Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Immediate Communication
  • Published:

Anxiety in healthy humans is associated with orbital frontal chemistry

Molecular Psychiatry volume 5, pages 482–488 (2000)Cite this article

Abstract

The present study examines relationships between regional brain chemistry (as identified by localized in vivo three-dimensional single-voxel proton magnetic resonance spectroscopy (1H-MRS) and anxiety (as measured by the State-Trait Anxiety Inventory) in 16 healthy subjects. The relative concentrations of N-Acetyl aspartate, choline, glutamate, glutamine, γ-aminobutyric acid, inositol, glucose and lactate were measured relative to creatine within six 8-cm3 brain voxels localized to: thalamus, cingulate, insula, sensorimotor, dorsolateral prefrontal, and orbital frontal cortices (OFC) in the left hemisphere. Analysis of variance, across brain regions, chemicals, and high and low anxiety groups, showed a relationship between anxiety and chemical composition of OFC, with high anxiety subjects demonstrating 32% increase in overall chemical concentrations within OFC, as compared to the lower anxiety group (F = 60.8, P < 10−7). Other brain regions, including cingulate, showed no detectable anxiety dependence. The combination of the state and trait anxiety was highly correlated with the concentration of OFC chemicals (r2 = 0.98), and N-Acetyl aspartate in OFC was identified as the strongest chemical marker for anxiety (changed by 43.2% between the two anxiety groups, F = 21.5, P = 0.000005). The results provide direct evidence that the OFC chemistry is associated with anxiety in healthy humans. The method can be used as a neuroimaging/behavioral tool for documentation of OFC chemistry changes in relation to anxiety per se and anxiety disorders. The presented relationship between regional brain chemistry and anxiety reflects the functional/behavioral state of the brain, pointing to possible mechanisms of the neurobiology of anxiety.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey Arch Gen Psychiatry 1994; 51: 8–19

    CAS  Google Scholar 

  2. Magee WJ, Eaton WW, Wittchen HU, McGonagle KA, Kessler RC . Agoraphobia, simple phobia, and social phobia in the National Comorbidity Survey Arch Gen Psychiatry 1996; 53: 159–168

    Article  CAS  Google Scholar 

  3. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG et al. The cross-national epidemiology of panic disorder Arch Gen Psychiatry 1997; 54: 305–309

    Article  CAS  Google Scholar 

  4. Anagnostaras SG, Craske MG, Fanselow MS . Nat Neurosci 1999; 2: 780–782

  5. Connor KM, Davidson JRT . Generalized anxiety disorder: neurobiological and pharmacotherapeutic perspectives Biol Psychiatry 1998; 44: 1286–1294

    Article  CAS  Google Scholar 

  6. Coplan JD, Lydiard RB . Brain circuits in panic disorder Biol Psychiatry 1998; 44: 1264–1276

    Article  CAS  Google Scholar 

  7. Barchas JD, Altemus M . Biochemical hypotheses of mood and anxiety disorders. In: Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds) Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th edn Lippincott-Raven Publishers: Philadelphia 1999; pp1073–1093

    Google Scholar 

  8. Ninan PT . The functional anatomy, neurochemistry, and pharmacology of anxiety J Clin Psychiatry 1999; 60: 12–17

    CAS  PubMed  Google Scholar 

  9. Davidson RJ, Abercrombie H, Nitschke JB, Putnam K . Regional brain function, emotion and disorders of emotion Curr Opin Neurobiol 1999; 9: 228–234

    Article  CAS  Google Scholar 

  10. Baxter LR Jr, Schwartz JM, Mazziotta JC, Phelps ME, Pahl JJ, Guze BH et al. Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder Am J Psychiatry 1988; 145: 1560–1563

    Article  Google Scholar 

  11. Nordahl TE, Benkelfat C, Semple WE, Gross M, King AC et al. Cerebral glucose metabolic rates in obsessive compulsive disorder Neuropsychopharmacology 1989; 2: 23–28

    Article  CAS  Google Scholar 

  12. Swedo SE, Schapiro MB, Grady CL, Cheslow DL, Leonard HL, Kumar A et al. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder Arch Gen Psychiatry 1989; 46: 518–523

    Article  CAS  Google Scholar 

  13. Rauch SL, Jenike MA, Alpert NM, Baer L, Breiter HC, Savage CR et al. Regional cerebral blood flow measured during symptom provcation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography Arch Gen Psychiatry 1994; 51: 62–70

    Article  CAS  Google Scholar 

  14. Breiter HC, Rauch SL, Kwong KK, Baker JR, Weisskoff RM, Kennedy DN et al. Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder Arch Gen Psychiatry 1996; 53: 595–606

    Article  CAS  Google Scholar 

  15. Javanmard M, Shlik J, Kennedy SH, Vaccarino FJ, Houle S, Bradwejn J . Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two time points Biol Psychiatry 1999; 45: 872–882

    Article  CAS  Google Scholar 

  16. Kimbrell TA, Georg MS, Parekh PI, Ketter TA, Podeli DM, Danielson AL et al. Regional brain activity during transient self-induced anxiety and anger in healthy adults Biol Psychiatry 1999; 46: 454–465

    Article  CAS  Google Scholar 

  17. Dager SR, Marro KI, Richards TL, Metzger GD . Preliminary application of magnetic resonance spectroscopy to investigate lactate-induced panic Am J Psychiatry 1994; 151: 57–63

    Article  CAS  Google Scholar 

  18. Dager SR, Richards T, Strauss W, Artru A . Single-voxel 1H-MRS investigation of brain metabolic changes during lactate-induced panic Psychiatry Res 1997; 76: 89–99

    Article  CAS  Google Scholar 

  19. Dager SR, Friedman SD, Heid A, Layton ME, Richards T, Artru A et al. Two-dimensional proton echo-planar spectroscopic imaging of brain metabolic changes during lactate-induced panic Arch Gen Psychiatry 1999; 56: 70–77

    Article  CAS  Google Scholar 

  20. Grachev ID, Apkarian AV . Chemical heterogeneity of the living human brain: a proton MR spectroscopy study on the effects of sex, age and brain region NeuroImage 2000; 11: 554–563

    Article  CAS  Google Scholar 

  21. Talairach J, Tournoux P . Co-planar Stereotactic Atlas of the Human Brain. 3-Dimensional Proportional System: an Approach to Cerebral Imaging Thieme: Stuttgart 1988

    Google Scholar 

  22. Grachev ID, Berdichevsky D, Rauch SL, Heckers S, Kennedy DN, Caviness VS, Alpert NM . A method for assessing the accuracy of intersubject registration of the human brain using anatomic landmarks NeuroImage 1999; 9: 250–268

    Article  CAS  Google Scholar 

  23. Michaelis T, Merboldt KD, Bruhn H, Hanicke W, Frahm J . Absolute concentrations of metabolites in the adult human brain in vivo: quantification of localized proton MR spectra Radiology 1993; 187: 219–227

    Article  CAS  Google Scholar 

  24. Salibi N, Brown MA . Clinical MR Spectroscopy: First Principles Wiley-Liss: Toronto 1998

    Google Scholar 

  25. Simmons A, Smail M, Moore E, Williams SCR . Serial precision of metabolite peak area ratios and water referenced metabolite peak areas in proton MR spectroscopy of the human brain Magn Reson Imaging 1998; 16: 319–330

    Article  CAS  Google Scholar 

  26. Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA . Manual for the State-Trait Anxiety Inventory Consulting Psychologists Press: Palo Alto CA 1983

    Google Scholar 

  27. Rauch SL, Savage CR, Alpert NM, Miguel EC, Baer L, Breiter HC et al. A positron emission tomographic study of simple phobic symptom provocation Arch Gen Psychiatry 1995; 52: 20–28

    Article  CAS  Google Scholar 

  28. Rauch SL, van der Kolk BA, Fisler RE, Alpert NM, Orr SP, Savage CR et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and scriptdriven imagery Arch Gen Psychiatry 1996; 53: 380–387

    Article  CAS  Google Scholar 

  29. Benkelfat C, Bradwejn J, Meyer E, Ellenbogen M, Milot S, Gjedde A et al. Functional neuroanatomy of CCK4-induced anxiety in normal healthy volunteers Am J Psychiatry 1995; 152: 1180–1184

    Article  CAS  Google Scholar 

  30. Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC . Pain affect encoded in human anterior cingulate but not somatosensory cortex Science 1997; 277: 968–971

    Article  CAS  Google Scholar 

  31. Bush G, Whalen PJ, Rosen BR, Jenike MA, McInerney SC, Rauch SL . The counting Stroop: an interference task specialized for functional neuroimaging—validation study with functional MRI Hum Brain Mapp 1998; 6: 270–282

    Article  CAS  Google Scholar 

  32. Whalen PJ, Bush G, McNally RJ, Wilhelm S, McInerney SC, Jenike MA et al. The emotional counting Stroop paradigm: a functional magnetic resonance imaging probe of the anterior cingulate affective division Biol Psychiatry 1998; 44: 1219–1228

    Article  CAS  Google Scholar 

  33. Peyron R, Garcia-Larrea L, Gregoire MC, Costes N, Convers P, Lavenne F et al. Haemodynamic brain responses to acute pain in humans: sensory and attentional networks Brain 1999; 122: 1765–1779

    Article  Google Scholar 

  34. Bechara A, Damasio AR, Damasio H, Anderson SW . Insensitivity to future consequences following damage to human prefrontal cortex Cognition 1994; 50: 7–15

    Article  CAS  Google Scholar 

  35. Bechara A, Damasio H, Tranel D, Damasio AR . Deciding advantageously before knowing the advantageous strategy Science 1997; 275: 1293–1295

    Article  CAS  Google Scholar 

  36. Bechara A, Damasio H, Tranel D, Anderson SW . Dissociation of working memory within the human prefrontal cortex J Neurosci 1998; 18: 428–437

    Article  CAS  Google Scholar 

  37. Damasio AR . The somatic marker hypothesis and the possible functions of the prefrontal cortex. In: Roberts AC, Robbins TW, Weiskrantz L (eds) The Prefrontal Cortex: Executive and Cognitive Functions Oxford University Press: New York 1998; pp36–50

    Chapter  Google Scholar 

  38. Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ . Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study Arch Gen Psychiatry 1998; 55: 715–720

    Article  CAS  Google Scholar 

  39. Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP et al. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues Nat Neurosci 1999; 2: 833–839

    Article  CAS  Google Scholar 

  40. Miller BL . A review of chemical issues in 1H NMR spectroscopy: N-acetyl-L-aspartate, creatine, and choline NMR Biomed 1991; 4: 47–52

    Article  CAS  Google Scholar 

  41. Gruetter R, Novotny EJ, Boulware SD, Rothman DL, Shulman RG . 1H NMR studies of glucose transport in the human brain J Cereb Blood Flow Metab 1996; 16: 427–438

    Article  CAS  Google Scholar 

  42. Shulman RG, Rothman DL . Interpreting functional imaging studies in terms of neurotransmitter cycling Proc Natl Acad Sci USA 1998; 95: 11993–11998

    Article  CAS  Google Scholar 

  43. Sibson NR, Dhankhar A, Mason GF, Rothman DL, Behar KL, Shulman RG . Stoichiometric coupling of brain glusose metabolism and glutamatergic neuronal activity Proc Natl Acad Sci USA 1998; 95: 316–321

    Article  CAS  Google Scholar 

  44. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG . Energy on demand Science 1999; 283: 496–497

    Article  CAS  Google Scholar 

  45. Grachev ID, Breiter HC, Rauch SL, Savage CR, Baer L, Shera DM et al. Structural abnormalities of frontal neocortex in obsessive-compulsive disorder Arch Gen Psychiatry 1998; 55: 181–182

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank S Huckins for technical assistance and P Sheehe for discussions of data analysis. The project was funded by NIH/NINDS NS35115 and Department of Neurosurgery at SUNY Upstate Medical University.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, 13210, New York, USA

    I D Grachev & A V Apkarian

  2. Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, 13210, New York, USA

    I D Grachev & A V Apkarian

Authors
  1. I D Grachev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A V Apkarian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I D Grachev.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grachev, I., Apkarian, A. Anxiety in healthy humans is associated with orbital frontal chemistry. Mol Psychiatry 5, 482–488 (2000). https://doi.org/10.1038/sj.mp.4000778

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000778

Keywords

This article is cited by

Search

Advanced search

Quick links