In-vivo neuroimaging allows the investigation of brain circuits involved in the experience of anxiety and of receptor changes associated with anxiety disorders. This review focuses on studies by research groups who have compared brain activation maps in different forms of anxiety and on binding studies of the benzodiazepine-GABAA receptor. Activation studies have revealed the involvement of many brain areas depending on the condition and the paradigm. However, the orbitofrontal cortex/anterior insula and the anterior cingulate are implicated in all the studies and may represent the nodal point between somatic and cognitive symptoms of any form of anxiety. Most studies of binding at the benzodiazepine-GABAA receptor are not interpretable because of substantial methodological problems, however, regional and/or global reductions are the most consistent finding in panic disorder.
Abadie P , Boulenger J P , Benali K , Barre L , Zarifian E , Baron JC (1999) Relationship between trait and state anxiety and the central benzodiazepine receptor: a PET study . Eur J Neurosci11: 1470–1478
2.
Bisaga A , Katz J L , Antonini A , Wright C E , Margouleff C , Gorman J M , Eidelberg D (1998) Cerebral glucose metabolism in women with panic disorder . Am J Psychiatry155: 1178–1183
3.
Commissaris R L , Harrington G M , Altman H J (1990) Benzodiazepine anti conflict effects in Maudsley reactive (MR/Har) and non reactive (MNRA/Har) rats . Psychopharmacology100: 287–292
4.
De Cristofaro M T , Sessarego A , Pupi A , Biondi F , Faravelli C (1993) Brain perfusion abnormalities in drug-naïve, lactate-sensitive panic patients: a SPECT study . Biol Psychiatry33: 505–512
5.
Demirgoren S , Majewska M D , Spivak C E , London E D (1991) Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor . Neuroscience45: 127–135
6.
Dorrow R , Horowski R , Paschelke G , Amin M , Braestrup C (1983) Severe anxiety induced by FG7142a b carboline ligand for benzodiazepine receptors . Lancetii: 98–99
7.
Fischer H , Wik G , Fredrikson M (1996) Functional neuroanatomy of robbery re-experience: affective memories studied with PET . NeuroReport7: 2081–2086
8.
Fontaine R , Breton G , Dery R , Fontaine S , Elie R (1990) Temporal lobe abnormalities in panic disorder: an MRI study . Biol Psychiatry27: 304–310
9.
Fredrikson M , Wik G , Greitz T , Eriksson L , Stone-Elander S , Ericson K , Sedvall G (1993) Regional cerebral blood flow during experimental phobic fear . Psychophysiology30: 126–130
10.
Fredrikson M , Wik G , Fischer H , Andersson J (1995) Affective and attentive neural networks in humans: a PET study of Pavlovian conditioning . NeuroReport7: 97–101
11.
Furey M L , Pietrini P , HaxbyJ V , Alexander G E , Lee HC , VanMeter J , Grady C L , Shetty U , Rapoport S I , Schapiro M B , Freo U (1997) Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory . Proc Natl Acad Sci USA94: 6512–6516
12.
Hurtig R R , Hichwa R D , O'Leary D S , Boles Ponto L L , Narayana S , Watkins G L , Andreasen NC (1994) effects of timing and duration of cognitive activation in [15O]water PET studies . J Cereb Blood Flow Metab14: 423–430
13.
Kang I , Miller L G (1991) Decreased GABAA receptor subunit mRNA concentrations following chronic lorazepam administration . Br J Pharmacol103: 1285–1287
14.
Kaschka W , Feistel H , Ebert D (1995) Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT . J Psychiatr Res29: 427–423
15.
Kuikka J T , Pitkanen A , Lepola U , Partanen K , Vainio P , Bergstrom K A , Wieler H J , Kaiser K P , Mittelbach L , Koponen H (1995) Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder . Nucl Med Commun16: 273–280
16.
Litton J E , Hall H , Pauli S (1994) Saturation analysis in PET ö analysis of errors due to imperfect reference regions . J Cereb Blood Flow Metab14:358–366
17.
Malizia A L (1997) PET studies in experimental and pathological anxiety . J Psychopharmacol11: A88-A88
18.
Malizia A L , Wilson S J , Nutt D J , Grasby PM (1996) Brain networks in conditioned anticipatory anxiety in normal volunteers . J Psychopharmacol10: A42-A42
19.
Malizia A L , Wilson S J , Bell C M , Nutt D J , Grasby P M (1997) Neural correlates of anxiety provocation in social phobia . Neuroimage5: S301-S301
20.
Malizia A L , CunninghamVJ, Bell C J , Liddle P F , Jones T , Nutt D J (1998) Decreased brain GABA (A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study . Arch Gen Psychiatry55: 715–720
21.
Maloteaux J M , Octave J N , Gossuin A , Laterre C , Trouet A (1987) GABA induces down regulation of the benzodiazepine GABA receptor complex in the rat cultured neurons . Eur J Pharmacol144: 173–183
22.
Middleton FA , Strick P L (1998) The cerebellum: an overview. Trends Neurosci 21: 367–369 Moss S J, Smart T G, Blackstone C D, Huganir R L (1992) Functional modulation of GABAA receptors by cAMP dependent protein phosphorylation . Science257: 661–665
23.
Ninan P T , Insel T H , Cohen R M , Cook J M , Skolnick P , Paul S M (1982) Benzodiazepine receptor mediated experimental anxiety in primates . Science218: 1332–1334
24.
Nordahl T E , Semple W E , Gross M , Mellman TA , Stein M B , Goyer P , King AC , Uhde T W , Cohen R M (1990) Cerebral glucose metabolic differences in patients with panic disorder . Neuropsychopharmacology3: 261–272
25.
Nutt D J , Glue P , Lawson C , Wilson S (1990) Flumazenil provocation of panic attacks . Arch Gen Psychiatry47: 917–925
26.
Onishi Y , Yonekura Y , Tanaka F (1996) Delayed image of iodine 123 iomazenil as a relative map of benzodiazepine receptor binding: the optimal scan time . Eur J Nuc Med23: 1491–1497
27.
Petersen E N , Jensen L H (1984) Proconflict effect of benzodiazepine receptor inverse agonists and other inhibitors of GABAAfunctionEur J Pharmacol133: 309–317
28.
Primus R J , Gallager DW (1992) GABAA receptor subunit mRNA levels are differentially influenced by chronic FG 7142 and diazepam exposure . Eur J Pharmacol226: 21–28
29.
Randall P K , Bremner J D , Krystal J H , Nagy L M , Heninger G R , Nicolaou A L , Charney D S (1995) effects of the benzodiazepine antagonist flumazenil in PTSD . Biol Psychiatry38: 319–324
30.
Rauch S L , Jenike M A , Alpert NA (1994) Regional cerebral blood flow measurement during symptom provocation in obsessive–compulsive disorder using 15-O labelled CO2 and positron emission tomography . Arch Gen Psychiatry52: 20–28
31.
Rauch S L , Savage C R , Alpert N M , Miguel EC , Baer L , Breiter HC , Fischman A J , Manzo PA , Moretti C , Jenike M A (1995) A positron emission tomographic study of simple phobic symptom provocation . Arch Gen Psychiatry52: 20–26
32.
Rauch S L , van der Kolk BA , Fisler R E , Alpert N M , Orr S P , Savage C R , Fischman A J , Jenike M A , Pitman R K (1996) A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery . Arch Gen Psychiatry53: 380–387
33.
Rauch S L , Savage C R , Alpert N M , Fischman A J , Jenike M A (1997) The functional neuroanatomy of anxiety: a study of three disorders using positron emission tomography and symptom provocation . Biol Psychiatry42: 446–452
34.
Reiman E M , Raichle M E , Robins E , Butler F K , Herscovitch P , Fox P , Perlmutter J (1986) The application of positron emission tomography to the study of panic disorder . Am J Psychiatry143: 469–477
35.
Reiman E M , Raichle M E , Robins E , Mintun M A , Fusselman M J , Fox P T , PriceJ L , Hackman K A (1989) Neuroanatomicalcorrelates ofalactateinduced anxietyattack .ArchGenPsychiatry46: 493–500
36.
Roy-Byrne P P , Cowley D S , Greenblatt D J , Shader R I , Hommer D (1990) Reduced benzodiazepine sensitivity in panic disorder . Arch Gen Psychiatry47: 259–272
37.
Saxena S , Brody A L , Schwartz J M , Baxter L R (1998) Neuroimaging and frontal-subcortical circuitry in obsessive–compulsive disorder . Br J Psychiatry (Suppl. 35): 26–37
38.
Schlegel S , Steinert H , Bockisch A , Hahn K , Schloesser R , Benkert O (1994) Decreased benzodiazepine receptor binding in panic disorder measured by Iomazenil SPECT. A preliminary report . Eur Arch Psychiatry Clin Neurosci244: 49–51
39.
Tokunaga M , Ida I , Higuchi T , Mikuni M (1997) Alterations of benzodiazepine receptor binding potential in anxiety and somatoform disorders measured by 123I Iomazenil SPECT . Diagn Radiol15:163–169
40.
Volkow N D , Mullani L , Gould L K , Adler S S , Gatley S J (1991) Sensitivity of measurements of regional brain activation with oxygen-15 water and PET to time of stimulation and period of image reconstruction . J Nucl Med32: 58–61
41.
Weizman R , Weizman A , Kook K A , Vocci F , Deutsch S I , Paul S M (1989) Repeated swim stress alters brain benzodiazepine receptors measured in vivo . J Pharmacol Exp Ther249: 701–707
42.
Weizman A , Weizman R , Kook K A , Vocci F , Deutsch S I , Paul S M (1990) Adrenalectomy prevents the stress induced decrease in in vivo [3H]Ro151788 binding to GABAA benzodiazepine receptors in the mouse . Brain Res519: 347–350
43.
Wik G , Fredrikson M , Ericson K , Eriksson L , Stone-Elander S , Greitz T (1993) A functional cerebral response to frightening visual stimulation . Psychiatr Res50:15–24
44.
Wik G , Fredrikson M , Fischer H (1996) Cerebral correlates of anticipated fear: a PET study of specific phobia . Int J Neurosci87: 267–276
45.
Wik G , Fredrikson M , Fischer H (1997) Evidence of altered cerebral blood-flow relationships in acute phobia . Int J Neurosci91: 253–263
46.
Woods S W , Charney D S , Silver J M , Krystal J H , Heninger G R (1991) Behavioral, biochemical, and cardiovascular responses to the benzodiazepine receptor antagonist flumazenil in panic disorder . Psychiatr Res36: 115–127
