Key Points
-
Functional MRI (fMRI) has had a major impact in cognitive neuroscience. It now has promising applications in clinical and translational medicine.
-
fMRI can assess changes in relative blood oxygenation accompanying increased blood flow in regions of the brain that are active while a task (for example, hand movement) is performed. The most well-established clinical application of fMRI is for presurgical mapping; this guides a neurosurgeon to spare brain tissue that, if injured, would cause new clinical deficits or limit good recovery.
-
In combination with simultaneously acquired electroencephalography (EEG), fMRI can image blood oxygenation state changes that accompany spontaneously generated changes in brain state in order to localize the source of seizure-inducing activity in epilepsy. The spatial definition of MRI allows this to be done at a much higher resolution than with EEG alone.
-
A frontier area for fMRI is in the identification of neurophysiologically based intermediate phenotypes in ways that can characterize even disorders that do not show structural changes in the brain. Recent applications suggest that functional intermediate phenotypes could better define heterogeneity in psychotic and affective disorders, and could be used to predict treatment outcomes.
-
In some instances, intermediate phenotypes that are heritable are endophenotypes. Because endophenotypes can be determined by smaller numbers of genes than conventional clinical phenotypes, in some cases plausible allelic associations have been identified with sample sizes smaller than those required in usual association studies.
-
By defining functional anatomy that is related to behavioural or perceptual states, fMRI can also help to directly understand the genesis of symptoms. For example, fMRI dissection of the subjective experience of pain into anatomically distinct activities of different functional systems provides a rationale for treatment approaches that are based on the modulation of different, interacting pathways.
-
Applications of fMRI as a pharmacodynamic (or pharmacokinetic) measure (pharmacological fMRI or phMRI) suggest that it might assume an important role in drug development. There are already several examples in which fMRI has been shown to be sensitive to change after a therapeutic intervention.
-
However, there remain practical problems that need to be resolved before fMRI can be used routinely. Signal changes are small, there are many confounds affecting the signal-to-noise ratio and the underlying physiological response itself is highly variable.
-
The promise of this new technique is substantial, but it is clear that the widespread introduction of clinical fMRI will demand new skills and working methods in clinical neuroradiology if this promise is to be delivered.
Abstract
Functional MRI (fMRI) has had a major impact in cognitive neuroscience. fMRI now has a small but growing role in clinical neuroimaging, with initial applications to neurosurgical planning. Current clinical research has emphasized novel concepts for clinicians, such as the role of plasticity in recovery and the maintenance of brain functions in a broad range of diseases. There is a wider potential for clinical fMRI in applications ranging from presymptomatic diagnosis, through drug development and individualization of therapies, to understanding functional brain disorders. Realization of this potential will require changes in the way clinical neuroimaging services are planned and delivered.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Matthews, P. M. & Jezzard, P. Functional magnetic resonance imaging. J. Neurol. Neurosurg. Psychiatr. 75, 6–12 (2004).
Belliveau, J. W. et al. Magnetic resonance imaging mapping of brain function. Human visual cortex. Invest. Radiol. 27, S59–S65 (1992).
Kwong, K. K. et al. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc. Natl Acad. Sci. USA 89, 5675–5679 (1992). This seminal paper describes the theory and phenomenon of fMRI, supported by a compelling series of experiments. A methods paper that is almost unrivalled for completeness and clarity in this young field.
Ogawa, S., Lee, T. M., Kay, A. R. & Tank, D. W. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc. Natl Acad. Sci. USA 87, 9868–9872 (1990).
Cabeza, R. & Nyberg, L. Imaging cognition II: an empirical review of 275 PET and fMRI studies. J. Cogn. Neurosci. 12, 1–47 (2000).
Yousry, T. A. et al. Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. Brain 120, 141–157 (1997).
Price, C. J. The anatomy of language: contributions from functional neuroimaging. J. Anat. 197, 335–359 (2000).
van Westen, D. et al. Fingersomatotopy in area 3b: an fMRI-study. BMC Neurosci. 5, 28 (2004).
Uylings, H. B., Rajkowska, G., Sanz-Arigita, E., Amunts, K. & Zilles, K. Consequences of large interindividual variability for human brain atlases: converging macroscopical imaging and microscopical neuroanatomy. Anat. Embryol. (Berl) 210, 423–431 (2005).
Haberg, A., Kvistad, K. A., Unsgard, G. & Haraldseth, O. Preoperative blood oxygen level-dependent functional magnetic resonance imaging in patients with primary brain tumors: clinical application and outcome. Neurosurgery 54, 902–914; discussion 914–915 (2004).
Lee, M. et al. The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis. Ann. Neurol. 47, 606–613 (2000). Provides evidence from patients with multiple sclerosis that adaptive plasticity acts as a general mechanism to limit expression of the disability caused by brain injury or disease, even in adults.
Adcock, J. E., Wise, R. G., Oxbury, J. M., Oxbury, S. M. & Matthews, P. M. Quantitative fMRI assessment of the differences in lateralization of language-related brain activation in patients with temporal lobe epilepsy. Neuroimage 18, 423–438 (2003).
Binder, J. R. et al. Determination of language dominance using functional MRI: a comparison with the Wada test. Neurology 46, 978–984 (1996).
Rutten, G. J. et al. Toward functional neuronavigation: implementation of functional magnetic resonance imaging data in a surgical guidance system for intraoperative identification of motor and language cortices. Technical note and illustrative case. Neurosurg. Focus 15, E6 (2003).
Fischer, M. J., Scheler, G. & Stefan, H. Utilization of magnetoencephalography results to obtain favourable outcomes in epilepsy surgery. Brain 128, 153–157 (2005).
Gralla, J. et al. Image-guided removal of supratentorial cavernomas in critical brain areas: application of neuronavigation and intraoperative magnetic resonance imaging. Minim. Invasive. Neurosurg. 46, 72–77 (2003).
Liegeois, F. et al. Language reorganization in children with early-onset lesions of the left hemisphere: an fMRI study. Brain 127, 1229–1236 (2004).
Richardson, M. P. et al. Pre-operative verbal memory fMRI predicts post-operative memory decline after left temporal lobe resection. Brain 127, 2419–2426 (2004).
Ramnani, N., Behrens, T. E., Penny, W. & Matthews, P. M. New approaches for exploring anatomical and functional connectivity in the human brain. Biol. Psychiatry 56, 613–619 (2004).
Wilms, G., Demaerel, P. & Sunaert, S. Intra-axial brain tumours. Eur. Radiol. 15, 468–484 (2005).
Devlin, J. T. et al. Reliable identification of the auditory thalamus using multi-modal structural analyses. Neuroimage 30, 1112–1120 (2006).
Behrens, T. E. et al. Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nature Neurosci. 6, 750–757 (2003).
Johansen-Berg, H. et al. Changes in connectivity profiles define functionally distinct regions in human medial frontal cortex. Proc. Natl Acad. Sci. USA 101, 13335–13340 (2004).
Hesselmann, V. et al. Intraoperative functional MRI as a new approach to monitor deep brain stimulation in Parkinson's disease. Eur. Radiol. 14, 686–690 (2004).
Georgi, J. C., Stippich, C., Tronnier, V. M. & Heiland, S. Active deep brain stimulation during MRI: a feasibility study. Magn. Reson. Med. 51, 380–388 (2004).
Brammer, M. J. in Functional MRI: An Introduction to Methods (eds Jezzard, P., Matthews, P. M. & Smith, S.) 243–250 (Oxford University Press, Oxford, 2001).
Tjandra, T. et al. Quantitative assessment of the reproducibility of functional activation measured with BOLD and MR perfusion imaging: implications for clinical trial design. Neuroimage 27, 393–401 (2005).
Johansen-Berg, H. et al. The role of ipsilateral premotor cortex in hand movement after stroke. Proc. Natl Acad. Sci. USA 99, 14518–14523 (2002). Illustrates, with the analysis of ipsilateral motor cortical activity in recovery after a motor stroke, the potential for transcranial magnetic stimulation to be used as a way of testing the functional significance of activity associated with a behaviour assessed by fMRI.
Schwarz, A. J. et al. Concurrent pharmacological MRI and in situ microdialysis of cocaine reveal a complex relationship between the central hemodynamic response and local dopamine concentration. Neuroimage 23, 296–304 (2004).
Shulman, R. G., Rothman, D. L., Behar, K. L. & Hyder, F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci. 27, 489–495 (2004).
Gracco, V. L., Tremblay, P. & Pike, B. Imaging speech production using fMRI. Neuroimage 26, 294–301 (2005).
Hadjikhani, N. et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc. Natl Acad. Sci. USA 98, 4687–4692 (2001). An elegant demonstration of how spontaneous activity can be imaged in the brain, using fMRI to better define the relationship between neurophysiological changes and symptoms in migraine.
Cao, Y., Aurora, S. K., Nagesh, V., Patel, S. C. & Welch, K. M. Functional MRI-BOLD of brainstem structures during visually triggered migraine. Neurology 59, 72–78 (2002).
Lemieux, L. Electroencephalography-correlated functional MR imaging studies of epileptic activity. Neuroimaging Clin. N. Am. 14, 487–506 (2004).
Boor, S. et al. EEG-related functional MRI in benign childhood epilepsy with centrotemporal spikes. Epilepsia 44, 688–692 (2003).
Gotman, J. et al. Generalized epileptic discharges show thalamocortical activation and suspension of the default state of the brain. Proc. Natl Acad. Sci. USA 102, 15236–15240 (2005). This paper makes the compelling argument that central generators for primary generalized epilepsy are localized in the thalamus on the basis of combined EEG and fMRI studies: a striking example of the application of this new integration of technology for exciting new clinical neuroscience.
Lemieux, L., Allen, P. J., Franconi, F., Symms, M. R. & Fish, D. R. Recording of EEG during fMRI experiments: patient safety. Magn. Reson. Med. 38, 943–952 (1997).
Niazy, R. K., Beckmann, C. F., Iannetti, G. D., Brady, J. M. & Smith, S. M. Removal of FMRI environment artifacts from EEG data using optimal basis sets. Neuroimage 28, 720–737 (2005).
Gottesman, I. I. & Gould, T. D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160, 636–645 (2003).
Egan, M. F. et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA 98, 6917–6922 (2001). One of a series of papers illustrating how imaging can be used as an endophenotype for the characterization of genes that influence complex disease expression. The Weinberger laboratory has pioneered this approach for psychiatric disease.
Egan, M. F. et al. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc. Natl Acad. Sci. USA 101, 12604–12609 (2004).
Fu, C. H. et al. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch. Gen. Psychiatry 61, 877–889 (2004). One of the first studies to show how fMRI could be used to provide a short-term outcome measure that is potentially predictive of longer-term clinical treatment responses.
Kippenhan, J. S. et al. Genetic contributions to human gyrification: sulcal morphometry in Williams syndrome. J. Neurosci. 25, 7840–7846 (2005).
Thompson, P. M. et al. Abnormal cortical complexity and thickness profiles mapped in Williams syndrome. J. Neurosci. 25, 4146–4158 (2005).
Tomaiuolo, F. et al. Morphology and morphometry of the corpus callosum in Williams syndrome: a T1-weighted MRI study. Neuroreport 13, 2281–2284 (2002).
Jones, W. et al. Cerebellar abnormalities in infants and toddlers with Williams syndrome. Dev. Med. Child. Neurol. 44, 688–694 (2002).
Meyer-Lindenberg, A. et al. Neural correlates of genetically abnormal social cognition in Williams syndrome. Nature Neurosci. 8, 991–993 (2005).
Meyer-Lindenberg, A. et al. Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron 43, 623–631 (2004).
Honey, G. D. et al. Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function. Brain 128, 2597–2611 (2005).
Honey, G. D. et al. The functional neuroanatomy of schizophrenic subsyndromes. Psychol. Med. 33, 1007–1018 (2003).
MacDonald, A. W. et al. Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis. Am. J. Psychiatry 162, 475–484 (2005).
Barch, D. M., Sheline, Y. I., Csernansky, J. G. & Snyder, A. Z. Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression. Biol. Psychiatry 53, 376–384 (2003).
Callicott, J. H. et al. Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. Am. J. Psychiatry 160, 709–719 (2003).
Whalley, H. C. et al. fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia. Brain 127, 478–490 (2004).
Morey, R. A. et al. Imaging frontostriatal function in ultra-high-risk, early, and chronic schizophrenia during executive processing. Arch. Gen. Psychiatry 62, 254–262 (2005).
Whalley, H. C. et al. Functional disconnectivity in subjects at high genetic risk of schizophrenia. Brain 128, 2097–2108 (2005).
Whalley, H. C. et al. Functional Imaging as a Predictor of Schizophrenia. Biol. Psychiatry 7 Feb 2006 (doi:10.1016/j.biopsych.2005.11.013).
Callicott, J. H. et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc. Natl Acad. Sci. USA 102, 8627–8632 (2005).
Hariri, A. R. et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch. Gen. Psychiatry 62, 146–152 (2005).
Hariri, A. R. et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400–403 (2002).
Pezawas, L. et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neurosci. 8, 828–834 (2005). An unusually complete paper that integrates information from brain structure, function as determined by fMRI and genetics to test more fully a compelling hypothesis regarding the genesis of depression.
Heinz, A. et al. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nature Neurosci. 8, 20–21 (2005).
Smith, K. A. et al. Cerebellar responses during anticipation of noxious stimuli in subjects recovered from depression. Functional magnetic resonance imaging study. Br. J. Psychiatry 181, 411–415 (2002).
Baghai, T. C., Moller, H. J. & Rupprecht, R. Recent progress in pharmacological and non-pharmacological treatment options of major depression. Curr. Pharm. Des. 12, 503–515 (2006).
Sheline, Y. I. et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol. Psychiatry 50, 651–658 (2001).
Canli, T. et al. Amygdala reactivity to emotional faces predicts improvement in major depression. Neuroreport 16, 1267–1270 (2005).
Killgore, W. D. & Yurgelun-Todd, D. A. Ventromedial prefrontal activity correlates with depressed mood in adolescent children. Neuroreport 17, 167–171 (2006).
Anand, A. et al. Antidepressant effect on connectivity of the mood-regulating circuit: an FMRI study. Neuropsychopharmacology 30, 1334–1344 (2005).
David, S. P. et al. Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: a functional magnetic resonance imaging study. Biol. Psychiatry 58, 488–494 (2005).
Myrick, H. et al. Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving. Neuropsychopharmacology 29, 393–402 (2004).
Reuter, J. et al. Pathological gambling is linked to reduced activation of the mesolimbic reward system. Nature Neurosci. 8, 147–148 (2005).
Paulus, M. P., Tapert, S. F. & Schuckit, M. A. Neural activation patterns of methamphetamine-dependent subjects during decision making predict relapse. Arch. Gen. Psychiatry 62, 761–768 (2005).
Kaufman, J. N., Ross, T. J., Stein, E. A. & Garavan, H. Cingulate hypoactivity in cocaine users during a GO-NOGO task as revealed by event-related functional magnetic resonance imaging. J. Neurosci. 23, 7839–7843 (2003).
Forman, S. D. et al. Opiate addicts lack error-dependent activation of rostral anterior cingulate. Biol. Psychiatry 55, 531–537 (2004).
Heinz, A. et al. Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving. Am. J. Psychiatry 161, 1783–1789 (2004). A pioneering study relating variations in apparent striatal dopamine receptor density determined by PET with inter-individual differences in orbitofrontal cortex activity and alcohol craving among abstinent alcoholics.
Wexler, B. E. et al. Functional magnetic resonance imaging of cocaine craving. Am. J. Psychiatry 158, 86–95 (2001).
Mattay, V. S. et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc. Natl Acad. Sci. USA 100, 6186–6191 (2003).
Schweinsburg, A. D. et al. An FMRI study of response inhibition in youths with a family history of alcoholism. Ann. NY Acad. Sci. 1021, 391–394 (2004).
Ballmaier, M. & Schmidt, R. Conversion disorder revisited. Funct. Neurol. 20, 105–113 (2005).
Marshall, J. C., Halligan, P. W., Fink, G. R., Wade, D. T. & Frackowiak, R. S. The functional anatomy of a hysterical paralysis. Cognition 64, B1–B8 (1997).
Halligan, P. W., Bass, C. & Wade, D. T. New approaches to conversion hysteria. BMJ 320, 1488–1489 (2000).
Mailis-Gagnon, A. et al. Altered central somatosensory processing in chronic pain patients with 'hysterical' anesthesia. Neurology 60, 1501–1507 (2003).
Spence, S. A., Crimlisk, H. L., Cope, H., Ron, M. A. & Grasby, P. M. Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement. Lancet 355, 1243–1244 (2000).
Werring, D. J., Weston, L., Bullmore, E. T., Plant, G. T. & Ron, M. A. Functional magnetic resonance imaging of the cerebral response to visual stimulation in medically unexplained visual loss. Psychol. Med. 34, 583–589 (2004).
Caesar, K., Thomsen, K. & Lauritzen, M. Dissociation of spikes, synaptic activity, and activity-dependent increments in rat cerebellar blood flow by tonic synaptic inhibition. Proc. Natl Acad. Sci. USA 100, 16000–16005 (2003).
Bookheimer, S. Y. et al. Patterns of brain activation in people at risk for Alzheimer's disease. N. Engl. J. Med. 343, 450–456 (2000). An early fMRI clinical applications study suggesting that the initial phases of Alzheimer's disease might not be manifested clinically because of adaptive changes in brain functions in compensation. These changes could be used as a marker of risk in some high-risk populations.
Reddy, H. et al. Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain 123, 2314–2320 (2000).
Rombouts, S. A. et al. Loss of frontal fMRI activation in early frontotemporal dementia compared to early AD. Neurology 60, 1904–1908 (2003).
Floyer-Lea, A. & Matthews, P. M. Changing brain networks for visuomotor control with increased movement automaticity. J. Neurophysiol. 92, 2405–2412 (2004).
Parry, A. M., Scott, R. B., Palace, J., Smith, S. & Matthews, P. M. Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. Brain 126, 2750–2760 (2003).
Iaria, G., Petrides, M., Dagher, A., Pike, B. & Bohbot, V. D. Cognitive strategies dependent on the hippocampus and caudate nucleus in human navigation: variability and change with practice. J. Neurosci. 23, 5945–5952 (2003). Illustrates how important cognitive strategy is to the pattern of fMRI brain activation associated with a given task.
Vlieger, E. J., Lavini, C., Majoie, C. B. & den Heeten, G. J. Reproducibility of functional MR imaging results using two different MR systems. AJNR Am. J. Neuroradiol. 24, 652–657 (2003).
Maxim, V. et al. Fractional Gaussian noise, functional MRI and Alzheimer's disease. Neuroimage 25, 141–158 (2005).
Krings, T. et al. Functional MRI for presurgical planning: problems, artefacts, and solution strategies. J. Neurol. Neurosurg. Psychiatry 70, 749–760 (2001).
Smith, S. M. et al. Variability in fMRI: a re-examination of inter-session differences. Hum. Brain Mapp. 24, 248–257 (2005).
Ward, N. S. & Frackowiak, R. S. Age-related changes in the neural correlates of motor performance. Brain 126, 873–888 (2003).
D'Esposito, M., Deouell, L. Y. & Gazzaley, A. Alterations in the BOLD fMRI signal with ageing and disease: a challenge for neuroimaging. Nature Rev. Neurosci. 4, 863–872 (2003).
Laurienti, P. J. et al. Relationship between caffeine-induced changes in resting cerebral perfusion and blood oxygenation level-dependent signal. AJNR Am. J. Neuroradiol. 24, 1607–1611 (2003).
Lawrence, N. S., Ross, T. J. & Stein, E. A. Cognitive mechanisms of nicotine on visual attention. Neuron 36, 539–548 (2002).
St Lawrence, K. S., Ye, F. Q., Lewis, B. K., Frank, J. A. & McLaughlin, A. C. Measuring the effects of indomethacin on changes in cerebral oxidative metabolism and cerebral blood flow during sensorimotor activation. Magn. Reson. Med. 50, 99–106 (2003).
Tracey, I. Nociceptive processing in the human brain. Curr. Opin. Neurobiol. 15, 478–487 (2005).
Gundel, H., O'Connor, M. F., Littrell, L., Fort, C. & Lane, R. D. Functional neuroanatomy of grief: an FMRI study. Am. J. Psychiatry 160, 1946–1953 (2003).
Saarela, M. V. et al. The compassionate brain: humans detect intensity of pain from another's face. Cereb. Cortex 22 Feb 2006 (doi:10.1093/cercor/bhj141).
Borsook, D., Ploghaus, A. & Becerra, L. Utilizing brain imaging for analgesic drug development. Curr. Opin. Investig. Drugs 3, 1342–1347 (2002).
Coghill, R. C., McHaffie, J. G. & Yen, Y. F. Neural correlates of interindividual differences in the subjective experience of pain. Proc. Natl Acad. Sci. USA 100, 8538–8542 (2003).
Wise, R. G. et al. Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil. Neuroimage 16, 999–1014 (2002).
Rogers, R., Wise, R. G., Painter, D. J., Longe, S. E. & Tracey, I. An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging. Anesthesiology 100, 292–301 (2004).
Koeppe, C. et al. The influence of the 5-HT3 receptor antagonist tropisetron on pain in fibromyalgia: a functional magnetic resonance imaging pilot study. Scand. J. Rheumatol. Suppl., 24–27 (2004).
Lieberman, M. D. et al. The neural correlates of placebo effects: a disruption account. Neuroimage 22, 447–455 (2004).
Petrovic, P. et al. Placebo in emotional processing — induced expectations of anxiety relief activate a generalized modulatory network. Neuron 46, 957–969 (2005). Synthesizes hypotheses regarding the placebo effect in the immediate context of recent imaging studies and suggests that the functioning of reward and motivational systems might account for mechanisms of the placebo effect across different types of noxious stimulus.
Wager, T. D. et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 303, 1162–1167 (2004).
Henderson, L. A., Bandler, R., Gandevia, S. C. & Macefield, V. G. Distinct forebrain activity patterns during deep versus superficial pain. Pain 120, 286–296 (2006).
Singer, T. et al. Empathy for pain involves the affective but not sensory components of pain. Science 303, 1157–1162 (2004).
Dierks, T. et al. Activation of Heschl's gyrus during auditory hallucinations. Neuron 22, 615–621 (1999).
Shergill, S. S. et al. Temporal course of auditory hallucinations. Br. J. Psychiatry 185, 516–517 (2004).
Shergill, S. S., Brammer, M. J., Williams, S. C., Murray, R. M. & McGuire, P. K. Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch. Gen. Psychiatry 57, 1033–1038 (2000).
Hunter, M. D. et al. A neural basis for the perception of voices in external auditory space. Brain 126, 161–169 (2003).
Jacobs, L. D. et al. Intramuscular interferon β-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N. Engl. J. Med. 343, 898–904 (2000).
Aylward, E. H. et al. Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington's disease. Mov. Disord. 15, 552–560 (2000).
den Heijer, T. et al. Use of hippocampal and amygdalar volumes on magnetic resonance imaging to predict dementia in cognitively intact elderly people. Arch. Gen. Psychiatry 63, 57–62 (2006).
Kim, J. S. et al. Functional MRI study of a serial reaction time task in Huntington's disease. Psychiatry Res. 131, 23–30 (2004).
Dickerson, B. C. et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 65, 404–411 (2005).
Chong, M. S. & Sahadevan, S. Preclinical Alzheimer's disease: diagnosis and prediction of progression. Lancet Neurol. 4, 576–579 (2005).
Honey, G. & Bullmore, E. Human pharmacological MRI. Trends Pharmacol. Sci. 25, 366–374 (2004).
Stein, E. A. et al. Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am. J. Psychiatry 155, 1009–1015 (1998).
Vollm, B. A. et al. Methamphetamine activates reward circuitry in drug naive human subjects. Neuropsychopharmacology 29, 1715–1722 (2004).
Gerdelat-Mas, A. et al. Chronic administration of selective serotonin reuptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects. Neuroimage 27, 314–322 (2005).
Pariente, J. et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann. Neurol. 50, 718–729 (2001).
Goekoop, R. et al. Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior. Neuroimage 25, 63–75 (2005).
Goekoop, R. et al. Challenging the cholinergic system in mild cognitive impairment: a pharmacological fMRI study. Neuroimage 23, 1450–1459 (2004).
Farahani, K., Slates, R., Shao, Y., Silverman, R. & Cherry, S. Contemporaneous positron emission tomography and MR imaging at 1.5 T. J. Magn. Reson. Imaging 9, 497–500 (1999).
Buxton, R. B., Uludag, K., Dubowitz, D. J. & Liu, T. T. Modeling the hemodynamic response to brain activation. Neuroimage 23, S220–S233 (2004).
Nahas, Z. et al. Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study. Neurocase 9, 274–282 (2003).
Rombouts, S. A., Barkhof, F., Van Meel, C. S. & Scheltens, P. Alterations in brain activation during cholinergic enhancement with rivastigmine in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 73, 665–671 (2002).
Saykin, A. J. et al. Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain 127, 1574–1583 (2004).
Mattay, V. S. et al. Dopaminergic modulation of cortical function in patients with Parkinson's disease. Ann. Neurol. 51, 156–164 (2002).
Wilkinson, D. & Halligan, P. The relevance of behavioural measures for functional-imaging studies of cognition. Nature Rev. Neurosci. 5, 67–73 (2004).
Matthews, P. M., Johansen-Berg, H. & Reddy, H. Non-invasive mapping of brain functions and brain recovery: applying lessons from cognitive neuroscience to neurorehabilitation. Restor. Neurol. Neurosci. 22, 245–260 (2004).
Sadato, N. How the blind 'see' Braille: lessons from functional magnetic resonance imaging. Neuroscientist 11, 577–582 (2005).
Burton, H. et al. Adaptive changes in early and late blind: a fMRI study of Braille reading. J. Neurophysiol. 87, 589–607 (2002).
Seitz, R. J. et al. Large-scale plasticity of the human motor cortex. Neuroreport 6, 742–744 (1995).
Calautti, C. & Baron, J. C. Functional neuroimaging studies of motor recovery after stroke in adults: a review. Stroke 34, 1553–1566 (2003).
Pantano, P. et al. Contribution of corticospinal tract damage to cortical motor reorganization after a single clinical attack of multiple sclerosis. Neuroimage 17, 1837–1843 (2002).
Reddy, H. et al. Relating axonal injury to functional recovery in MS. Neurology 54, 236–239 (2000).
Lee, M. A. et al. Axonal injury or loss in the internal capsule and motor impairment in multiple sclerosis. Arch. Neurol. 57, 65–70 (2000).
Rocca, M. A. et al. Evidence for widespread movement-associated functional MRI changes in patients with PPMS. Neurology 58, 866–872 (2002).
Luft, A. R. et al. Lesion location alters brain activation in chronically impaired stroke survivors. Neuroimage 21, 924–935 (2004).
Reddy, H. et al. Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Brain 125, 2646–2657 (2002).
Taub, E., Uswatte, G. & Elbert, T. New treatments in neurorehabilitation founded on basic research. Nature Rev. Neurosci. 3, 228–236 (2002).
Ward, N. S. et al. Motor system activation after subcortical stroke depends on corticospinal system integrity. Brain 129, 809–819 (2006).
Ward, N. S. & Cohen, L. G. Mechanisms underlying recovery of motor function after stroke. Arch. Neurol. 61, 1844–1848 (2004).
Wade, D. T. Rehabilitation research — time for a change of focus. Lancet Neurol. 1, 209 (2002).
Johansen-Berg, H. et al. Correlation between motor improvements and altered fMRI activity after rehabilitative therapy. Brain 125, 2731–2742 (2002). An early demonstration of how fMRI can be used to relate functional changes in specific brain regions to behavioural improvements after neurorehabilitation post-stroke, with findings that suggest that motor learning and stroke recovery share some common mechanisms.
Luft, A. R. et al. Repetitive bilateral arm training and motor cortex activation in chronic stroke: a randomized controlled trial. JAMA 292, 1853–1861 (2004).
Silani, G. et al. Brain abnormalities underlying altered activation in dyslexia: a voxel based morphometry study. Brain 128, 2453–2461 (2005).
Eckert, M. Neuroanatomical markers for dyslexia: a review of dyslexia structural imaging studies. Neuroscientist 10, 362–371 (2004).
Price, C. J. & Crinion, J. The latest on functional imaging studies of aphasic stroke. Curr. Opin. Neurol. 18, 429–434 (2005).
Turkeltaub, P. E., Gareau, L., Flowers, D. L., Zeffiro, T. A. & Eden, G. F. Development of neural mechanisms for reading. Nature Neurosci. 6, 767–773 (2003).
Temple, E. et al. Neural deficits in children with dyslexia ameliorated by behavioral remediation: evidence from functional MRI. Proc. Natl Acad. Sci. USA 100, 2860–2865 (2003).
Montague, P. R. et al. Hyperscanning: simultaneous fMRI during linked social interactions. Neuroimage 16, 1159–1164 (2002).
Franceschini, M. A. & Boas, D. A. Noninvasive measurement of neuronal activity with near-infrared optical imaging. Neuroimage 21, 372–386 (2004).
Logothetis, N. K. The underpinnings of the BOLD functional magnetic resonance imaging signal. J. Neurosci. 23, 3963–3971 (2003).
Attwell, D. & Iadecola, C. The neural basis of functional brain imaging signals. Trends Neurosci. 25, 621–625 (2002).
Magistretti, P. J. & Pellerin, L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos. Trans. R. Soc. Lond. B Biol. Sci. 354, 1155–1163 (1999).
Buerk, D. G., Ances, B. M., Greenberg, J. H. & Detre, J. A. Temporal dynamics of brain tissue nitric oxide during functional forepaw stimulation in rats. Neuroimage 18, 1–9 (2003).
Thulborn, K. R., Waterton, J. C., Matthews, P. M. & Radda, G. K. Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochim. Biophys. Acta 714, 265–270 (1982).
Yang, Y., Gu, H. & Stein, E. A. Simultaneous MRI acquisition of blood volume, blood flow, and blood oxygenation information during brain activation. Magn. Reson. Med. 52, 1407–1417 (2004).
Schwindack, C. et al. Real-time functional magnetic resonance imaging (rt-fMRI) in patients with brain tumours: preliminary findings using motor and language paradigms. Br. J. Neurosurg. 19, 25–32 (2005).
Gasser, T. et al. Intraoperative functional MRI: implementation and preliminary experience. Neuroimage 26, 685–693 (2005).
Hoge, R. D. & Pike, G. B. Oxidative metabolism and the detection of neuronal activation via imaging. J. Chem. Neuroanat. 22, 43–52 (2001).
Hoge, R. D. et al. Linear coupling between cerebral blood flow and oxygen consumption in activated human cortex. Proc. Natl Acad. Sci. USA 96, 9403–9408 (1999).
Iannetti, G. D. et al. Simultaneous recording of laser-evoked brain potentials and continuous, high-field functional magnetic resonance imaging in humans. Neuroimage 28, 708–719 (2005).
Sibson, N. R. et al. MRI detection of early endothelial activation in brain inflammation. Magn. Reson. Med. 51, 248–252 (2004).
Biswal, B., Yetkin, F. Z., Haughton, V. M. & Hyde, J. S. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn. Reson. Med. 34, 537–541 (1995).
Raichle, M. E. et al. A default mode of brain function. Proc. Natl Acad. Sci. USA 98, 676–682 (2001).
Lowe, M. J., Dzemidzic, M., Lurito, J. T., Mathews, V. P. & Phillips, M. D. Correlations in low-frequency BOLD fluctuations reflect cortico-cortical connections. Neuroimage 12, 582–587 (2000).
De Luca, M., Beckmann, C. F., De Stefano, N., Matthews, P. M. & Smith, S. M. fMRI resting state networks define distinct modes of long-distance interactions in the human brain. Neuroimage 29, 1359–1367 (2006).
Kiviniemi, V. et al. Slow vasomotor fluctuation in fMRI of anesthetized child brain. Magn. Reson. Med. 44, 373–378 (2000).
Wise, R. G., Ide, K., Poulin, M. J. & Tracey, I. Resting fluctuations in arterial carbon dioxide induce significant low frequency variations in BOLD signal. Neuroimage 21, 1652–1664 (2004).
Leopold, D. A. & Logothetis, N. K. Spatial patterns of spontaneous local field activity in the monkey visual cortex. Rev. Neurosci. 14, 195–205 (2003).
Moosmann, M. et al. Correlates of alpha rhythm in functional magnetic resonance imaging and near infrared spectroscopy. Neuroimage 20, 145–158 (2003). An insightful series of experiments providing direct evidence that resting state networks observed with fMRI arise from low-frequency modulations of faster EEG activity. Particularly exciting is the suggestion that distinct resting state networks can be related to modulation of different frequencies of EEG activity.
Laufs, H. et al. EEG-correlated fMRI of human alpha activity. Neuroimage 19, 1463–1476 (2003).
Salvador, R. et al. Neurophysiological architecture of functional magnetic resonance images of human brain. Cereb. Cortex 15, 1332–1342 (2005).
Achard, S., Salvador, R., Whitcher, B., Suckling, J. & Bullmore, E. A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs. J. Neurosci. 26, 63–72 (2006).
Greicius, M. D., Srivastava, G., Reiss, A. L. & Menon, V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc. Natl Acad. Sci. USA 101, 4637–4642 (2004).
Acknowledgements
The authors are grateful to L. Lemieux, I. Tracey, H. Laufs, R. Wise and S. Sunaert for sharing images for figures. P.M.M. gratefully acknowledges the Medical Research Council and the Multiple Sclerosis Society of Great Britain and Northern Ireland for research support in the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
P.M.M. and E.T.B. are employees of GlaxoSmithKline.
Related links
Related links
DATABASES
OMIM
Glossary
- Positron emission tomography
-
(PET). A technique that images the distribution of positron-emitting tracer isotopes (for example, 11C-choline) incorporated into compounds of interest by tomographical mapping that is based on photons emitted from positron collisions.
- Functional MRI
-
(fMRI). An application of magnetic resonance to image physiological changes rather than structure. Use of blood-oxygen-level-dependent (BOLD) contrast is currently the most popular type.
- Diffusion MRI
-
An application of magnetic resonance to image the moility (diffusion) of tissue water, an index of microstructure sensitive to many pathologies.
- Functional neurosurgery
-
Neurosurgical procedures directed towards altering brain function through the ablation of tissue or implantation of stimulation electrodes.
- Voxel
-
A voxel is the three-dimensional (3D) equivalent of a pixel; a finite volume within 3D space. This corresponds to the smallest element measured in a 3D anatomical or functional brain image volume.
- Transcranial magnetic stimulation
-
A method by which a single or series of brief magnetic pulses that are applied externally to the skull focally modulate brain function through the generation of intracortical electrical currents. Effects can be stimulatory or inhibitory depending on the approach.
- Functional connectivity
-
A measure typically derived from the relative temporal correlation of brain regions in a physiological image that is interpreted to express the degree to which regions are functionally interacting.
- Functional plasticity
-
Changes in the functional association of activity in a brain region, provoked by alterations of intrinsic brain function rather than by the context of the activities alone.
Rights and permissions
About this article
Cite this article
Matthews, P., Honey, G. & Bullmore, E. Applications of fMRI in translational medicine and clinical practice. Nat Rev Neurosci 7, 732–744 (2006). https://doi.org/10.1038/nrn1929
Issue Date:
DOI: https://doi.org/10.1038/nrn1929
This article is cited by
-
First implementation of dynamic oxygen-17 (17O) magnetic resonance imaging at 7 Tesla during neuronal stimulation in the human brain
Magnetic Resonance Materials in Physics, Biology and Medicine (2023)
-
A state-of-the-art review on deep learning for estimating eloquent cortex from resting-state fMRI
Neurosurgical Review (2023)
-
Arterial occlusion duration affects the cuff-induced hyperemic response in skeletal muscle BOLD perfusion imaging as shown in young healthy subjects
Magnetic Resonance Materials in Physics, Biology and Medicine (2023)
-
Utilization of functional MRI language paradigms for pre-operative mapping: a systematic review
Neuroradiology (2020)
-
Assessing inter-individual differences with task-related functional neuroimaging
Nature Human Behaviour (2019)