Cortical and subcortical gamma amino acid butyric acid deficits in anxiety and stress disorders: Clinical implications

Table 1 Neuroimaging studies of gamma amino acid butyric acid function in anxiety disorders

Method	Finding	Design	Clinical significance	Ref.
123I-Iomazenil SPECT	Decreased L hippocampus and precuneus GABAA R binding	Parallel gp, 13 PD patients vs 16 healthy control subjects (HCs)	Chronic stress due to active PD can result in impaired limbic processing via reduced GABAA receptor density or function	Bremner et al[24]
1H-MRS	Decreased OC GABA in PD	14 PD vs 14 matched HCs (historical)	Could be related to impaired production of GABA or of GABA-glutamine cycling in PD	Goddard et al[21]
GABA, 1.5T	No change in OC GABA pre and post-acute and chronic BZD Rx	10 PD vs 9 HCs	Suggests low GABA is a trait-like biomarker for PD	Goddard et al[30]
1H-MRS GABA, 3T	Decreased ACC and BG GABA in patients	22 PD (medicated) vs 24 matched HCs, single voxel study	Impaired top-down inhibition of limbic activity in PD	Ham et al[23]
11C-flumazenil PET	Reduced GABAA R binding in L and R insula Cx of PD	11 PD vs 21 HCs	Interoceptive/somaticsensitivity in PD likely could be insula-mediated	Cameron et al[25]
1H-MRS-GABA, 4T	Reduced thalamic GABA in SAD	10 SAD patients vs 10 matched HCs	Impaired GABA function in thalamus in SAD could affect social cognition via amplification of external threat cues	Pollack et al[28]
11C-flumazenil PET	Reduced frontal, temporal, parietal Cx GABAA binding pot. in PD	15 BZD-naïve PD vs 18 HCs	Generalized cortical impairment in GABAA function in PD could be a cause or effect of PD. If endogenous BZD-like ligands overproduced could be evidence of a compensatory response to chronic stress	Hasler et al[26]
1H-MRS-GABA, 3T	Normal PFC GABA in PD	Parallel gp 17 PD vs 17 sex-matched HCs	In contrast to previous + results in ACC and OC ROIs	Hasler et al[27]
1H-MRS-GABA, 3T	Reduced mPFC GABA in OCD	24 OCD patients vs 22 matched HCs	Could contribute to cortical-striatal circuit dysfunction in OCD	Simpson et al[29]
1H-MRS-GABA, 3T	Reduced ACC/mPFCx GABA in PD	Parallel gp 11 PD vs 8 matched HCs	Effect size greater in FHx+ PD	Long et al[22]
			ACC GABA negatively correlated with enhanced ACC-precuneus, connectivity, 2 DMN nodes	Shin et al[70]
1H-MRS-GABA, 4T	Low R Ar insula Cx GABA in PTSD	13 PTSD patients vs 13 matched HCs	Relationship btw low insula GABA and higher state-trait anxiety levels	Rosso et al[50]
1H-MRS-GABA, 4T	Lower GABA in tempo-parietal Cx and occipital-parietal Cx in PTSD	27 PTSD patients vs 18 trauma- exposed controls	Low GABA finding mediated by high levels of insomnia	Meyerhoff et al[51]
1H-MRS-GABA, 3T	Elevated DLPFC and ACC GABA and glutathione levels	12 PTSD patients vs 17 non-PTSD trauma controls	Oxidative stress implicated in the pathophysiology of PTSD, as well as elevated prefrontal inhibitory neurotransmission	Michel et al[52]

SAD: Social anxiety disorder; PTSD: Post-traumatic stress disorder; GABA: Gamma amino acid butyric acid; mPFC: Medial prefrontal cortex; PET: Positron emission tomography; FDG: Fluorodeoxyglucose; PGB: Pregabalin; ACC: Anterior cingulate cortex; BZD: Benzodiazepine full agonist; MRS: Magnetic resonance spectroscopy; CNS: China national standards.

Table 2 Gamma amino acid system butyric acid effects of psychotropics with anxiolytic activity

Drug	Effect on GABA system	Test paradigm	Comments	Ref.
Benzodiazepines	Agonists at GABAA receptor complex	Alprazolam blocked ACC activation induced by CCK4 in controls.	fMRI study in 16 healthy male subjects	Leicht et al[71]
		Preclinical study of BZD effects on conditioned and unconditioned fear in mice	α2 subunit-containing GABAA receptors sufficient for BZD anxiolysis of unconditioned fear. α1 and α2 subunits needed to suppress conditioned fear	Smith et al[72]
SSRIs	Increased cortical GABA levels	Clinical MRS-GABA in MDD patients		Sanacora et al[73]
	Increased neuroactive steroid levels in the CNS	CSF ALLO increases in SSRI treated MDD patients (n = 15)		Uzunova et al[74]
TCAs	Increased release of GABA	Preclinical; desipramine effects studied		Korf et al[75]
MAOIs	Increase total brain GABA	Preclinical study of phenelzine effects		Paslawski et al[76]
Gabapentin	Increased cortical GABA	MRS-GABA in seizure patients	Chronic medication admin	Petroff et al[77]
PGB	Increased release of GABA	PGB decreases activation of left insula and amygdala in response to emotional images	fMRI activation study in 16 healthy humans	Aupperle et al[78]
Tiagabine	Blocks GAT-1 and inhibits synaptic GABA reuptake	FDG-PET study pre and post a 6-week tiagabine trial for social phobia	15 social anxiety disorder patients and 10 controls. vmPFC metabolism increased with treatment	Evans K et al[79]
Vigabatrin	Blocks GABA transaminase	Blocks CCK4 panic in healthy humans	Not clinically available due to ocular AEs	Zwanger et al[80]

GABA: Gamma amino acid butyric acid; mPFC: Medial prefrontal cortex; PET: Positron emission tomography; FDG: Fluorodeoxyglucose; PGB: Pregabalin; ACC: Anterior cingulate cortex; BZD: Benzodiazepine full agonist; MRS: Magnetic resonance spectroscopy; CNS: China national standards.