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</ref>. Additionally, the effects of repetitive TMS are variable between subjects and also for the same subject. A variant of this technique is the ‘enhancement’ technique, where repetitive TMS is delivered to enhance performance. This is even harder to achieve than the ‘knock-out’ technique.
</ref>. Additionally, the effects of repetitive TMS are variable between subjects and also for the same subject. A variant of this technique is the ‘enhancement’ technique, where repetitive TMS is delivered to enhance performance. This is even harder to achieve than the ‘knock-out’ technique.

==Investigation of attentional processes==
In a recent article in “The Psychologist” Chris Chambers (School of Psychology, [[University of Cardiff]] and the Institute of Cognitive Neuroscience, [[University College London]]) focused on recent advances in the cognitive neuroscience of attention using TMS <ref>Chambers, C., (2008), A stimulating take on attention, The Psychologist, Vol 21, Part 6, June 2008, 502–505</ref>.
The use of TMS in cognitive neuroscience has revealed that:
*1. There are at least two critical periods underlying attentional control in the [[parietal cortex]].
*2. Mutual inhibition between the [[Cerebral hemisphere|hemispheres]] is important for maintaining an even distribution of attention across space.
*3. While the psychological concept of attention may appear singular, it nevertheless arises from a series of distinct neural processes.

===Attentional mechanisms===
Evidence from [[EEG]] studies had suggested that, during attention, selection of particular stimuli might require at least two periods of cortical processing - an initial ‘feedforward’ wave of sensory activity, followed by a later ‘feedback’ sweep from attentional gatekeepers in the parietal cortex and [[frontal cortex]] (Martinez, 1999 and Noesselt et al., 2002) <ref>Martinez, A., 1999. Involvement of striate and extrastriate visual cortical areas in spatial attention. Nature Neuroscience, 2, 364–369</ref> <ref>Noesselt, T., Hillyard, S.A., Woldorff, M.G. et al, 2002. Delayed striate cortical activation during spatial attention. Neuron, 35, 575–587</ref>.

Since a single TMS pulse generally has a very transient effect on brain activity, comparing the consequences of TMS at different onset times can reveal the timecourse of cortical involvement (Amassian et al., 1989) <ref> Amassian, V.E., Cracco, R.Q., Maccabee, P.J. et al., 1989. Suppression of visual perception by magnetic coil stimulation of human occipital cortex. Electroencephalography & Clinical Neurophysiology/Evoked Potentials Section, 74, 458–462</ref>

In one of their first TMS studies Chambers, Payne et al. (2004), using single-pulse TMS, stimulated the [[angular gyrus]] (a sub-division of the inferior parietal cortex) at one of many possible times, while participants shifted their attention in space. The results revealed a surprising ‘twin’ timecourse, in which TMS of the angular gyrus disrupted shifts of attention either early (90-120ms) or late (210-240ms) after the target appeared <ref> Chambers, C.D., Payne, J.M., Stokes, M.G. & Mattingley, J.B., 2004, Fast and slow parietal pathways mediate spatial attention. Nature Neuroscience, 7, 217–218</ref>

===TMS enhancing attention===
It has long been known that stroke patients who have suffered parietal [[brain damage]] are likely to show attentional deficits (Driver & Mattingley, 1998)<ref> Driver, J. & Mattingley, J.B., 1998, Parietal neglect and visual awareness. Nature Neuroscience, 1, 17–22</ref>. Many such patients with lesions to the right hemisphere exhibit a pathological gradient of attention towards the right visual field (or hemifield). This syndrome, termed “unilateral neglect”, occurs in the absence of primary sensory loss, and is believed to arise from disruption of normal inhibitory interactions that operate between the left and right parietal lobes (Kinsbourne, 1977)<ref>Kinsbourne, M., 1977, Hemi-neglect and hemisphere rivalry. Advances in Neurology, 18, 41–49</ref>. Following damage to the right parietal cortex, the left hemisphere becomes ‘disinhibited’, causing a rightward attentional bias and a leftward inattention.

A number of researchers have found that TMS in normal participants can sometimes facilitate attention (Chambers et al., 2006; Hilgetag et al., 2001; Seyal et al., 1995) with the mechanism apparently lying in the balance of attentional control between left and right [[cerebral hemispheres]] <ref> Chambers, C.D., Stokes, M.G., Janko, N.E. & Mattingley, J.B., 2006, Enhancement of visual selection during transient disruption of parietal cortex. Brain Research, 1097, 149–155 </ref> <ref>Hilgetag, C.C., Theoret H. & Pascual-Leone, A., 2001, Enhanced visual spatial attention ipsilateral to rTMS-induced ‘virtual lesions’ of human parietal cortex. Nature Neuroscience, 4, 953–957</ref> <ref>Seyal, M., Ro, T. & Rafal, R. (1995). Increased sensitivity to ipsilateral cutaneous stimuli following transcranial magnetic stimulation of the parietal lobe. Annals of Neurology, 38, 264–267</ref>

These experiments have shown that TMS of the right parietal cortex can indeed facilitate the selection of stimuli in the right hemifield. Furthermore, such benefits can be fast, occurring within 130ms of stimulus onset (Chambers et al., 2006). Considered alongside unilateral neglect, these observations suggest that parietal interference tips the delicate balance of attention between the hemispheres, causing an involuntary ‘over-attention’ to the right side of space.

===The “Fat Controller” hypothesis===
Another question examined by Chambers was: "To what extent a common neural mechanism determines the selection of different stimulus characteristics, such as location, colour or shape?" In other words, is there a ‘Fat Controller’ in the parietal or frontal lobe that oversees all aspects of attentional control.
Observations from human neuroimaging studies had provided some evidence of the “Fat Controller’ mechanism. When allocating attention to different stimulus dimensions, such as location or colour, a remarkably similar pattern of activity is seen in frontal and parietal areas (Giesbrecht et al., 2003; Slagter et al., 2007) <ref>Giesbrecht, B., Woldorff, M.G., Song, A.W. & Mangun, G.R., 2003, Neural mechanisms of top-down control during spatial and feature attention. NeuroImage, 19, 496–512</ref> <ref> Slagter, H.A., Giesbrecht, B., Kok, A. et al., 2007, fMRI evidence for both generalized and specialized components of attentional control. Brain Research, 1177, 90–102</ref>

Functional MRI and EEG studies had also found that orienting spatial attention in vision, hearing or touch produced largely indistinguishable patterns of activity in the parietal and temporal lobe. Brain imaging could not reveal, however, for example, which activations are necessary for visual or tactile attention. Using TMS, it is possible to apply a more direct test.

The work of Chambers and colleagues now suggests that at least some parietal regions appear to be uniquely specialised for orienting attention to visual stimuli (Chambers et al., 2007; Chambers, Stokes et al., 2004)<ref>Chambers, C.D., Payne, J.M. & Mattingley, J.B., 2007. Parietal disruption impairs reflexive spatial attention within and between sensory modalities. Neuropsychologia, 45, 1715–1724</ref> <ref>Chambers, C.D., Stokes, M.G. & Mattingley, J.B.,2004, Modality-specific control of strategic spatial attention in parietal cortex. Neuron, 44, 925–930</ref>

It thus seems clear that spatial attention is coordinated by a series of modality-specific ‘gatekeepers’, rather than a single "Fat Controller".

===Future work===
Chambers suggests that one key research development is the combination of TMS with neuroimaging methods such as [[fMRI]] (Ruff et al., 2006)<ref>Ruff, C.C., Blankenburg, F., Bjoertomt, O. et al., 2006, Concurrent TMS-fMRI and psychophysics reveal frontal influences on human retinotopic visual cortex, Current Biology, 16, 1479–1488</ref> and [[EEG]] (Fugetta et al., 2006) <ref> Fugetta, G., Pavone, E.F., Walsh V. et al., 2006, Cortico-cortical interactions in spatial attention: A combined ERP/TMS study. Journal of Neurophysiology, 95, 3277–3280</ref>. The hope is that a combination of techniques will enable researchers to gain new insights into the role of ‘top down’ signals from parietal to [[visual cortex]], and between higher-level regions in opposite hemispheres.


==Risks of TMS and rTMS==
==Risks of TMS and rTMS==

Revision as of 18:44, 12 August 2008

Transcranial magnetic stimulation (TMS) is a noninvasive method to excite neurons in the brain: weak electric currents are induced in the tissue by rapidly changing magnetic fields (electromagnetic induction). This way, brain activity can be triggered with minimal discomfort, and the functionality of the circuitry and connectivity of the brain can be studied.

Repetitive transcranial magnetic stimulation is known as rTMS and can produce longer lasting changes. Numerous small-scale pilot studies have shown it could be a treatment tool for various neurological conditions (e.g. migraine, stroke, Parkinsons Disease, dystonia, tinnitus) and psychiatric conditions (e.g. major depression, auditory hallucinations).

Background and history

The principle of inductive brain stimulation with eddy currents has been noted since the 19th century. The first successful TMS study was performed in 1985 by Anthony Barker et al.[1] in Sheffield, England. Its earliest application was in the demonstration of conduction of nerve impulses from the motor cortex to the spinal cord. This had been done with transcranial electrical stimulation a few years earlier, but use of this technique was limited by severe discomfort. By stimulating different points of the cerebral cortex and recording responses, e.g., from muscles, one may obtain maps of functional brain areas. By measuring functional imaging (e.g. MRI) or EEG, information may be obtained about the cortex (its reaction to TMS) and about area-to-area connections.

TMS publications.

Pioneers in the use of TMS in neuroscience research include Anthony Barker, Vahe Amassian, John Rothwell of the Institute of Neurology, Queen Square, London, Mark S. George, MD of the Medical University of South Carolina, David H. Avery, MD of the University of Washington at Seattle, Charles M. Epstein of Emory University, Drs. Mark Hallett, Leonardo G. Cohen, and Eric Wassermann of the National Institutes of Health, and Alvaro Pascual-Leone of Harvard Medical School. Currently, thousands of TMS stimulators are in use. More than 3000 scientific publications have been published describing scientific, diagnostic, and therapeutic trials.

How TMS affects the brain

The exact details of how TMS functions are still being explored. The effects of TMS can be divided into two types depending on the mode of stimulation:

  • Single or paired pulse TMS. The pulse(s) causes a population of neurons in the neocortex to depolarise and discharge an action potential. If used in the primary motor cortex, it produces a motor-evoked potential (MEP) which can be recorded on electromyography (EMG). If used on the occipital cortex, 'phosphenes' (flashes of light) might be detected by the subject. In most other areas of the cortex, the participant does not consciously experience any effect, but his or her behaviour may be slightly altered (e.g. slower reaction time on a cognitive task), or changes in brain activity may be detected using Positron Emission Tomography or fMRI. These effects do not outlast the period of stimulation. A review of TMS can be found in the Handbook of Transcranial Magnetic Stimulation.[2]
  • Repetitive TMS (rTMS) produces effects which last longer than the period of stimulation. rTMS can increase or decrease the excitability of corticospinal or corticocortical pathways depending on the intensity of stimulation, coil orientation and frequency of stimulation. The mechanism of these effects is not clear although it is widely believed to reflect changes in synaptic efficacy akin to long-term potentiation (LTP) and long-term depression (LTD). A recent review of rTMS can be found in Fitzgerald et al, 2006[3].

As such, it is important to distinguish TMS from repetitive TMS (rTMS) as they are used in different ways for different purposes.

TMS and rTMS techniques in research

One reason TMS is important in cognitive psychology/neuroscience is that it can demonstrate causality. A noninvasive mapping technique such as fMRI allows researchers to see what regions of the brain are activated when a subject performs a certain task, but this is not proof that those regions are actually used for the task; it merely shows that a region is associated with a task. If activity in the associated region is suppressed (i.e. 'knocked out') with TMS stimulation and a subject then performs worse on a task, this is much stronger evidence that the region is used in performing the task.

For example: subjects asked to memorize and repeat a stream of numbers would likely show activation in the prefrontal cortex (PFC) via fMRI, indicating the role of this brain region in short-term memory. If the researcher then interfered with the PFC via TMS, the subjects' ability to remember numbers would decline, and the researcher would have evidence that the PFC is important for short-term memory, because reducing subjects' PFC capability led to reduced short-term memory.

This ‘knock-out’ technique (also known as virtual lesioning) can be done in two ways:

  • Online TMS: where subjects perform the task and at a specific timepoint (usually in the order of 1-200ms) of the task, a TMS pulse is given to a particular part of the brain. This should affect the performance of the task specifically, and thus demonstrate that this task involves this part of the brain at this particular time point. The advantage of this technique is that any positive result can provide a lot of information about how and when the brain processes a task, and there is no time for a placebo effect or other brain areas to compensate. The disadvantages of this technique is that in addition to the location of stimulation, one also has to know roughly when the part of the brain is responsible for the task so lack of effect is not conclusive.
  • Offline repetitive TMS: where performance at a task is measured initially and then repetitive TMS is given over a few minutes, and the performance is measured again. This technique has the advantage of not requiring knowledge of the timescale of how the brain processes. However offline repetitive TMS is very susceptible to the placebo effect due to the contribution of dopamine to the placebo effect[4]. Additionally, the effects of repetitive TMS are variable between subjects and also for the same subject. A variant of this technique is the ‘enhancement’ technique, where repetitive TMS is delivered to enhance performance. This is even harder to achieve than the ‘knock-out’ technique.

Risks of TMS and rTMS

As it induces an electrical current in the human brain, TMS and rTMS can produce a seizure. The risk is very low with TMS except in patients with epilepsy and patients on medications. The risk is significantly higher, but still very low, in rTMS especially when given at rates >5Hz at high intensity.
The only other effects of TMS which are reported in most subjects are:

  • Discomfort or pain from the stimulation of the scalp and associated nerves and muscles on the overlying skin
  • Hearing from the loud click made by the TMS pulse

Clinical uses of TMS and rTMS

The uses of TMS and rTMS can be divided into diagnostic and therapeutic uses.

TMS for diagnostic purposes

TMS is used currently clinically to measure activity and function of specific brain circuits in humans. The most robust and widely-accepted use is in measuring the connection between the primary motor cortex and a muscle (i.e. MEP amplitude, MEP latency, central motor conduction time). This is most useful in stroke, spinal cord injury, multiple sclerosis and motor neuron disease. There are numerous other measures which have been shown to be abnormal in various diseases but few are validated or reproduced and more importantly, no one knows the significance of these measures. The most famous is short-interval intracortical inhibition (SICI) which measures the internal circuitry (intracortical circuits) of the motor cortex described by Kujirai et al. in 1993.[5]

Plasticity of the human brain can also be measured now with repetitive TMS (and variants of the technique, e.g. theta-burst stimulation, paired associative stimulation) and it has been suggested that this abnormality of plasticity is the primary abnormality in a number of conditions.

TMS for therapeutic purposes

A large number of studies with TMS and rTMS have been conducted for a variety of neurological and psychiatric conditions but few have been confirmed and most show very modest effects, if any. Some conditions which have been reported to be responsive to TMS-based therapy are:

It is important to stress that in a vast majority of these studies, no adequate control of placebo effect was possible and thus it is tempting to wonder if this effect is placebo.

TMS equipment

The major manufacturers for general purpose TMS and repetitive TMS equipment are:

  • The Magstim Company, UK
  • Medtronics, USA
  • Nexstim, Finland
  • Cadwell, USA
  • Dantec, Denmark
  • Schwarzer, Germany
  • Neuronetics,Inc., USA

Several TMS/rTMS devices are approved by the US Food and Drug Administration (FDA) for stimulation of peripheral nerve and, therefore, can be used "off label" by individual physicians to treat brain disorders, essentially in any way they believe appropriate, analogous to the off label use of medications. However, most legitimate use of TMS in the USA and elsewhere is currently being done under research protocols approved by hospital ethics boards and, in the US, often under Investigational Device Exemption from the FDA. The requirement for FDA approval for research use of TMS is determined by the degree of risk as assessed by the investigators, the FDA, and the local ethics authority. An application for clearance of TMS Therapy as a treatment for depression was submitted to the FDA in 2006. The FDA convened its Neurological Devices Panel on January 26, 2007 to review the TMS Therapy application. The results of this panel meeting were mixed with no concerns regarding the safety of this treatment, however, there was clear questioning of the efficacy of this treatment.[8] A final decision from the FDA in regard to approving TMS as a treatment for depression is expected in the first half of 2008. As regulated medical devices, TMS devices are not sold to the general public. They are also expensive (US$25,000-100,000 for basic equipment; US$500,000 for state-of-the-art targeting and recording instruments). In Europe, TMS devices that have been manufactured according to the Medical Device Directive have been granted the CE mark and can thus be freely marketed within the EU.

Technical information on TMS

TMS is simply the application of the principle of induction to get electrical current across the insulating tissues of the scalp and skull without discomfort. A coil of wire, encased in plastic, is held to the head. When the coil is energized by the rapid discharge of a large capacitor, a rapidly changing current flows in its windings. This produces a magnetic field oriented orthogonally to the plane of the coil. The magnetic field passes unimpeded through the skin and skull, inducing an oppositely directed current in the brain that flows tangentially with respect to skull. The current induced in the structure of the brain activates nearby nerve cells in much the same way as currents applied directly to the cortical surface. The path of this current is complex to model because the brain is a non-uniform conductor with an irregular shape. With stereotactic MRI-based control, the precision of targeting TMS can be approximated to a few millimeters (Hannula et al., Human Brain Mapping 2005).

Typical data: [9]

  • magnetic field: often about 2 tesla on the coil surface and 0.5 T in the cortex
  • current rise time: zero to peak, often around 70-100 microseconds
  • wave form: monophasic or biphasic
  • repetition rate for rTMS: below 1 Hz (slow TMS), above 1 Hz (rapid-rate TMS)

TMS coil types

A number of different types of coils exist, each of which produce different magnetic field patterns. Some examples:

  • round coil: the original type of TMS coil
  • figure-eight coil (i.e. butterfly coil): results in a more focal pattern of activation
  • double-cone coil: conforms to shape of head, useful for deeper stimulation
  • Deep TMS (or H-coil): currently being used in a clinical trial for the treatment of patients suffering from clinical depression.[10]

References

  1. ^ Barker AT, Jalinous R, Freeston IL. (1985). "Non-invasive magnetic stimulation of human motor cortex". The Lancet. 1 (8437): 1106–1107. PMID 2860322. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Alvaro Pascual-Leone, Nick Davey, John Rothwell, Eric M. Wassermann, Besant K. Puri (2002). Handbook of Transcranial Magnetic Stimulation. Hodder Arnold. ISBN 0340720093. {{cite book}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Paul B. Fitzgerald, Sarah Fountain, Zafiris J. Daskalakis (2006). "A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition". Clinical Neurophysiology. 117 (12): 2584–2596. doi:10.1016/j.clinph.2006.06.712. PMID 16890483. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Strafella AP, Ko JH, Monchi O. (2006). "Therapeutic application of transcranial magnetic stimulation in Parkinson's disease: the contribution of expectation". Clinical Neurophysiology. 31 (4): 1666–72. PMID 16545582. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ T. Kujirai, M. D. Caramia, J. C. Rothwell, B. L. Day, P. D. Thompson, A. Ferbert, S. Wroe, P. Asselman, and C. D. Marsden (1993). "Corticocortical inhibition of the motor cortex". The Journal of Physiology. 471: 501–509. PMID 8120818. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link).
  6. ^ Naeser Aphasia Research
  7. ^ Press Releases
  8. ^ Bridges, Andrew (2007). "Panel questions magnet therapy results". {{cite journal}}: Cite journal requires |journal= (help); Unknown parameter |month= ignored (help)
  9. ^ "TMS terminology", BioMag Laboratory at Helsinki University Central Hospital
  10. ^ "Israeli scientists probe deeper to lift depression", Reuters.com
  • Highfield, Roger (16 May, 2008). "How a magnet turned off my speech". Daily Telegraph. Retrieved 2008-05-18. Words failed me. I stuttered as Prof Vincent Walsh turned off the speech centre of my brain for a few thousandths of a second to demonstrate the power of transcranial magnetic stimulation, a popular way to interfere with the most complex known object in the universe. {{cite news}}: Check date values in: |date= (help); Cite has empty unknown parameter: |coauthors= (help)

See also