Decreased GABA levels in anterior cingulate cortex/medial prefrontal cortex in panic disorder
Highlights
► GABA-edited MRS was used to study GABA levels in ACC/mPFC and OCC in panic patients. ► A GABA deficit was found in the ACC/mPFC of panic disorder patients. ► No other significant metabolic changes were found in either brain region. ► Patients with positive family history tend to have a more pronounced GABA deficit.
Introduction
Panic disorder (PD) is one of the most common psychiatric disorders with a lifetime prevalence of up to 5% in the US (Grant et al., 2006). Emerging evidence has implicated dysfunction in the main CNS inhibitory neurotransmitter system, the γ-aminobutyric acid (GABA) system, in the pathophysiology of PD. For example, abnormal reductions in GABAA-benzodiazepine receptor binding were consistently found in various brain regions by positron emission tomography (PET) and single-photon emission computed tomography (SPECT) (Cameron et al., 2007, Hasler et al., 2008, Kaschka et al., 1995, Malizia et al., 1998, Schlegel et al., 1994), consistent with abnormal inhibitory neuromodulation in PD.
Magnetic resonance spectroscopy (MRS) provides a unique opportunity to noninvasively detect and quantify in vivo brain metabolites such as GABA in humans. In the conventional short-echo-time (short-TE) 1H spectrum, a series of metabolites can be directly measured. These include N-Acetyl-aspartate (NAA, a neuronal marker), creatine and phosphocreatine (often referred to as total creatine, tCr, an energy buffer and shuttle), myo-inositol (mI, a glial cell marker), choline (Cho, involved in cell membrane synthesis and degradation), glutamate (Glu, the major excitatory neurotransmitter) and the sum of glutamate and glutamine (Glx). The GABA signal within these spectra is usually covered by other larger, overlapping peaks due to its small concentration (about 1 mM in vivo) and multiplet structure. Hence special GABA editing techniques are needed in order to achieve signal identification and separation of the relatively small GABA peak.
Both short-TE and GABA-edited MRS have been used to study metabolite changes in PD in the last decade with mixed results. Goddard et al. first showed decreased occipital GABA in unmedicated PD patients using a GABA editing sequence, a decrease which was later suggested to be associated with family history (Goddard et al., 2001, Goddard et al., 2004). Ham et al. observed decreased GABA levels in the anterior cingulate cortex (ACC) and basal ganglia without using a GABA editing sequence. In addition, these authors found increased lactate and Cho in the ACC in medicated patients with PD (Ham et al., 2007). In contrast, no changes of prefrontal cortical GABA, Glx, Cho, and NAA were observed in unmedicated, non-depressed patients with PD by Hasler et al. (2009). Reduced tCr, NAA and Cho were found in the right medial temporal lobe of unmedicated PD patients (Massana et al., 2002). Yet another study reported reduced NAA/Cr and unchanged Cr and Cho/Cr in the left hippocampus in medicated PD patients (Trzesniak et al., 2010). Overall, the literature leads us to hypothesize that metabolite changes, especially GABA deficits, occur in certain brain regions in PD patients.
The ACC appears to regulate both cognitive processing and emotional processing relevant to anxiety (Bush et al., 2000). The occipital cortex and posterior cingulate cortex have been implicated in visual/spatial processing and response preparation to a physical threat (Vogt et al., 1992), functions which could be relevant to anticipatory anxiety in PD. We therefore studied GABA levels, both in the ACC and occipital cortex (OCC), using the MEGA-PRESS J-editing technique (Edden and Barker, 2007, Mescher et al., 1998).
PD is thought to be familial, with genetic factors accounting for 30–40% of the variation in causation (Finn and Smoller, 2001, Smoller et al., 2008, Weissman, 1993, Weissman and Merikangas, 1986). Normal subjects with a family history of anxiety disorder in their first-degree relatives have been found to be more vulnerable to lactate-induced panic attacks than those without a family history of anxiety disorder (Balon et al., 1989). Therefore, we also hypothesize that cortical metabolite changes, especially GABA deficits, depend on family history and may be more profound in PD patients with a family history of PD.
Section snippets
Subjects
Eleven PD patients (PDP, n = 11, five females) and eight age- and gender-matched healthy controls (n = 8, four females) without a family history of psychopathology were recruited for our study. Written informed consent was obtained from all subjects prior to participation in the study. For a preliminary estimate on the effect of family history, PD patients were further separated into two groups: patients with a PD family history (1st degree relatives) (Pw/F, n = 5, three females) and patients without
Results
Patients showed no significant difference in age (t(17) = 0.227, p = 0.823) and Trails Making Test Part B (TMT-B) scores (t(17) = 0.980, p = 0.341), but significantly higher mean VAS anxiety level (t(11.44) = − 3.076, p < 0.01) and mean Panic Disorder Severity Scale than controls (t(10) = − 9.746, p < 0.0001). Mean values and standard deviations of these metrics for each group and subgroup are listed in Table 1.
Discussion
Using a GABA-edited MRS technique and a fitting method to minimize macromolecule contamination, we found that GABA deficits were present in the ACC/mPFC of PD patients, a result that supports the hypothesis that GABA neuronal dysfunction is intrinsic to PD. No other metabolite differences between patients and controls were observed in either the ACC/mPFC or the OCC. Patients and controls with a personal or family history of major depressive disorder were carefully excluded by the study design.
Conclusion
Our results suggest that a GABA deficit exists in the ACC/mPFC of panic patients. This deficit may be more pronounced in those patients with a positive panic family history. The role of GABA in the pathophysiology of PD may also vary by brain region and needs to be studied taking into account family history status.
Acknowledgments
The authors gratefully acknowledge Michele Beal and Courtney Robbins for their professional and dedicated work in MRS data acquisition (Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine). We want to thank Dr. Anantha Shekhar and the staff of the Indiana CTSI center for their support of this project. We further thank Dr. James B. Murdoch for helpful discussions about GABA fitting methods.
This work was supported by a Collaborative
References (32)
- et al.
Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects
Biol Psychiatry
(2007) - et al.
Cognitive and emotional influences in anterior cingulate cortex
Trends Cogn Sci
(2000) - et al.
No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage first-episode schizophrenia
Prog Neuropsychopharmacol Biol Psychiatry
(2010) - et al.
Decreased GABA levels in anterior cingulate and basal ganglia in medicated subjects with panic disorder: a proton magnetic resonance spectroscopy (1H-MRS) study
Prog Neuropsychopharmacol Biol Psychiatry
(2007) - et al.
Prefrontal cortical gamma-aminobutyric acid levels in panic disorder determined by proton magnetic resonance spectroscopy
Biol Psychiatry
(2009) - et al.
Influence of work shift on glutamic acid and gamma-aminobutyric acid (GABA): evaluation with proton magnetic resonance spectroscopy at 3T
Psychiatry Res
(2011) - et al.
Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT
J Psychiatr Res
(1995) Enzymes involved in glutamatergic and GABAergic neurotransmission
Int Rev Cytol
(1993)- et al.
Reduced levels of creatine in the right medial temporal lobe region of panic disorder patients detected with (1)H magnetic resonance spectroscopy
Neuroimage
(2002) - et al.
Elevated gamma-aminobutyric acid levels in chronic schizophrenia
Biol Psychiatry
(2010)
(1)H magnetic resonance spectroscopy imaging of the hippocampus in patients with panic disorder
Psychiatry Res
Family genetic studies of panic disorder
J Psychiatr Res
Family history of anxiety disorders in control subjects with lactate-induced panic attacks
Am J Psychiatry
Reduced gamma-aminobutyric acid(A)-benzodiazepine binding sites in insular cortex of individuals with panic disorder
Arch Gen Psychiatry
Spatial effects in the detection of gamma-aminobutyric acid: improved sensitivity at high fields using inner volume saturation
Magn Reson Med
The genetics of panic disorder
Curr Psychiatry Rep
Cited by (74)
Excitatory and inhibitory neurochemical markers of anxiety in young females
2024, Developmental Cognitive NeuroscienceNeurometabolic alterations in children and adolescents with functional neurological disorder
2024, NeuroImage: ClinicalBreathing in waves: Understanding respiratory-brain coupling as a gradient of predictive oscillations
2023, Neuroscience and Biobehavioral ReviewsTwo-channel EEG based diagnosis of panic disorder and major depressive disorder using machine learning and non-linear dynamical methods
2023, Psychiatry Research - Neuroimaging