Our knowledge regarding the brain and its relationship to depression and other psychiatric disorders has grown considerably. Neuroimaging studies have found structural and functional brain changes that are associated with various psychiatric disorders.1,2 Further, genetics and environment have been shown to interact to produce psychiatric symptoms such as depression.3 New brain stimulation techniques are being used to investigate, as well as treat, various neuropsychiatric disorders.4 Medications to treat depression and other disorders not only are being found by accident but also are being designed to target specific receptors.5–7
Despite these advances, a large number of our patients continue to suffer debilitating mental illness despite “adequate” treatment with current therapies. A significant problem with choosing among available treatments and developing new therapies is that we do not understand the fundamental neuropathology associated with the disorders we treat. One method to investigate this neuropathology is to study the neurocircuitry of these disorders. With an understanding of how different parts of the brain work – or fail to work – together in various neuropsychiatric disorders, the potential exists to formally develop and test treatment options in a specific disease model (diagnosed by pathology) versus a syndromic model (diagnosed by symptoms) which may contain a number of different neuropathological diseases.
Transcranial magnetic stimulation (TMS) is a relatively new technology that uses magnetic energy to stimulate the brain. Although using magnetic fields for this purpose is not new, the modern era of TMS started in 1985 with Barker stimulating the motor cortex.8 TMS uses an electrical current passed through a round or figure-eight coil to produce a rapid (0.2 to 0.3 millisecond) and very powerful (approximately 1.5 to 2.5 teslas) magnetic pulse. The pulse passes relatively unimpeded from the scalp to the cortex, where the magnetic energy is able to depolarize neurons.9 Stimulation over certain regions of the brain can produce a behavioral change. The exact neurophysiology leading to that behavioral change, however, is not well understood.
As an example, stimulating with TMS on the scalp over the motor cortex area representing the thumb can induce movement in the corresponding, contralateral digit.8 Similarly, stimulating over primary visual cortex can produce phosphenes (a luminous visual sensation).10,11 Conversely, TMS can also be used to inhibit a function, such as stimulating over Broca's area to interrupt speech.12,13 The nature of the behavioral change is dependent upon the location of stimulation, as well as the stimulating parameters used.
When the TMS pulses are delivered in a repeated manner at equal intervals, it is referred to as repetitive TMS (rTMS).9 Some evidence supports the idea that fast rTMS (greater than 1 hertz) is excitatory to the cortex14 and slow rTMS (1 hertz or less) is inhibitory to the cortex.15,16 Variability, however, exists in the effect of TMS frequency on brain activity across regions of the brain17 and with differences in the number of TMS trains.18
Because of the ability of TMS to noninvasively and temporarily alter brain function in a safe manner when used properly,19,20 it has been used extensively to investigate normal and abnormal brain functions. In addition, as described elsewhere in this issue, rTMS is being investigated as a potential treatment option for depression and other neuropsychiatric conditions.4
Another very promising technology to investigate the neurocircuitry of the brain is blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI).21 As the name implies, BOLD fMRI measures functional changes in the brain. When an area of the brain becomes more active, there is an increase in blood flow to that area. The increase in blood flow results in an increase in the ratio of oxygenated to deoxygenated blood. Because oxygenated blood and deoxygenated blood have different magnetic properties, the magnetic resonance (MR) scanner can detect a signal change in the region that had an increase in oxygenated blood (and activity). Importantly, these are relative and not absolute signal changes. BOLD fMRI is able to achieve better spatial and temporal resolution than techniques such as positron emission tomography and single photon emission computed tomography.22 Further, because of the lack of ionizing radiation, BOLD fMRI can be repeatedly performed safely in all age groups.
Although TMS and BOLD fMRI individually have increased our knowledge of brain function, when used together they offer a unique opportunity to study the neurocircuitry of the brain and psychiatric disorders.23 These complementary techniques are also being used to study the neurocircuitry of language,24,25 brain injuries, and diseases such as stroke and epilepsy.26,27
The two technologies have been used together in a number of ways. One approach is to use the technologies separately and then compare the results achieved by each method. This requires that the TMS coil be positioned over a brain region with an easily observable behavioral outcome, usually the motor cortex. The TMS coil is positioned on the scalp in the location in which the maximal motor movement is elicited with a pulse. Separately, the patient performs the task of interest while being imaged with an fMRI. The location of increased activity is identified using various analysis packages and is superimposed onto a structural image. The location of maximal TMS response and maximal BOLD fMRI activation are then compared. TMS and BOLD fMRI techniques used to identify the central nervous system location associated with a particular motor task have produced similar but not precisely the same results.28–32 Interestingly, the results from fMRI and TMS for more complex interactional tasks do not always appear to agree.33
Another approach is to use the results from a BOLD fMRI study to target the location of TMS stimulation on the scalp. Unlike TMS-induced finger movement or speech arrest, most areas of the brain do not have an immediately obvious behavioral change. Thus, choosing where to place the TMS coil on the scalp to stimulate the cortex can be problematic. Using BOLD fMRI to identify the location in the brain, TMS can then be targeted to stimulate that location to facilitate or inhibit a particular task.
Various techniques for using frameless stereotactic localization have been tested to make it possible to use functional (or structural) images to target TMS.28,34,35 These technologies allow one to take a structural MRI (or fMRI superimposed on a structural MRI) and coregister it with a subject's brain in real time. Easily identified external landmarks (eg, tragus of the ear, bridge of the nose) on the MRI and the subject are used to coordinate a positional system. Thus, one can take a location on the scalp and determine which brain region it is over with the MRI.
As an example of using fMRI to target TMS, Herwig et al.36 used BOLD fMRI with a memory task to determine the location in the premotor cortex of increased activation during the rehearsal portion of the task for each subject. Because of the nature of BOLD fMRI, when an area of activation is identified, one can only say that a particular region was associated with the task; one cannot state that the region was directly involved or essential in the performance of the task.
To determine the importance of the identified region, one method is to temporarily interrupt that region (with TMS) to see if there is a change in the task tested. TMS has been shown to temporarily and safely inhibit (eg, speech arrest) or induce (eg, finger movement) behavioral tasks. Because there is considerable individual variability and no obvious behavioral change (eg, finger movement) to localize the positioning of the TMS coil over the premotor cortex, the strategy in this study of memory was to take the fMRI data for each subject and stereotactically guide the TMS coil to the within-individual fMRI BOLD determined maximal spot of activation. The maximal spot of activation was determined by choosing the voxel within a cluster of significantly activated voxels in the premotor region that had the largest activation. This enabled positioning of the TMS coil based on a brain function measure.
Using TMS over this region during the rehearsal portion of the task, error rates were increased in the premotor regions versus stimulating with TMS over the parietal or prefrontal cortex. This provided additional evidence that the pre-motor region first identified with BOLD fMRI was important in the rehearsal portion of this memory task. Stimulating the control areas of the parietal cortex and prefrontal cortex was important in determining that the effect of the TMS was regionally specific and not a general effect (eg, distraction due to TMS).
Rushworth et al.37 used a similar strategy to individually locate a function (task switching and the medial frontal cortex) using BOLD fMRI and then test the importance of that region with TMS. First, the areas of significant activation were determined for two types of task switching, which produced partially overlapping activation in the medial pre-frontal cortex. Using a frameless stereo-tactic system, TMS was targeted to each patient's medial prefrontal region of activation and a control region during both tasks. The targeted TMS over the medial prefrontal cortex disrupted one of the switching tasks but not the other. This study highlights the concept that even though an area shows significant activation on fMRI, it may not be necessary or essential.
In addition to whether a region is essential for a particular task, knowing the point in time that activation in the region is necessary for a task can also provide important insight into the function of that region. Interrupting the tasks at different time points revealed that the medial prefrontal cortex played an important role in task switching only at a specific time in the task performance. Thus, this technique offers the ability to not only test if a brain region is essential for a task, but also at which point in time the region is essential for that task.
Another method of integrating the two technologies is referred to as interleaved TMS/fMRI. This is an exciting and technically challenging method which stimulates the brain with TMS and almost simultaneously images the resulting neuronal activity changes with BOLD fMRI (Sidebar, see page 132). This enables noninvasive testing of the functional neurocircuitry of the brain. Although this initially was thought not to be technically feasible, researchers have performed interleaved TMS/fMRI over the motor cortex successfully.38,39 Further work revealed that single pulse designs could be used40 and that a linear increase in signal was observed with an increasing number of pulses.41 In addition, the TMS induced change in BOLD signal during thumb cortex stimulation was similar in location and magnitude to the BOLD signal associated with volitional movement42 and could be reliably reproduced with respect to anatomic location.43
Relative Merits of Interleaved TMS/fMRI
- Noninvasive stimulation of focal area of cortex
- Ability to resolve changes in activity within a second
- No Ionizing Radiation (safe to repeat and perform in all age groups)
- Non-invasive brain stimulation and neuronal activity measurement
- Able to test functional connectivity of circuits
- Noninvasive stimulation coupled with non-invasive imaging while subjects perform behaviors
- Technically very challenging (with only two research groups in the world effectively mastering it)
- Signal loss directly under the coil
- Exact action of TMS is still not well understood (eg, which layers of the cortex are stimulated, which cells, and how do different TMS parameters inhibit or excite)
- Exact physiology underlying BOLD response not well understood
The nature of what is responsible for the BOLD signal change during interleaved TMS/fMRI has generated some controversy. Baudewig et al.44,45 reported that the BOLD signal change during interleaved TMS/fMRI over the motor cortex was not from direct stimulation but the result of afferent processes due to the movement induced by the TMS pulse. In addition, further work is being done to clarify possible sources of artifacts,46 test the BOLD response to various frequencies of stimulation,45,47 and develop a head holder with an accurate method for MR-guided TMS (Figure 1, see page 133).48
Interleaved TMS/fMRI setup with MRI coil top off (top) and with MRI coil top on (bottom).
Using the technique of interleaved TMS/fMRI, a number of very interesting questions can be asked and tested. McConnell et al.49 wondered if the previously reported age-related decrease in BOLD fMRI response was attributed to cortical changes or to peripheral neural changes. Using TMS/fMRI to activate the brain directly without the confound of the peripheral nervous system revealed similar levels of BOLD activation in young and old subjects.
Using the interleaved technique to stimulate over the prefrontal cortex, Nahas et al.50 demonstrated differences in the pattern of activation based on the intensity of the TMS stimulation — 80%, 100%, or 120% (Figure 2, see page 134). This could have important implications when using TMS to treat disorders such as depression. For example, Li et al.51 demonstrated that in a heterogeneous group of depressed subjects, it was possible to image the activation of frontal-subcortical circuits using pre-frontal TMS/fMRI.
Interleaved TMS/fMRI in a healthy patient. Left prefrontal 1 hertz TMS (green bar) at 120% motor threshold causes changes in left dorsolateral prefrontal cortex (site of stimulation), right orbitofrontal cortex, bilateral auditory cortex, and right anterior temporal pole. Images are coronal section of the brain, with areas of increase activity indicated with red and yellow.The top left image is the furthest rostral, and the bottom left is the furthest caudal.
Using this technique, Li et al.52 also investigated the interaction of lamotrigine on brain circuits using stimulation over both the motor and prefrontal cortex in normal controls. As expected, lamotrigine inhibited cortical activation with stimulation over the motor cortex. Interestingly, however, lamotrigine increased the TMS induced activation in the limbic regions of the brain. Although requiring replication, these studies demonstrate the unique and important questions about neurocircuitry in depression that can be addressed using this novel technique.
New methods of integrating these technologies with each other are currently being developed. One is the potential to use paired-pulse TMS interleaved with fMRI. The technique would enable numerous areas of the cortex (instead of just the motor cortex) to be tested for cortical excitability.
An additional technology being developed to study the structural integrity of brain circuits is diffusion tensor imaging (DTI). DTI uses the motion of water molecules to investigate the microstructure and organization of white matter tracts in the brain. This can provide a quantitative means to determine the integrity of anatomical connections between regions of the brain.53 DTI also may be used to investigate white matter anatomy in healthy and disease states. For example, this technology has been used to investigate the nature of white matter hyperintensities54 and to predict treatment response in geriatric subjects with depression.55 TMS/fMRI combined with DTI is being developed to test both structural and functional connectivity of brain circuits noninvasively.
Although these approaches are presently not able to aid clinicians in treatment decisions, the integration of TMS, BOLD fMRI, and DTI holds great promise in providing insight into the neuropathology of depression and other neuropsychiatric disorders. With such insight, new treatments can be developed and established ones can be more effectively used.
Although our knowledge concerning the neurobiology of depression and other psychiatric disorders has dramatically increased, we still do not understand their fundamental pathology. A number of recent advances in technology, however, have enabled researchers to directly study the function of the brain. Two of these technologies, transcranial magnetic stimulation (TMS) and blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), offer great promise to help elucidate (and for TMS possibly treat) the neuropathology of these disorders. Each alone has provided important information, but combined, they offer a very unique opportunity to study the diseases that our patients struggle to overcome.
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