Integrative Processes: Neuroscience Clinical Imaging Biomarkers

  • Igor D. Grachev
  • Richard J. Hargreaves


The promise of neuroimaging to speed up the discovery of drugs and the development in the neurosciences is high and there is considerable enthusiasm for the wide-spread implementation of many techniques. However, there is a need to balance advocacy with objectivity as we test the decision making value of differing imaging approaches and choose which to integrate into our routine discovery processes. Today the most commonly used are Positron Emission Tomography (PET) often with novel target-specific tracers, and functional magnetic resonance imaging (fMRI). These neuroimaging technologies can be scientifically validated and clinically qualified for use in preclinical investigations and clinical studies in healthy volunteers and patients to assess the efficacy of novel targets, pick the best molecules, and provide estimates of target engagement, dose response and pharmacodynamic effects of drugs within the brain. Neuroimaging has the potential to shorten the development cycle and help bring safe and effective medicines for neurological and psychiatric disorders faster to those who need them.


Positron Emission Tomography Single Photon Emission Compute Tomography Positron Emission Tomography Imaging Arterial Spin Label Positron Emission Tomography Tracer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Addy C et al (2008) The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 7(1):68–78PubMedCrossRefGoogle Scholar
  2. Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2007) <http://www.nia.nih. gov/Alzheimers/ResearchInformation/ClinicalTrials/ADNI.htm>
  3. Baliki MN, Geha PY, Apkarian AV, Chialvo DR (2008) Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci 28(6):1398–1403PubMedCrossRefGoogle Scholar
  4. Becerra L, Harter K, Gonzalez RG, Borsook D (2006) Functional magnetic resonance imaging measures of the effects of morphine on central nervous system circuitry in opioid-naive healthy volunteers. Anesth Analg 103(1):208–216PubMedCrossRefGoogle Scholar
  5. Bednar B, Zhang G-J, Williams DL Jr, Hargreaves R, Sur C (2007) Optical molecular imaging in drug discovery and clinical development. Expert Opin Drug Discov 2:65–85CrossRefGoogle Scholar
  6. Belliveau JW, Kennedy DN, McKinstry RC, Buchbinder BR, Weisskoff RM, Cohen MS et al (1991) Functional mapping of the human visual cortex by magnetic resonance imaging. Science 254:716–719PubMedCrossRefGoogle Scholar
  7. Bergström M et al (2004) Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry 55:1007–1012PubMedCrossRefGoogle Scholar
  8. Borsook D, Becerra L, Hargreaves R (2006) A role for fMRI in optimizing CNS drug development. Nat Rev Drug Discov 5(5):411–424 (Review)PubMedCrossRefGoogle Scholar
  9. Breiter HC, Rauch SL, Kwong KK, Baker JR, Weisskoff RM, Kennedy DN et al (1996a) Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder. Arch Gen Psychiatry 53:595–606PubMedGoogle Scholar
  10. Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL et al (1996b) Response and habituation of the human amygdala during visual processing of facial expression. Neuron 17:875–887PubMedCrossRefGoogle Scholar
  11. Burns HD et al (2007) [18F]MK-9470, a positron emission tomography (PET)tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci USA 104:9800–9805PubMedCrossRefGoogle Scholar
  12. David A, Blamire A, Breiter H (1994) Functional magnetic resonance imaging: a new technique with implications for psychology and psychiatry. Br J Psychiatry 164:2–7PubMedCrossRefGoogle Scholar
  13. Deroose CM et al (2007) Multimodality imaging of tumor xenografts and metastases in mice with combined small-animal PET, small-animal CT and bioluminescence imaging. J Nucl Med 48:295–303PubMedGoogle Scholar
  14. Erondu N et al (2006) Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. Cell Metab 4:275–282PubMedCrossRefGoogle Scholar
  15. Frank R, Hargreaves R (2003) Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2:566–580PubMedCrossRefGoogle Scholar
  16. Gefvert O, Bergström M, Långström B, Lundberg T, Lindström L, Yates R (1998) Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (Seroquel) in patients with schizophrenia. Psychopharmacology (Berl) 135(2):119–126CrossRefGoogle Scholar
  17. Geha PY, Baliki MN, Chialvo DR, Harden RN, Paice JA, Apkarian AV (2007) Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy. Pain 128(1–2):88–100PubMedCrossRefGoogle Scholar
  18. Grachev ID, Fredrickson BE, Apkarian AV (2000) Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study. Pain 89(1):7–18PubMedCrossRefGoogle Scholar
  19. Grachev ID, Kumar R, Ramachandran TS, Szeverenyi NM (2001) Cognitive interference is associated with neuronal marker N-acetyl aspartate in the anterior cingulate cortex: an in vivo (1)H-MRS study of the Stroop Color-Word task. Mol Psychiatry 6(5):496, 529–539Google Scholar
  20. Grachev ID, Fredrickson BE, Apkarian AV (2002a) Brain chemistry reflects dual states of pain and anxiety in chronic low back pain. J Neural Transm 109(10):1309–1334PubMedCrossRefGoogle Scholar
  21. Grachev ID, Thomas PS, Ramachandran TS (2002b) Decreased levels of N-acetylaspartate in dorsolateral prefrontal cortex in a case of intractable severe sympathetically mediated chronic pain (complex regional pain syndrome, type I). Brain Cogn 49(1):102–127PubMedCrossRefGoogle Scholar
  22. Grachev ID, Ramachandran TS, Thomas PS, Szeverenyi NM, Fredrickson BE (2003) Association between dorsolateral prefrontal N-acetyl aspartate and depression in chronic back pain: an in vivo proton magnetic resonance spectroscopy study. J Neural Transm 110(3):287–312PubMedCrossRefGoogle Scholar
  23. Gross S, Piwnica-Worms D (2005) Spying on cancer – molecular imaging in vivo with genetically encoded reporters. Cancer Cell 7:5–15PubMedGoogle Scholar
  24. Hammoud DA, Hoffman JM, Pomper M (2007) Molecular neuroimaging: from conventional to emerging techniques. Radiology 245:21–42PubMedCrossRefGoogle Scholar
  25. Hargreaves R, Wagner J (2006) Imaging as a biomarker for decision making in drug development. In: Beckmann N (ed) In vivo MR techniques in drug discovery and development. Taylor & Francis, New York Ch. 3, 31–46Google Scholar
  26. Jones C, Kapur S, Remington G, Zipursky RB (2000) Transient d2 dopamine receptor occupancy in low EPS-incidence drugs: PET evidence. Biol Psychiatry 47(8 suppl 1):S112CrossRefGoogle Scholar
  27. Kapur S, Zipursky RB, Remington G (1999) Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 156(2):286–293PubMedGoogle Scholar
  28. Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000) A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57(6):553–559PubMedCrossRefGoogle Scholar
  29. Keller M et al (2006) Lack of efficacy of the substance P (neurokinin 1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 59:216–223PubMedCrossRefGoogle Scholar
  30. Koroshetz WJ, Gonzalez G (1997) Diffusion-weighted MRI: an ECG for “brain attack”? Ann Neurol 41:565–566PubMedCrossRefGoogle Scholar
  31. Logothetis NK (2008) What we can do and what we cannot do with fMRI? Nature 453:869–878PubMedCrossRefGoogle Scholar
  32. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497PubMedCrossRefGoogle Scholar
  33. Mamo D, Kapur S, Shammi CM, Papatheodorou G, Mann S, Therrien F, Remington GA (2004) PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry 161(5):818–825PubMedCrossRefGoogle Scholar
  34. Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S (2007) Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 164(9):1411–1417PubMedCrossRefGoogle Scholar
  35. Massoud TF, Gambhir SS (2007) Integrating non-invasive molecular imaging into molecular medicine – an evolving paradigm. Trends Mol Med 13:183–191PubMedCrossRefGoogle Scholar
  36. Medarova Z, Pham W, Farrar C, Petkova V, Moore A (2007) In vivo imaging of siRNA delivery and silencing in tumors. Nat Med 13:372–377PubMedCrossRefGoogle Scholar
  37. Pomper MG, Lee JS (2005) Small animal imaging in drug development. Curr Pharm Des 11:3247–3272PubMedCrossRefGoogle Scholar
  38. Rudin M, Weissleder R (2003) Molecular imaging in drug discovery and development. Nat Rev Drug Discov 2:123–131PubMedCrossRefGoogle Scholar
  39. Rueger MA et al (2007) Role of in vivo imaging of the central nervous system for developing novel drugs. Q J Nucl Med Mol Imaging 51:164–181PubMedGoogle Scholar
  40. Salibi N, Brown MA (1998) Clinical MR spectroscopy: first principles. Wiley-Liss, TorontoGoogle Scholar
  41. Schuster DP (2007) The opportunities and challenges of developing imaging biomarkers to study lung function and disease. Am J Respir Crit Care Med 176:224–230PubMedCrossRefGoogle Scholar
  42. Schweinhardt P, Kalk N, Wartolowska K, Chessell I, Wordsworth P, Tracey I (2008) Investigation into the neural correlates of emotional augmentation of clinical pain. Neuroimage 40(2):759–766PubMedCrossRefGoogle Scholar
  43. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, Macklin ML, Lasko NB, Cavanagh SR, Krangel TS, Orr SP, Pitman RK, Whalen PJ, Rauch SL (2005) A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 62(3):273–281PubMedCrossRefGoogle Scholar
  44. Sosnovik DE, Weissleder R (2007) Emerging concepts in molecular MRI. Curr Opin Biotechnol 18:4–10PubMedCrossRefGoogle Scholar
  45. Tauscher J, Jones C, Remington G, Zipursky RB, Kapur S (2002a) Significant dissociation of brain and plasma kinetics with antipsychotics. Mol Psychiatry 7:317–321PubMedCrossRefGoogle Scholar
  46. Tauscher J, Küfferle B, Asenbaum S, Tauscher-Wisniewski S, Kasper S (2002b) Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. Psychopharmacology (Berl) 162(1):42–49CrossRefGoogle Scholar
  47. Whalen PJ, Rauch SL, Etcoff NL, McInerney SC, Lee MB, Jenike MA (1998) Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. J Neurosci 18:411–418PubMedGoogle Scholar
  48. Whalen PJ, Johnstone T, Somerville LH, Nitschke JB, Polis S, Alexander AL, Davidson RJ, Kalin NH (2008) A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder. Biol Psychiatry 63(9):858–863PubMedCrossRefGoogle Scholar
  49. Williams DS, Detre JA, Leigh JS, Koretsky AP (1992) Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci USA 89:212–216PubMedCrossRefGoogle Scholar
  50. Wise RG, Rogers R, Painter D, Bantick S, Ploghaus A, Williams P, Rapeport G, Tracey I (2002) Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil. Neuroimage 16(4):999–1014PubMedCrossRefGoogle Scholar
  51. Wise RG, Williams P, Tracey I (2004) Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain. Neuropsychopharmacology 29(3):626–635PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Schering-Plough, IncKenilworthUSA

Personalised recommendations