scored on a scale from 0-4) relevant to panic disorder,
including frequency of panic symptoms, distress during panics, phobic symptoms,
anticipatory anxiety, and functioning (see Shear et al20
for a review of psychometric properties). All patients had a weekly panic
attack frequency of 1 or more in the month before study entry. Baseline mean
± SD scores were as follows: Hamilton Anxiety Rating Scale (HAM-A),21 17 ± 8 (n = 14); 25-item Hamilton Depression
Rating Scale (HAM-D),22 20 ± 10 (n =
14); 17-item HAM-D,23 14 ± 6; and Clinician-Rated
Anxiety Scale (CRAS) (contains 37 items, each rated on a scale from 0-4, covering
panic attacks, phobias, and many symptoms of generalized anxiety),24, 25 31 ± 16 (n = 14). All patients
had normal physical examination findings and normal results on follow-up tests,
including urine toxicology, urinalysis, electrocardiogram, serum electrolytes
and glucose, liver and thyroid function tests, blood cell count and serum
gonadotrophin levels (for women), and human immunodeficiency virus testing.
Of the women, 1 was menopausal, 1 was perimenopausal, 3 were at the end of
their menstrual cycle just before the scan, 1 was midcycle, 1 was in the first
half of the cycle, and 1 was in the second half of the cycle. Patients met DSM-IV criteria26 for a
current principal diagnosis of panic disorder with or without agoraphobia.
The panic diagnosis was confirmed using a semistructured interview (either
the Anxiety Disorders Interview Schedule DSM-IV version27 or the Structured Clinical Interview for DSM-IV28) administered by experienced
research personnel under the supervision of the principal investigator (A.W.G.).
Patients with a lifetime history of a psychotic disorder, a bipolar
disorder, major depressive disorder, obsessive-compulsive disorder, an eating
disorder, posttraumatic stress disorder, alcohol dependence, or a major personality
disorder were excluded. In addition, patients were excluded if they had had
a substance abuse disorder within 6 months of the diagnostic interview. Patients
2, 9, and 14 (Table 1) were smokers
(>10 cigarettes per day). Patient 11 had a probable comorbid somatoform disorder
(conversion disorder), and patient 8 carried an additional diagnosis of social
phobia–specific subtype. Of 14 patients studied, 9 were medication naive
(patients 1, 4, 5, 7, 10, 11, 12, 13, and 14). Of the remaining 5 patients,
2 had discontinued medication use 3 months before study entry (patient 9 was
taking desipramine hydrochloride and clonazepam and patient 6 was taking sertraline
hydrochloride and clonazepam) and 3 were taking occasional as-needed doses
of short-acting BZD medications (patients 3 and 10 were taking 0.25- and 0.5-mg
tablets of alprazolam, respectively, and patient 2 was taking one half of
a 0.5-mg tablet of clonazepam). The 3 patients who had taken medications as
needed were completely medication free for at least 1 week before the first
MRS scan.
Control subjects (in good physical health and medication free) were
part of the Yale Magnetic Resonance Center's control database of 30 subjects.
They had no lifetime history of psychiatric illness by clinical assessment.
Structured Clinical Interview evaluations were not conducted on controls.
Controls were paired with patients retrospectively based on sex and age. Complete
sex matching was accomplished, and we attempted to ensure that patient-control
pairs were close in age (mean ± SD age difference in the 14 patient-control
pairs, 4 ± 4 years). The mean ± SD time between matched control
and patient scans was 6 ± 4 months, with control scans generally occurring
before patient scans. Recruitment and assessment procedures for controls and
patients remained constant during MR data acquisition (27 months). Controls
were recruited from flyers placed in the Yale Medical Center.
SPECTROSCOPIC AND IMAGING PROCEDURES
We used a parallel-group design to test whether unmedicated patients
with panic disorder had lower occipital cortical total GABA levels (cortical
GABA plus homocarnosine, a GABA-containing dipeptide) than retropsectively
age- and sex-matched controls. Each patient and control subject underwent
an MRS scan (lasting approximately 1.5 hours). The concentration of GABA was
measured by comparing the integrated GABA resonance from the MRS edited spectrum
with the integrated creatine resonance obtained during the same scan.
A trained research assistant or registered nurse under supervision of
the principal investigator accompanied the patient throughout the MRS test
(approximately 1.5 hours). The imaging and spectroscopy work was conducted
at Yale Magnetic Resonance Center using a 2.1-T, 1-m bore magnet (Oxford Magnet
Technologies, Oxford, England) with a spectrometer (Bruker Avance Biospec;
Bruker Instruments, Billericay, Mass) and actively shielded magnetic field
gradients (Oxford Magnetic Technologies). A workstation (Silicon Graphics
Inc, Chippewa Falls, Wis) was used for image and spectroscopic analysis.
Before spectroscopy, T1-weighted, gradient echo magnetic resonance images
were taken to select a 13.5-cm3 (1.5 x 3.0 x 3.0-cm)
volume in the occipital cortex for MRS. The 1.5-cm dimension was along the
axis that was perpendicular to the surface coil plane, and the volume was
centered 1.5-cm deep to the dura mater. For each ROI, approximately 95% of
the nuclear magnetic resonance signal was derived from the voxel selected.
The occipital ROI was centered on the midline, included the visual cortex
(on the left and right sides), and was identical to the ROI used in previous
works.16, 19 Participants lay supine
on a pallet with their occiput resting next to an 8-cm radiofrequency surface
coil tuned to the 1H-nuclear magnetic resonance frequency of 89.43
MHz. An automated shimming protocol was used to maximize B0 field
uniformity in the ROI.29 Three-dimensional
localization of the sensitive volume was accomplished by means of an image-selected
in vivo spectroscopy sequence (comprising 8-millisecond phase-swept, hyperbolic
secant inversion pulses, µ = 5; bandwidth, 2000 Hz). Water suppression
was achieved by an 80-millisecond hyperbolic secant-selective inversion pulse
and a semiselective refocusing pulse (90° pulse; duration, 120 microseconds).16 Other spectral acquisition parameters for collection
of GABA data included a sweep width of 2500 Hz, an acquisition time of 510
milliseconds, a repetition time of 3.39 seconds, and an echo time of 68 milliseconds.
GABA Editing Procedure
A homonuclear J-editing procedure was used to separate the GABA C4 triplet
resonance at 3.0 ppm from overlapping resonances. This was done by applying
a 26.5-millisecond DANTE (Delays-Alternating with Nutations-for Tailored Excitation)
inversion pulse to the 1.9-ppm C3 GABA multiplet resonance.16
Subtraction of a spectrum acquired with the DANTE pulse from one in which
the DANTE pulse was not applied provided the edited spectrum that reflected
total cortical GABA levels.
Cortical GABA Measurement
The C4 GABA resonance from the edited spectrum was integrated and compared
with an integrated creatine resonance (3.03 ppm) obtained during the same
acquisition. In vivo time domain data were zero filled to 32K and multiplied
by a 3-Hz exponential function before Fourier transformation. In the edited
spectrum, the C4 GABA resonance was integrated over a 0.30-ppm bandwidth centered
over 3.0 ppm. The creatine signal was integrated over a 0.2-ppm bandwidth
centered at 3.0 ppm of the GABA-inverted spectrum. Cortical GABA concentrations
were calculated from the following formula, which compares the integrated
GABA resonance from the MRS edited spectrum with the integrated creatine
resonance16:
where G* is the GABA integral in the edited spectrum, Cr* is the creatine
integral, M is the contribution of macromolecule resonances at 3.0 ppm, ICF
is a correction factor for the limited integral bandwidths determined from
localized edited spectra of solutions of GABA and creatine line broaded to
match the in vivo processed line widths, EE is a correction factor for loss
of signal intensity during the editing procedure, 3/2 is the creatine-GABA
proton ratio, and [Cr] is the concentration of creatine in the human occipital
cortex (average cortical concentration, 9 mmol/kg).
The correction factors ICF and EE were obtained by subjecting a GABA
solution in an 11.5-cm bottle to the same localization and editing procedure
used in vivo. The GABA signal from the cortex was also calibrated by comparison
with phantoms containing known solutions of GABA and creatine (the phantom
studies were designed to simulate in vivo coil loading).16
Integration of GABA over a 0.3-ppm bandwidth was based on the assumption that
the GABA line shape was constant. The assumption was validated based on the
creatine line width, which was measured to vary by less than 1 Hz between
studies. Measurements of pure GABA and creatine levels in solution show that
small changes in line width have a minimal effect on the relative integrals.
STATISTICAL ANALYSIS
Nonparametric statistical procedures were used for all analyses. Paired
tests were performed for all between-group analyses because the control sample
had been carefully age and sex matched to the patient sample. The primary
analysis, testing for a patient-control difference in cortical GABA levels,
used the Wilcoxon signed rank test. Other subgroup analyses comparing groups
on some clinical and demographic characteristics also used this test. Within-group
Spearman correlational analyses were performed to determine whether cortical
GABA levels were associated with measures of clinical illness severity, such
as the HAM-A, PDSS, HAM-D, and CRAS, as well as to examine whether age correlated
with cortical GABA levels in either group. The  level for all statistical
analyses was set at .05, and all tests were 2-tailed. Values are expressed
as mean ± SD.
RESULTS
EFFECT OF PANIC DIAGNOSIS ON TOTAL CORTICAL GABA LEVELS
Inspection of the cortical GABA raw scores revealed that 12 of 14 patients
with panic disorder had lower occipital cortex GABA levels compared with their
matched controls (Table 1). Sex
matching was perfect and age matching was good. The effect of diagnosis on
cortical GABA level was statistically significant, with a 22% reduction in
mean GABA levels in patients with panic disorder vs controls (1.38 ±
0.38 vs 1.77 ± 0.35 mmol/kg; Wilcoxon W = -75.0, n = 14 pairs; P<.02) (see Figure 1 for examples of representative spectra from a patient and a nonpaired
control). There was no significant effect of sex on cortical GABA levels (women,
1.64 ± 0.47 mmol/kg; men, 1.49 ± 0.31 mmol/kg; Mann-Whitney U26 = 76.5; P = .37).
However, women panickers vs controls (GABA level, 1.39 ± 0.43 vs 1.89
± 0.38 mmol/kg; W = -30, n = 8 pairs; P
= .04) had a statistically significant reduction in occipital cortex GABA
concentration compared with men vs controls (GABA level, 1.35 ± 0.32
vs 1.61 ± 0.26 mmol/kg; W = -11, n = 6 pairs; P = .31). Age did not correlate with cortical GABA levels in either
patients (n = 14; r = -0.09; P = .8) or controls (n = 14; r = -0.28; P = .34). A statistically significant reduction in patient
GABA levels relative to controls remained (W = -60, n = 12 pairs; P<.02) despite removal of 2 patient-control pairs (pairs
4 and 5) from the Wilcoxon analysis who were not closely age matched. Inspection
of a subgroup of medication-naive patients with panic disorder (patients 1,
4, 5, 7, and 10-14) indicated that 7 of 9 had lower GABA levels compared with
controls (1.39 ± 0.47 vs 1.85 ± 0.4 mmol/kg; W = -33,
n = 9 pairs; P = .055).
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Representative -aminobutyric acid (GABA) spectra from a control
subject and a patient with panic disorder (not paired). Top 2 traces, Subtraction
spectra (control and patient) highlighting the GABA peaks. Bottom 2 traces,
Control spectra with and without application of the DANTE (Delays-Alternating
with Nutations-for Tailored Excitation) pulse. Cho indicates choline; Cr,
creatine; NAA, N-acetylaspartate; and diff, difference.
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OTHER CLINICAL VARIABLES AND TOTAL CORTICAL GABA LEVELS
To examine possible associations between cortical GABA levels and some
illness severity measures (HAM-A, HAM-D, PDSS, and CRAS), we performed Spearman
correlations on the patient data. The following correlation coefficients were
observed: for GABA levels and the HAM-A, r = 0.35,
n = 14, P = .23; the HAM-D, r
= 0.29, n = 14, P = .32; the PDSS, r = 0.28, n = 13, P = .36; and the CRAS, r
= 0.27, n = 14, P = .34. A modest positive correlation
was observed between cortical GABA concentration and degree of agoraphobia,
as measured on PDSS item 4 (r = 0.56; n = 13; P = .048). However, this finding did not remain statistically
significant after Bonferroni correction. Finally, we found no significant
association between prescan state anxiety (as measured on a visual analogue
scale of anxious mood from 0-100 mm) and cortical GABA levels (r = -0.03; n = 13; P = .9).
MEASUREMENTS OF THE REFERENCE METABOLITE, CREATINE
We did not systematically collect additional short echo spectra for
analysis of creatine, water, and other metabolites in our study sample. However,
we have these data for patients 8 and 12 and controls 4, 13, and 14. Creatine
values of 9.0 mmol/kg were observed in each case. Thus, these limited data
suggested that creatine levels were similar between groups and similar to
those reported in the literature.30
COMMENT
We observed abnormally reduced total occipital cortex GABA levels in
a sample of unmedicated patients with panic disorder who did not have major
depression, adding support to preclinical and clinical evidence suggesting
that deficits in GABA function contribute to the pathophysiologic process
of panic. The finding was relatively consistent, with 12 of 14 patients having
lower GABA levels than their respective matched controls. The result was not
fully explained by previous medication exposure. Women with panic disorder
seemed to have more pronounced reductions in cortical GABA levels than men
in our sample, although the significance of this finding is uncertain because
it might be more related to sample size.
There are several limitations of the present study that merit additional
comment. First, we used a retrospective control group, which limited our ability
to match for variables such as age and, in females, phase of the menstrual
cycle, both of which might affect central nervous system GABA levels.31, 32 Follow-up studies should more carefully
control for these variables by assessing control groups prospectively.
Second, we obtained data from a single occipital cortex ROI and therefore
cannot say at this point whether our observation is limited to certain cortical
regions or present throughout the cortex.
Third, in most of our sample, we did not apply a segmentation procedure
to adjust our GABA measurements based on the percentage of gray matter per
voxel of interest. However, we obtained this information systematically for
the last 3 patient-control pairs using a method devised by our group.33 The mean percentage of gray matter per voxel in these
patient scans was 61% compared with 63% in controls (as determined from quantitative
images of the T1 relaxation constant of tissue water). Thus, these
pilot data suggest that the reduction in GABA is not due to reduced cortical
gray matter content. However, subsequent studies are benefiting from the systematic
application of segmentation protocols.
Fourth, the related compound, homocarnosine (GABA plus a histidine residue),34 is coresonant with GABA and was not assessed in this
study. Thus, the observed changes could be related to changes in the central
nervous system level of homocarnosine in panic. Homocarnosine is of particular
interest because of its potential neuromodulatory role in the central nervous
system.35
Fifth, we determined the concentration of cortical GABA by reference
to total creatine level (creatine plus phosphocreatine). Although this is
a common method of quantification in MRS, changes in creatine levels would
alter the GABA measurements. However, total cortical GABA levels determined
by our MRS technique16 compare favorably to
GABA levels determined using standard chemical assays of postmortem brain
tissue and brain biopsy tissue in animals and humans.36, 37
The GABA transaminase inhibitor vigabatrin produces marked amplification of
the GABA MRS signal in animals and humans, as expected.38, 39
Magnetic resonance spectroscopic measurements of occipital cortex GABA levels
in healthy humans performed by the University of Alabama group,40
with a highly sensitive 4-T magnet, compared favorably with the data our group
has already generated. Further validity and reliability41
studies are ongoing.
If replicated, the low occipital cortex GABA finding is likely to have
implications for our understanding of the relationship between panic and other
neuropsychiatric disorders. Recently, abnormally low occipital cortex GABA
levels were observed in depressed patients.19
Therefore, the low cortical GABA concentration observed in this study might
be a nonspecific finding reflecting a history of neuropsychiatric disease.
However, it is notable, in this regard, that our group has not observed low
occipital cortex GABA levels in schizophrenia (W. Abi-Saab, MD, unpublished
data, 2000) or in patients with bipolar depression.42
Alternatively, low cortical GABA concentration could be a traitlike abnormality
that predisposes to a variety of behavioral disturbances (depression, panic
disorder, and alcoholism). Another possibility is that low cortical GABA levels
are associated with distinct pathophysiologic processes (eg, panic disorder,
depression, epilepsy, and alcoholism). Follow-up investigations are indicated
to discriminate among these possibilities. Attention to the prescan medication-free
period (>4 weeks; including no as-needed medications), to protect against
the potentially confounding effects of medication withdrawal syndromes, and
the within-scan acquisition of other informative metabolite measurements (eg,
creatine, choline, N-acetylaspartate, glutamate,
and homocarnosine) will add to the quality of future studies.
AUTHOR INFORMATION
Accepted for publication January 22, 2001.
This work was supported by grants NIMH K-08 MH-01322 and R01 MH-58657
(Dr Goddard); grant NIMH MH-30929 (Mental Health Clinical Research Center
at Yale, New Haven, Conn) (Drs Goddard, Krystal, and Mason); the Department
of Veterans Affairs VA–Yale Alcohol Research Center and National Center
for PTSD, West Haven, Conn (Dr Krystal); grants NIAAA K02 1 AA00261-01 (Dr
Krystal), NINDS R01-N53218 (Dr Petroff), R29-N5032126 (Dr Rothman), and R01-NS34813
(Dr Behar); and by the Connecticut Department of Mental Health and Addiction
Services, Hartford.
Presented in part at the 8th International Society for Magnetic Resonance
in Medicine Meeting, Philadelphia, Pa, May 25, 1999.
We thank the staff of the Yale Anxiety Clinic and Program for their
contributions to this work.
From the Departments of Psychiatry (Drs Goddard, Mason, Almai, and
Krystal), Biomedical Engineering (Dr Mason), Internal Medicine (Dr Rothman),
Radiology (Dr Rothman), and Neurology (Drs Behar and Petroff), Yale University
School of Medicine, New Haven, Conn; and the National Institute of Mental
Health, Rockville, Md (Dr Charney).
Corresponding author and reprints: Andrew W. Goddard, MD, Yale Anxiety
Clinic, Yale Department of Psychiatry, 100 York St, Room 2J, New Haven, CT
06511 (e-mail: andrew.goddard{at}yale.edu).
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