The disruption of normal brain physiology is known to result in disorders of emotion and thought, as well as in physical disorders such as paralysis. Such altered neurological states can all be viewed as resulting from disruption of the course of neuronal signals due to dysfunction of at least one brain region. In recent years a number of methods for evaluating the functional activity of the human brain have been developed. Unfortunately, most imaging methods are limited to providing information on brain anatomy only, and offer little information regarding brain function. Many brain disorders can be detected using modalities such as CT, MRI, positron emission tomography (PET), single photon emission computed tomography (SPECT), electroencephalography (EEG), magnetoencephalography (MEG), and magnetic resonance spectroscopy (MRS). While most previous imaging modalities have provided only static information about brain anatomy, magnetic source imaging (MSI), the most recently introduced functional brain imaging method, combines the anatomic detail of MRI with the dynamic functional information provided by MEG to form a single magnetic source image.
Magnetoencephalography (MEG). MEG technique was first used to measure brain activity in 1968 by David Cohen.(1,2) Predominately because of the extremely long acquisition times and even longer processing times, 20 more years would pass before useful clinical results were generated using MEG and MSI. Early MEG examinations could easily require 8 to 12 hours of acquisition time and subsequently days to weeks for analysis. Currently, MEG examinations for routine clinical procedures are now commonly conducted in less than 1 hour each for acquisition and processing.(2,3)
Biomagnetic signals recorded from the human brain are faint in comparison to the earth’s magnetic field; background magnetic noise from power lines, indoor electricity, and moving magnetic objects may be 100,000 times the neuronal magnetic field. To record the weak signals from these minute magnetic fields emanating from the human brain, and discriminate them from background noise, a sensitive recording system is required.
Clinical magnetometers able to detect magnetic fields emanating from the human brain are so sensitive that they can be easily overwhelmed by background magnetic noise. To compensate for background noise, the room in which the equipment is kept must be magnetically shielded. Even extreme levels of shielding will fail to provide a completely noise-free environment. Nonetheless, current shielding designs are sufficient to permit exceedingly precise clinical evaluations.
MEG is a noninvasive modality that assesses the brain’s magnetic impulses in a manner that is in many respects similar and complementary to EEG. Both MEG and EEG share the definite advantage of real-time temporal resolution on a millisecond by millisecond scale. Additionally, MEG has inherent advantages compared with EEG. Mathematical analysis of MEG recordings of magnetic signals can provide precise anatomical localization of the origins of specific brain activities. Unlike the corresponding electrical signals of EEG, magnetic signals recorded by MEG are not distorted by the differential conductivities of cerebrospinal fluid, the meninges, the skull, and the scalp.
The temporal and spatial accuracy of MEG combined with the anatomic and pathological specificity of MRI result in a powerful synthesis, the magnetic source image. This potent combination allows simultaneous viewing of brain structure and function in various disease states, with corresponding tremendous implications for both neuroscience and clinical medicine.
Currently the clinical use of MSI includes one or more of the following four types of examinations:
- presurgical functional mapping,
- characterization of epileptiform activity,
- characterization of abnormal low frequency magnetic activity (ALFMA), and
- characterization of abnormal information processing.
Presurgical Functional Mapping. Accurate presurgical functional mapping greatly facilitates the neurosurgeon’s approach to surgical lesions. Since preservation of eloquent cortex is critical when resecting intracranial masses, neurosurgeons need to know the precise location of essential cortical functions in order to plan the appropriate treatment of brain lesions such as neoplasms, abscesses, or vascular malformations. Characterization of brain matter functionality can also be helpful for surgical planning. When primary or secondary epileptic activity is identified, surgical resection of dysfunctional brain tissue may be appropriate. In cases where intracranial masses impinge upon vital cortex, postoperative neurological deficits can be minimized if information regarding the locations of essential cortex is available.(4,7)
Although it is possible in many cases for neurosurgeons to determine the general location of primary sensory and motor cortex by direct visual inspection of a patient’s brain without resorting to functional imaging, normal variations are common enough that making these determinations visually is not consistently accurate. In fact, two neuroradiologists who are blinded to each other’s readings will not always be in consensus as to the location of the central sulcus or primary motor and sensory cortex on imaging studies either.(8) Additionally, distortion of the brain resulting from structural pathology frequently makes determination of the central sulcus even more difficult. In these sensitive cases involving eloquent brain areas, noninvasive MSI technique can be invaluable for directing the best surgical approach.
Prior to the development of accurate MSI technique, invasive procedures such as electrocorticography and direct electrical stimulation of the brain were required for functional mapping. However, the noninvasive technique of MSI is highly accurate when compared to these two invasive procedures that have historically been most accepted for localization of the somatosensory cortex, the brain region responsible for sense of touch. Electrocorticographic (EcoG) monitoring of somatosensory evoked responses requires that a craniotomy be performed and an electrode grid subsequently placed directly on the brain surface. The data arising from the EcoG study are not always readily interpreted, which can be problematic in the operating room when immediate results are needed. Direct electrical stimulation of the motor cortex, the brain region responsible for causing movement, with simultaneous monitoring for movement of the corresponding body part, is another invasive method of determining the exact location of sensorimotor cortex. Invasive testing carries several disadvantages and associated dangers compared to MSI. First, extensive intraoperative monitoring can substantially extend the length of the surgical procedure. Also, seizure activity can result from direct brain stimulation. Finally, another significant disadvantage that EcoG and direct electrical stimulation both share is the inability to provide critical brain functional information during the planning of the surgical approach.
MSI examination for presurgical mapping of the somatosensory cortex is regarded as the simplest and most straightforward use of this modality. The procedure involves signal-averaging methods consisting of presenting a stimulus many times in rapid succession. The data epochs spanning the stimulus are recorded and averaged together to separate time-locked neuromagnetic signals from the background noise. The end result is a highly accurate and detailed functional map of the cortex.
Characterization of Epileptiform Activity. Neuroimaging in epilepsy patients has increased tremendously in recent years. Anticonvulsant medications are ineffective or contraindicated in as many as one out of five epilepsy patients. The two primary reasons for medical intractability of seizures are either intolerance of side effects or ineffectiveness in seizure activity control. Many of these individuals are considered to be surgical candidates.(9,10) Epilepsy is a disorder of brain function(11,12) and various strategies exist to guide the use of structural and functional brain imaging for seizure characterization and surgical planning. Epileptic foci can sometimes be associated with lesions visible on the MR image.
Most brain lesions identified with structural neuroimaging, however, are not associated with epileptogenic activity. In other words, brain lesions in patients with epilepsy may not be causing the tissue to be epileptogenic. A patient may have a number of lesions identified on CT or MRI studies; a functional method of evaluation is often necessary to discern which abnormality is responsible for the epilepsy. A successful neurosurgical approach must minimize inadvertent damage to nearby healthy tissue involved in critical brain functions. Before epilepsy surgery can be undertaken, it is crucial to locate the exact site of the seizure initiation. The functional localization of the seizure focus takes precedence over lesion identification in the evaluation of patients being considered for surgery. Functional and structural neuroimaging techniques are becoming increasingly complementary in this regard.(12)
Traditionally, the favored standard for localizing an epileptic focus before surgery has been the use of depth-electrode monitoring.(13) In this procedure the electrodes are inserted through the skull and other brain coverings, then physically attached to the brain in the areas of interest. This is an expensive surgical procedure that assumes attendant risks. Children, in particular, have difficulty tolerating this procedure; some patients have accidentally ripped the depth electrodes from their brain and skull. Furthermore, the number of patients who can be evaluated by this technique is severely limited since only a few hospitals have the required facilities for depth-electrode monitoring. Substantially decreased risk and cost, as well as increased patient comfort, are all advantages that noninvasive methods of preoperative evaluation such as MSI can provide over invasive monitoring techniques.
Improved MSI monitoring often makes evaluation of the entire brain possible at a single setting. In many cases the information obtained from MSI is superior to that provided by a depth-electrode examination. Often MSI will preclude the need for electrode monitoring during surgery; in certain cases that still require depth-electrode monitoring, MSI will at least provide more directed placement of the electrodes. The recent advent of large array detectors has contributed greatly to the accuracy and efficiency of MSI examinations of epilepsy patients.
MSI can reliably identify the focus of epileptiform events, and distinguish different events that may be problematic to evaluate with standard EEG recordings(4,14-18) (Figure 3). Studies comparing EEG and MEG have indicated that the two modalities are complementary.(19,20) Furthermore, MEG has proven superior in the evaluation of the trigger zone for spike activity.(21) MEG usually serves as a refinement of the information available from other modalities such as EEG, PET, and SPECT for cases of temporal lobe epilepsy. Some of MEG’s greatest benefits in epilepsy evaluation have been in children, since children do not tolerate depth-electrode placement well.
Autism Spectrum Disorders. Autism now is widely accepted to be a neurobiological condition; however, the linkage between clinical symptoms and neuromagnetic and pathological evidence of cerebellar and hippocampal abnormalities is unclear.(22,26) Autism is characterized by developmental delay, impaired social interactions, bizarre repetitive behaviors, sensory defensiveness, poor language skills, and abnormal cognitive skills. More than 30% of patients with autism spectrum disorders have normal early development interrupted by autistic regression at age 2 or 3. The clinical symptoms resemble those seen in Landau-Kleffner syndrome (LKS), which is an acquired language disorder suspected to be caused by epileptiform activity. Additionally, more than 30% of autistic children experience one or more seizures before they reach adolescence. This evidence suggests that epileptiform activity may play a significant role in some cases of autism.
A recent study was done to determine if there is a neurobiological overlap between the conditions of autism and classic LKS.22 Children with LKS and autistic regression were evaluated during Stage III sleep. MEG data were compared with simultaneously recorded EEG data as well as with data from previous 1-hour and 24-hour recordings. The same brain regions identified as abnormal in LKS were typically identified as abnormal in autism as well, but autistic children generally had additional areas of abnormality(22) (right).
Characterization of Abnormal Low Frequency Magnetic Activity. Abnormal low frequency magnetic activity (ALFMA) is a shared commonality in the MEG and MSI data sets of patients spanning a broad range of neurological disorders. These disorders may include epilepsy, cerebrovascular disease, intracranial masses, trauma, dementia, substance abuse, learning disabilities, and several psychiatric disorders. MEG localization of ALFMA is routinely achieved.
For these examinations the patient is asked to sit quietly under the sensor system with eyes closed. He or she must remain awake and alert for the accurate identification of ALFMA. Therefore, the patient is typically asked to listen to a story. In general, waveforms with a frequency below 6 Hz and an amplitude of between 200 and 400 femtotesla are classified as ALFMA. Dipole modeling is applied to the signals that meet criteria for ALFMA localization. This type of detected brain activity is thought to receive contributions from larger regions of the brain than evoked or epileptic spike MEG analysis. Therefore, the localization of ALFMA is considered to be less accurate than these other types of MEG studies. MEG ALFMA data can be incredibly relevant and useful, however, in identifying the affected lobe or region and in documenting the presence of persistent dysfunction.
Mild Traumatic Brain Injury. Traditional neuroimaging studies often fail to explain the observed neurological consequences of relatively minor head injury. Clinical problems such as headaches, nausea, cognitive decline, and personality changes may occur in the absence of demonstrable pathology on CT, MR, or EEG studies. Many patients who have actual neurological bases for their brain dysfunction symptoms will fail to be diagnosed with traumatic brain injury (TBI), or will be misdiagnosed as having psychiatric problems.(27,28) In cases of mild head trauma, there is a reluctance to treat postconcussive complaints unless there is a clear, demonstrable neurobiological basis for the problem.
These problems are especially relevant when 1) predicting long-term outcome, 2) deciding on a therapeutic strategy, and 3) making decisions about whether a person is fit to return to work.(21)
A sensitive method to detect evidence of damage to a particular brain region with mild TBI would help clinicians develop relevant treatments for these patients.(28,29) The very high spatial and temporal resolution of MSI(21) offers tremendous promise as a responsive diagnostic test for mild TBI.(28) A recent study of patients with mild head injuries confirms that significant neuropsychological dysfunction may exist despite the absence of abnormalities on MRI or EEG.(28,35) ALFMA examination proves to be the best measure of pathophysiology in patients with postconcussive syndromes. MSI diagnostic sensitivity was more than three times that of MR imaging, and also was more sensitive than EEG. The false-positive rate associated with MEG was low (<10%) for both the normal and patient groups without postconcussive syndromes. In other words, no MSI abnormalities were found when there were no postconcussive syndromes. MEG was the only method to correlate both the postconcussive syndromes and the degree of recovery.(28)
Significantly more patients with postconcussive syndromes have brain dysfunction indicated by MEG than with EEG or MR imaging. Reliance on the latter two modalities will result in underdiagnosis of these patients. Demonstration of objective evidence of brain injury in patients with postconcussive syndromes facilitates the appropriate treatment of specific related clinical problems such as persistent headaches, nausea, cognitive decline, and personality changes(29) (Figure 5).
Characterization of Abnormal Information Processing. Studies incorporating signal-averaging and evoked-response techniques are used to analyze abnormal information processing, and may be helpful to supplement other MSI applications. Waveforms in multiple sclerosis, for example, appear very different than waveforms in normal subjects,(4,21,36) and ALFMA also may be discovered in individuals with multiple sclerosis.
Cortical reorganization occurring in patients who have peripheral and/or central nervous system pathology may be identified using MSI somatosensory processing techniques. Following limb amputation, cortical reorganization occurs that includes expansion of other somatosensory representations. In evaluations that occur before and after restorative plastic surgery to separate fused digits, somatotopic changes have also been shown. MSI has even demonstrated that ipsilateral somatosensory representation can develop after surgical resection or early childhood stroke.(21,31,37,38)
Progress in MSI technique over the past few years has permitted new and exciting developments in its clinical application. Currently, presurgical mapping and electrical activity mapping remain the principal clinical applications of MSI. The availability of large array systems has permitted incredible progress in developing routine clinical applications, so that ALFMA evaluations of conditions, including autism(22) and head trauma,(28) are now becoming well established. MEG monitoring has been demonstrated to provide an objective measure of auditory dysfunction in some patients with tinnitus. Soon, evaluations of the fetus(21,39) and of conditions such as dementia(40) may also become routine clinical studies.(41) Preliminary work in other clinical conditions such as psychiatric dysfunction, substance abuse, and learning disabilities indicates very encouraging initial results.
Successful directed treatment for those afflicted with a number of brain disorders is possible with improved understanding of human brain function. MSI technique shows great promise for detecting and characterizing myriad brain disorders. Clinical medicine has two major obstacles in this and all forms of new technology: training investigators in the new techniques and obtaining payment for advanced medical applications. In spite of these challenges, several hospitals now incorporate MSI as a vital component of their routine care.
William W. Orrison, Jr, MD, is professor and chair of radiology, and John T. Davis, PhD, is clinical neuroscientist, and Kevin R. Moore, MD, is limited term instructor, at the University of Utah School of Medicine, Salt Lake City, Utah.