The clinical potential of functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) has had a huge impact on understanding the healthy human brain. To date it has had much less impact in clinical neuroscience or clinical practice. The reasons for this are in part that the image acquisition, paradigm design, and data analysis strategies used presently are not sufficiently standardized. This makes the comparison of results across individuals, scanning sessions, and centers difficult. Nevertheless, there are emerging applications for clinical fMRI, and as the field matures the number of applications is likely to grow. It seems certain that fMRI has an important role to play in helping us understand the mechanisms of neuropsychiatric diseases and in helping to identify effective therapeutic strategies.     

Frontiers of brain mapping using MRI

Over the past dozen years, the use of MRI techniques to map brain function (fMRI) has sparked a great deal of research. The ability of fMRI to image several different physiological processes concurrently (i.e., blood oxygenation, blood flow, metabolism) and noninvasively over large volumes make it the ideal choice for many different areas of neuroscience research in addition to countless applications in clinical settings. Furthermore, with the advent of high magnetic fields (and other hardware advancements, i.e., parallel imaging) for both human and animal research, spatial and temporal resolutions continue to be pushed to higher levels because of increases in the sensitivity as well as specificity of MR-detectable functional signals. fMRI methodology continues to grow and has the ability to cater to many different research applications. There seems to be no foreseeable end in sight to the advancement of fMRI techniques and its subsequent use in basic research as well as in clinical settings. In this work, fMRI techniques and the ongoing development of existing techniques are discussed with implications for the future of fMRI.     

PACS-based functional magnetic resonance imaging.

The picture archiving and communication system (PACS) technology reaches its 10th anniversary. Retrospectively no one could foresee the impact the PACS would have to the health care enterprise, but it is common consent today, that PACS is the key technology crucial to daily clinical image operations and especially to image related basic and clinical research. During the past 10 years the PACS has been matured from a research and developmental stage into commercial products which are provided by all major modality and health care equipment vendors. The PACS, originally implemented in the Radiology Department, needs to grow and has already carried well beyond departmental limits conquering all image relevant areas inside the hospital. During the past 10 years a dramatic development in imaging techniques especially within MRI emerged. Advanced 3D- and 4D-MR imaging techniques result in much more images and more complex data objects than ever before which need to be implemented into the existing PACS. These new imaging techniques require intensive post-processing apart from the imaging modality which need to be integrated into the image workflow and the PACS implementation. Along with these new imaging techniques new clinical applications, e.g. stroke detection, and research applications, e.g. study of heart and brain function, in Neurology and Cardiology require changes to the traditional PACS concept. Therefore inter-disciplinary image distribution will become the high-water mark for the next 10 years in the PACS endeavor. This paper focuses on one new advanced imaging technique, functional magnetic resonance imaging (fMRI), and discusses how fMRI data is defined, what fMRI requires in terms of clinical and research applications and how to implement fMRI in the existing PACS.     

Exploring brain function with magnetic resonance imaging.

Since its invention in the early 1990s, functional magnetic resonance imaging (fMRI) has rapidly assumed a leading role among the techniques used to localize brain activity. The spatial and temporal resolution provided by state-of-the-art MR technology and its non-invasive character, which allows multiple studies of the same subject, are some of the main advantages of fMRI over the other functional neuroimaging modalities that are based on changes in blood flow and cortical metabolism. This paper describes the basic principles and methodology of fMRI and some aspects of its application to functional activation studies. Attention is focused on the physiology of the blood oxygenation level-dependent (BOLD) contrast mechanism and on the acquisition of functional time-series with echo planar imaging (EPI). We also provide an introduction to the current strategies for the correction of signal artefacts and other image processing techniques. In order to convey an idea of the numerous applications of fMRI, we will review some of the recent results in the fields of cognitive and sensorimotor psychology and physiology.     

The role of fMRI in drug discovery

Pharmacological functional (phMRI) studies are making a significant contribution to our understanding of drug-effects on brain systems. Pharmacological fMRI has an additional contribution to make in the translation of disease models and candidate compounds from preclinical to clinical investigation and in the early clinical stages of drug development. Here it can demonstrate a proof-of-concept of drug action in a small human cohort and thus contribute substantially to decision-making in drug development. We review the methods underlying pharmacological fMRI studies and the links that can be made between animal and human investigations. We discuss the potential fMRI markers of drug effect, experimental designs and caveats in interpreting hemodynamic fMRI data as reflective of changes in neuronal activity. Although there are no current published examples of fMRI applied to novel compounds, we illustrate the potential of fMRI across a range of applications and with specific reference to processing of pain in the human brain and pharmacological analgesia. Pharmacological fMRI is developing to meet the neuroscientific challenges. Electrophysiological methods can be used to corroborate the drug effects measured hemodynamically with fMRI. In future, pharmacological fMRI is likely to extend to examinations of the spinal cord and into pharmacogenetics to relate genetic polymorphisms to differential responses of the brain to drugs.     

Functional MR study of a motor task and the Tower of London task at 1.0 T

Introduction The use of functional magnetic resonance imaging (fMRI) for clinical applications and basic neuroscience is constantly increasing. The discussion about minimum performance requirement for a correct implementation of fMRI is still open, and one of the critical points is the magnetic field strength. We tested the feasibility of fMRI at 1.0 T during motor and cognitive tasks.Methods Fourteen healthy subjects were scanned during a motor task and 12 while performing the Tower of London task. In the activated areas, the percentage signal change due to BOLD (blood oxygenation level dependent) contrast was analysed. To check basic image quality of the acquisition system we measured quality indices in a temporal series of images of a phantom.Results Motor and cognitive brain activations matched previous results obtained at higher field strengths. The mean percentage change over subjects in the motor task was in the range 1.3–2.6% for the primary motor area and 0.8–6.7% for the cerebellum. In the cognitive task, the mean percentage change over subjects was 0.7–1.2% for a frontal area and 0.6–2.8% for a parietal area. The percentage noise of the phantom temporal series was less than 0.4%. Percentage changes and signal to noise ratio, although lower than that obtained with high-field systems, allowed activation maps to be obtained in all subjects.Conclusion Our results replicate previous fMRI results demonstrating reproducible motor-related brain activations and extend the field to a complex cognitive task, thus providing evidence of the safety for routine clinical use of 1-T equipment.A.B. and O.R. contributed equally to the realization of the study and to the drafting of the paper.     

Clinical applications of functional magnetic resonance imaging

Despite its immediate success as a tool for basic research, the clinical application of functional MRI(fMRI) is still limited. FMRI has proven useful for presurgical functional mapping of the eloquent cortices. Localization of the sensorimotor cortex by fMRI may be of relatively limited value because the sensorimotor cortex can often be readily localized by means of anatomical methods. In contrast, the language cortices may not be localized anatomically and the language dominant hemisphere has been determined by invasive Wada test. Previous reports have shown that fMRI can be a promising alternative to the Wada test. A recent clinical trial has suggested that fMRI can be used to diagnose Alzheimer's disease in its earliest stage, detecting subclinical deterioration of the memory function. FMRI may be useful to predict the future decline of memory in people with genetic risks. Monitoring of the functional recovery of post-stroke brains may be another promising clinical application of fMRI. FMRI has demonstrated functional reorganization of the brain that may be related to the restoration of motor and language functions.     

Ethics in fMRI Studies*

Abstract  Functional magnetic resonance imaging (fMRI) has surfaced as a powerful method to study brain function in humans. While the involvement of neuroradiologists in fMRI studies in the clinical setting is obvious, in neuroscience research most of the investigators are not specialists trained in reading brain images. Advances in neuroimaging are increasingly intersecting with issues of ethical, legal, and social interest. Debate on fMRI is starting, mainly under the impetus of a new interdisciplinary field, neuroethics. The objective of this review is to bring forth reflection and discussion about ethical issues regarding fMRI, with emphasis to the perspective of the neuroradiologist. EMBASE^? and MEDLINE^? were searched for articles pertaining to ethics in fMRI, between 1991 and 2007. A total of 42 articles were retrieved, 95% published in the last 6 years. Only 10% were published in radiology journals. The major potential ethical issues identified in the reviewed articles concerned recruitment of vulnerable groups; informed consent; incidental findings; limitations of the technique, interpretation and validity of results; risks and safety; confidentiality and privacy; fMRI applications outside the laboratory (presurgical planning; diagnostic and predictive potential; forensic, security, military and commercial use); and public communication of research results. Not all the identified issues in this review were directly relevant to neuroradiologists in particular, but for sure some did. Neuroradiologists must find the time and energy to have an important role in identifying and solving ethical (and related) issues in fMRI, working in collaboration with ethicists, social scientists, clinicians, neuroscience researchers, patients, healthy volunteers, journalists, marketers, lawyers, and policy makers. * This work received the award for the best scientific presentation at the 32^nd Congress of the European Society of Neuroradiology 2007.     

PET in neuroscience: dopaminergic, GABA/benzodiazepine, and opiate system

This article gives an overview on radiotracer imaging with positron emission tomography (PET) in measuring various aspects of neurotransmission. The review focuses on the dopaminergic system, the GABA/benzodiazepine system, and the opiate system. Besides dealing with the current clinical applications for brain PET studies with specific radiopharmaceuticals this article outlines an idea on potential future developments for the use of these methods in basic neuroscience.     

Applications of arterial spin labeled MRI in the brain

Perfusion provides oxygen and nutrients to tissues and is closely tied to tissue function while disorders of perfusion are major sources of medical morbidity and mortality. It has been almost two decades since the use of arterial spin labeling (ASL) for noninvasive perfusion imaging was first reported. While initial ASL magnetic resonance imaging (MRI) studies focused primarily on technological development and validation, a number of robust ASL implementations have emerged, and ASL MRI is now also available commercially on several platforms. As a result, basic science and clinical applications of ASL MRI have begun to proliferate. Although ASL MRI can be carried out in any organ, most studies to date have focused on the brain. This review covers selected research and clinical applications of ASL MRI in the brain to illustrate its potential in both neuroscience research and clinical care.     

Implementations of clinical functional magnetic resonance imaging using character-based paradigms for the prediction of Chinese language dominance

PURPOSE: Recently, functional MRI (fMRI) using word generation (WG) tasks has been shown to be effective for mapping the Chinese language-related brain areas. In clinical applications, however, patients' performance cannot be easily monitored during WG tasks. In this study, we evaluated the feasibility of a word choice (WC) paradigm in the clinical setting and compared the results with those from WG tasks. METHOD: Intrasubject comparisons of fMRI with both WG and WC paradigms were performed on six normal human subjects and two tumor patients. Subject responses in the WC paradigm, based on semantic judgments, were recorded. Activation strength, extent, and laterality were evaluated and compared. RESULTS: Our results showed that fMRI with the WC paradigm evoked weaker neuronal activation than that with the WG paradigm in Chinese language-related brain areas. It was sufficient to reveal language laterality for clinical use, however. In addition, it resulted in less nonlanguage-specific brain activation. CONCLUSION: Results from the patient data demonstrated strong evidence for the necessity of incorporating response monitoring during fMRI studies, which suggested that fMRI with the WC paradigm is more appropriate to be implemented for the prediction of Chinese language dominance in clinical environments.     

Molecular imaging: an overview and clinical applications

Molecular imaging is a new medical discipline that integrates cell biology, molecular biology and diagnostic imaging. Clinical applications of molecular imaging include the use of nuclear medicine, magnetic resonance imaging (MRI) and ultrasound (US). The nuclear medicine applications utilize devices such as single photon emission computerized tomography (SPECT) and positron emission tomography (PET). Molecular imaging has two basic applications. The first is diagnostic imaging, which is used to determine the location and extent of targeted molecules specific to the disease being assessed. The second is therapy, which is used to treat specific disease-targeted molecules. The basic principle of the diagnostic imaging application is derived from the ability of cell and molecular biologists to identify specific receptor sites associated with target molecules that characterize the disease process to be studied. The biology teams then develop molecular imaging agents, which will bind specifically to the target molecules of interest. The principle for using molecular targeting therapy is based on an extension of the diagnostic imaging principle. Basically, it is assumed that if the molecular probe does target the specific disease molecules of interest, the same molecular agent can be loaded with an agent that will deliver therapy to the targeted cells. Patients and physicians have the clinical expectation that molecular imaging, when used for diagnostic purposes, will significantly improve the time-liness as well as the accuracy of detecting the presence and extent of disease. When applied to therapy, the expectation is that FDA-approved agents will have been shown in clinical trials to provide a significant improvement in clinical outcomes over traditional therapy methods. The eventual clinical owners of molecular imaging may be a specialty group that is a hybrid by conventional measures. For example, the clinical owner should have fundamental knowledge in basic cellular and molecular biology but must also be certified as well as competent in the specific diagnostic imaging specialty applied (i.e. nuclear, MR or ultrasound). If the owner is also to be involved with therapy, experience and appropriate certification will also be required. Another issue relates specifically to the therapy applications in oncology. It is conceivable that traditional chemotherapy and radiotherapy may be replaced in part with molecular imaging therapy that utilizes target-specific agents to treat cancer on a non-toxic, outpatient basis. The issue to be addressed by the radiology administrator is whether this new discipline will be performed in the radiology department or oncology and radiotherapy departments. Clearly, radiology and its associated diagnostic imaging subspecialties are the most logical owner of molecular imaging. However, to make this ownership a reality will require major shifts in training requirements, as well as exertion of political influence from the radiology administrators against other specialties that have much to lose in terms of patient populations and revenue to their practice.     

Diagnostic functional MRI: illustrated clinical applications and decision-making

Functional magnetic resonance imaging (fMRI) has become a popular research tool, yet its use for diagnostic purposes and actual treatment planning has remained less widespread. The literature yields rather sparse evidence-based data on clinical fMRI applications and accordant decision-making. Notwithstanding, blood oxygenation level dependent (BOLD)- and arterial spin labeling (ASL)-fMRI can be judiciously combined with perfusion measurements, electroencephalographic (EEG) recordings, diffusion-weighted imaging (DWI), and fiber tractographies to assist clinical decisions. In this article we provide an overview of clinical fMRI applications based on illustrative examples. Assessment of cochlear implant candidates by fMRI is covered in some detail, and distinct reference is made to particular challenges imposed by brain tumors, other space-occupying lesions, cortical dysplasias, seizure disorders, and vascular malformations. Specific strategies, merits, and pitfalls of analyzing and interpreting diagnostic fMRI studies in individual patients are highlighted.     

Functional magnetic resonance imaging of median nerve stimulation in rats at 2.0 T

An animal model of sensory activation using fMRI at 2.0 T has been developed, demonstrating that fMRI studies on animals need not be limited to high field magnets. These methods produced reliable image intensity changes of 2% using median nerve stimulation in rats at 3 Hz and propofol as the anesthetic agent. At 6 Hz the activation was slightly but not statistically significantly greater. The feasibility of fMRI studies in animals using propofol suggests that it may be a useful anesthetic for fMRI studies in agitated adult patients or in children.     

Clinical applications of 99mTc-sestamibi scintimammography

Mammography is the imaging modality of choice in detection of early, nonpalpable breast cancer. However, scintimammography may prove to be a very useful adjunct to a nondiagnostic or difficult mammography. Future prospective studies will have to be designed so that the specific clinical applications of scintimammography will be well defined. To be clinically relevant, each niche where scintimammography is potentially indicated should be clearly evaluated and incorporated into an algorithm of investigation of breast cancer, taking into consideration the relative advantages and limitations of scintimammography. Special care to obtain high-quality scintimammographic studies is mandatory. Because poor quality studies may be the major drawback, the nuclear medicine community should remind the lesson learned from radiologic mammography. Furthermore, it is also hoped that significant improvement in the scintigraphic equipment and data acquisition will be seen in a very near future to have more widespread clinical diagnostic applications of scintimammography.     

Real-time functional MRI: development and emerging applications.

Real-time functional magnetic resonance imaging (fMRI) is an emerging technique for assessing the dynamic and robust changes in brain activation during an ongoing experiment. Real-time fMRI allows measurement of several processes within the brain as they occur. The extracted information can be used to monitor the quality of acquired data sets, serve as the basis for neurofeedback training, and manipulate scans for interactive paradigm designs. Although more work is needed, recent results have demonstrated a variety of potential applications for real-time fMRI for research and clinical use. We discuss these developments and focus on methods enabling real-time analysis of fMRI data sets, novel research applications arising from these approaches, and potential use of real-time fMRI in clinical settings.     

Effects of the acoustic noise of the gradient systems on fMRI: A study on auditory,motor, and visual cortices

MR acoustic, or sound, noise due to gradient pulsing has been one of the problems in MRI, both in patient scanning as well as in many areas of psychiatric and neuroscience research, such as brain fMRI. Especially in brain fMRI, sound noise is one of the serious noise sources that obscures the small signals obtainable from the subtle changes occurring in oxygenation status in the cortex and blood capillaries. Therefore, we have studied the effects of acoustic, or sound, noise arising in fMR imaging of the auditory, motor, and visual cortices. The results show that the effects of acoustic noise on motor and visual responses are opposite. That is, for motor activity, there is an increased total motor activation, whereas for visual stimulation, the corresponding (visual) cortical activity is diminished substantially when the subject is exposed to a loud acoustic sound. Although the current observations are preliminary and require more experimental confirmation, it seems that the observed acoustic-noise effects on brain functions, such as in the motor and visual cortices, are new observations and could have significant consequences in data observation and interpretation in future fMRI studies.     

Neurofunktionelle MRT bei hohen Feldern

Clinical/methodical issue

Functional magnetic resonance imaging (fMRI) examinations are limited in their sensitivity due to the low activation-induced signal change. Within short tolerable scan times the spatial resolution is thus limited.

Standard radiological methods

fMRI is a reliable tool in neuroscience as well as for clinical applications such as presurgical mapping of brain function.

Methodical innovations

The fMRI sensitivity improves greatly (more than linearly) with increasing magnetic field strengths. For many years this was the main driving force in the push towards higher field strengths, such as 7 T.

Performance

The sensitivity gain is greatest for high spatial resolution and fMRI with very high sub-millimeter resolution becomes feasible. Current results demonstrate that the localization of the blood oxygenation level dependent (BOLD) signal is better than previously assumed.

Achievements

High-field fMRI not only allows quantitative improvements but also opens the way to new information content, such as columnar and layer-dependent functional structures of the cortex. This may pave the way for further information, e.g. the directionality of cortico-cortical connections; however, these possibilities also pose new challenges. New methods for processing such high resolution data are required which do not require spatial smoothing and preserve the high information content.

Practical recommendations

Common spatial resolutions of 2–3 mm are still very well suited for examinations at 3 T where they benefit from the low signal void, lower geometrical distortion and reduced acoustic noise. To achieve higher resolution at 7 T parallel imaging and geometric distortion correction are essential and permit the best congruence with structural data. The echo time at 7 T should be adjusted to about 20–25 ms. Data processing for single subjects or patients should be performed with little or no smoothing to retain resolution. Group studies could achieve good correlation with local normalization. New methods for information extraction, such as multivariate pattern analysis may allow combination of group data without the need for voxel-based congruence.     

Investigations of the human visual system using functional magnetic resonance imaging (FMRI)

The application of functional magnetic resonance imaging (fMRI) in studies of the visual system provided significant advancement in our understanding of the organization and functional properties of visual areas in the human cortex. Recent technological and methodological improvements allowed studies to correlate neuronal activity with visual perception and demonstrated the ability of fMRI to observe distributed neural systems and to explore modulation of neural activity during higher cognitive processes. Preliminary applications in patients with visual impairments suggest that this method provides a powerful tool for the assessment and management of brain pathologies. Recent research focuses on obtaining new information about the spatial localization, organization, functional specialization and participation in higher cognitive functions of visual cortical areas in the living human brain and in further establishment of the method as a useful clinical tool of diagnostic and prognostic significance for various pathologic processes affecting the integrity of the visual system. It is anticipated that the combined neuroimaging approach in patients with lesions and healthy controls will provide new insight on the topography and functional specialization of cortical visual areas and will further establish the clinical value of the method for improving diagnostic accuracy and treatment planning.