Let’s (Briefly) Break the Brain Introduction to TMS and an Overview of Current Projects Arman Abrahamyan

Skype Chat … are there TMS studies? Of course. There are a lot. Someone say now is TMS world [unedited] I was chatting on Skype with a Japanese colleague who attended the Japanese Conference on Biomagnetism recently. I asked her if she noticed any TMS studies. Well, someone at the conference told her that it is “TMS world” currently. TMS may not be dominating the world affairs, but it is currently an influential and important method for understanding how does the brain work. Skype Chat

Break It … to Understand So why TMS is so appealing? As we all know, the fastest way understand how does something work is to break it. Break It … to Understand [1]

Accidental Brain Breakdown Indeed, functional specificity of brain areas has been uncovered as a result of a break down in specific areas of the brain. Some of them are classics, such as Broca’s area involved in the production of speech, the frontal lobe damage of Phineas Gage and subsequent changes in his behaviour and personality. But how to study a living brain without breaking it permanently? This is where TMS is indispensible. [2] [3] Accidental Brain Breakdown

So what is transcranial magnetic stimulation So what is transcranial magnetic stimulation? TMS is a method for stimulating cortical areas of the brain through the intact skull. The stimulation can temporarily and reversibly interfere with or break the functions of an isolated area in the brain being stimulated. This enables us to study both spatial and temporal characteristics of a brain area. [4] What is TMS?

Talk Structure Introduction to TMS Current Projects This talk consists of two major parts. In the first part I will introduce you to TMS: how it works, how it is being used for research purposes, safety issues, and the future of TMS. In the second part I will be talking about some pilot data we have collected and improvements that we are implementing use the TMS apparatus more efficiently for research purposes. Talk Structure

Introduction to TMS How does TMS work? TMS apparatus, major coil types, and modes of stimulation “Virtual lesion” paradigm MRI guided coil positioning Is it safe? In the first part I will introduce you to the principles of the transcranial magnetic stimulation and a short history of its development and then introduce you to the TMS apparatus. Then I will talk about TMS as a tool for studying the brain mechanisms. I will also talk about safety and ethical issues. At then I will introduce you to TMS laboratory facilities and conclude with a few words about the future of TMS. In the second part of the talk I will be talking about current projects. In particular, the experiment that we are currently piloting and also talk about improvements that we are trying to achieve by using a computer to control the TMS apparatus. Introduction to TMS

How Does TMS Work? I will now give you more intimate introduction to the principles behind transcranial magnetic stimulation.

Electromagnetic Induction 1831 [5] In 1831 Michael Faraday found that when two coils are in close proximity, but not touching each other, running an electrical current through the right coil magnetises the iron and the magnetic field of the iron induces brief electrical currents in the left coil. The current passing through the right coil is called primary current and the current passing through the left coil is called secondary current. TMS is based on the principle that the secondary current can be induced in any conductor: be it a potato, apple, orange, or a brain. It is important to note that the secondary current is induced only briefly when the circuit is close or open. [6] Electromagnetic Induction

Early Attempts: d’Arsonval Reported seeing phosphenes 1896 As the principle of the electromagnetic induction have been known since 1831, there have been early attempts to stimulate the brain. In 1896 d’Arsonval placed participants’ head in a big cylindrical coil and ran a current through the coil. As a result, participants reported seeing flashes of light which were possibly induced by stimulating retinal cells. These flashes of light are called phosphenes and I will talk more about them later on. [7], [8] Early Attempts: d’Arsonval

Early Attempts: Thompson Replicated d’Arsonval’s results 1910 Silvanus Thompson experimented with electromagnetic stimulation of the brain in 1910. Like d’Arsonval, he observed flashes of light or phosphenes, which were possible result of stimulating the retinal cells. [9], [10] Early Attempts: Thompson

Early Attempts: Magnusson & Stevens Electromagnetic field is still not large and rapidly- changing enough 1911 To increase the strength of the magnetic field, Magnussen and Stevens in 1914, piled up a few coils on top of each other. However, they still couldn’t achieve requisite large, rapidly-changing electromagnetic fields. Early Attempts: Magnusson & Stevens [11], [12]

Thyristor Allows starting and stopping large electrical currents within microseconds An important engineering advance that enabled devising TMS was thyristor. Thyristor allows starting and stopping large electrical currents within microseconds. If you remember, electromagnetic induction takes place only when you start or stop the primary current. [13] Thyristor

1985 A progenitor of modern TMS machines was developed Royal Halamshire Hospital and the University of Sheffield in 1980s. In 1985, Tony Barker and colleagues successfully demonstrated transrcanial magnetic stimulation of the brain by stimulating the motor cortex and observing finger twitches. First TMS apparatus [14, 31]

In TMS, a large primary current passing through the coil results in magnetic field. The magnetic field can efficiently pass through the scalp and skull, reach the cortex and induce the secondary current at the cortical level which results in cortical excitation. EM Induction and TMS [15, 31]

TMS causes depolarisation of neuronal membranes Depolarisation can result in action potential On a microscopic level, as a result of stimulation, the induced secondary current causes electric charges being accumulated on neural membranes resulting in depolarisation. Depolarisation, in turn, can result in action potential. http://en.wikipedia.org/?title=Action_potential#Action_Potential_Initiation Figure: http://en.wikipedia.org/wiki/Image:Neurons_big1.jpg [16] Microscopic Level

Stimulated Area: 1-4 cm3 Affected Neurons: 1-5 billion [17], [18] The stimulated cortical area is estimated to be within 1 to 4 cubic centimeters and it is estimated that the stimulation affects 1 to 5 billion neuron. Macroscopic Level

TMS Apparatus, Coil Types, and Stimulation Modes

In general, TMS machines consist of one, two, or three big briefcase-sized components, a coil for magnetic stimulation, and a user interface to control the machine. The upper component is the mainframe and it also contains a thyristor. The bottom component is a capacitor to store large electrical currents. The user interface let you control stimulation parameters, such as stimulation level or stimulation frequency. [4] TMS Apparatus

If you look at the first TMS machine, you will notice that the stimulation coil was round. Intuitively, it may seem that the maximum magnetic field as in the centre of the coil. Circular Coil [14]

Secondary Current Induced by Round Coil Large Area of Stimulation However, the magnetic field is the strongest around the edges of the coil. Therefore, using a circular coil results in stimulating relatively large cortical area. While this may be useful in some cases, such as when treating patients presented with depression, a more focal stimulation is better suitable for research purposes. [19] Secondary Current Induced by Round Coil

Secondary Current Induced by Double Coil Induced Electric Field Focal Area of Stimulation The second major type of the coil is double coil also called figure-of-eight coil or butterfly coil. This coil was implemented by Ueno and colleagues in 1988. This type of coil is more preferable for research purposes because the magnetic field reaches its peak at the point between the two coils and it is more focal. [33, 19] Secondary Current Induced by Double Coil

spTMS rTMS Stimulation Modes [32, 21] Single pulse stimulation Less than 0.2 Hz Applied online rTMS Repetitive stimulation Above or below 1 Hz Can be applied online or offline TMS can be used in two stimulation modes. Single-pulse TMS or spTMS is when the frequency of stimulation is paced so that there is at least 5 sec gap between each pulse. spTMS is usually applied online, while participants are doing the task. The spTMS is usually applied at 0 to 500 ms after the stimulus presentation depending on the functions being studied. Repetitive TMS, or rTMS refers to transcranial magnetic stimulation that is applied at frequencies below or above 1 Hz. Repetitive stimulation below 1 Hz When stimulation is delivered while participants are doing the task, this is called online rTMS. When stimulation delivered before participants commit to the task, this is called offline stimulation. Stimulation Modes [32, 21]

“Virtual Lesion” Paradigm

Cognitive Neuroscience Diagnosis & Treatment Cognitive Neuroscience Movement disorders Epilepsy Depression Anxiety disorders Stuttering Schizophrenia Dementia Perception Attention Memory Learning Emotions Broadly, TMS is used for diagnosis and treatment and in cognitive neuroscience. Here, I will introduce how TMS is being used in cognitive neuroscience for studying the brain mechanisms. Use of TMS

“Virtual Lesion” or Breaking the Brain [11, 20, 21] In 1989 Amassian and colleagues observed that the TMS applied over the occipital cortex between 80 and 100 ms is able to suppress visual perception. As a result of stimulation, TMS induced transient interruption of normal brain activity in the visual cortex. This experiment became a starting point for a concept of virtual lesion induced by TMS. In other words, TMS allows to break down the normal functioning of a part of the brain for a short duration of time, which usually lasts for about 100 ms. “Virtual Lesion” or Breaking the Brain

Mechanisms of Interference No TMS [25] So what causes the interference with the task as a result of transcranial magnetic stimulation? Let’s have a look at an example using a visual stimulus to understand the mechanisms. Let’s say a participant has to identify number of circles in the figure. Mechanisms of Interference

Neural Activity: No TMS vs TMS condition [26] Picture on the right denotes a pattern of neural activity in some part of the visual cortex when the participants is doing the task without TMS. When participant is doing the same task combined with TMS, the pattern of activation changes because the dormant neurons are firing as a result of transcranial magnetic stimulation. [26] Neural Activity: No TMS vs TMS condition

Noise Injection or Signal Suppression? [22] [23] This change in the goal-state of the stimulated area results in interference with the task. There are two competing theories as to what causes the interference. The Noise Injection theory proposes that activation of dormant neurons as a result of TMS will inject noise into the system. Perceptually, this may manifest as seeing visual noise together with original stimuli, which may interfere with the task. An alternative explanation is that the signal gets suppressed as a result of stimulation, which has been recently demonstrated by Harris and colleagues. According to the signal suppression theory, activation of dormant neurons as a result of TMS will result in signal suppression because the original information being encoded in a cluster of neurons has been distorted or suppressed. Perceptually, signal suppression could manifest as loss in contrast, size, or shape. Noise Injection or Signal Suppression?

MRI Guided Stereotaxic Navigation of the Coil

Brain is Difficult to See Through the Skull [26] Positioning the TMS coil on the skull to point at the desired anatomical landmark on the brain isn’t easy. Some areas of the brain are easier to locate while others are not. For example, observing phosphenes can tell us that we are stimulating the visual cortex. But what about other areas where there are no behavioural indicators to help to identify the area being stimulated? Brain is Difficult to See Through the Skull

MRI Guided Neuronavigation [28] [27] [29] One way to overcome this problem is to use participants’ MRI and a stereotaxic neuronavigation system to navigate the coil on the brain. This type of system consists of a neuronavigation equipment which allows to obtain coordinates of the coil and the head and we also need participant’s MRI to co-register with their brain. After the co-registration, it is possible to see on the screen in real-time where the coil is positioned. The precision of coil targeting can be within a few millimeters. MRI Guided Neuronavigation

[27] Safety

There are no known side effects associated with single-pulse TMS, when used properly rTMS is known to cause seizure when stimulation parameters are well beyond accepted safety guidelines [8, 11, 32] There are no known side effects associated with single-pulse TMS, when used properly rTMS is known to cause seizure when stimulation parameters are well beyond accepted safety guidelines Risks of TMS

Safety of Participants Currently established safety guidelines for using TMS in rMTS mode are far below the risk margin for inducing a seizure Participants undergo a screening check TMS has been in use for 23 years and there are currently more than 3000 TMS machines used around the world. Therefore, there are currently rigorous stimulation guidelines and participant screening procedures in place to ensure safety of participants. Currently established safety guidelines for using TMS in rTMS mode are far below the risk margin for inducing a seizure To lower the risk of a seizure, participants undergo a screening check using a questionnaire [8, 11, 32] Safety of Participants

Safety of Participants Participants will be excluded if: Personal or family history of epilepsy Brain-related abnormal conditions Head or brain injuries Migraines or headaches Medications for a neurological or psychiatric condition Implanted devices Heart condition Pregnancy Participants will be excluded if: Personal or family history of epilepsy Brain-related abnormal conditions Head or brain injuries Migraines or headaches Medications for a neurological or psychiatric condition Implanted devices Heart condition Pregnancy [8, 11, 32] Safety of Participants

Conclusions

Conclusions TMS operates on the principle of electromagnetic induction TMS is relatively easy to operate and apply TMS can create a “virtual lesion” in a stimulated area of the brain by interfering with a neural activity in that area The “virtual lesion” paradigm is useful approach for mapping the temporal and functional characteristics of an area of the brain Following currently established safety guidelines for TMS, it is possible to significantly reduce, if not eliminate, risks associated with TMS Conclusions

Current Projects Preliminary results of a pilot experiment Improving phosphene threshold identification In the second part of this talk I will introduce you to the preliminary results of a pilot study that we recently conducted using TMS. And then I will talk about improvements we are currently implementing to optimise the phosphene threshold identification. Current Projects

TMS as a Pedestal in Visual Perception In this pilot experiment we probed whether transcranial magnetic stimulation of the occipital pole at the level which below the phosphene threshold can serve as a pedestal for a visual stimulus.

Phosphene Threshold Phosphene threshold Suprathreshold TMS Minimum stimulation level at the occipital pole that induces phosphenes Suprathreshold TMS Stimulation level above the phosphene threshold Subthreshold TMS Stimulation level below the phosphene threshold Phosphene threshold is defined as a minimum stimulation level at the occipital pole that induces phosphenes. Suprathreshold TMS refers to the stimulation level above the phosphene threshold Subthreshold TMS refers to stimulation level below the phosphene threshold Phosphene Threshold

Suprathreshold TMS Impairs visual perception It has been demonstrated that TMS delivered at the occipital pole at the level which is above the phosphene threshold can impair the perception of visual stimuli. Suprathreshold TMS

Subthreshold TMS But what about subthreshold TMS? If suprathreshold TMS impairs stimulus identification as a result of either noise injection or signal suppression, what would when TMS is delivered at the level which is below the threshold? If we assume that noise injection theory, is it possible that subthreshold TMS will inject some amount of noise into the visual system which will act as a pedestal for the visual stimulus? Subthreshold TMS

Subthreshold magnetic stimulation of the occipital pole will act as a pedestal for a visual stimulus and lower stimulus detection threshold Hypothesis

Method 2-interval forced-choice task Task: “Left Shift” button when stimulus is in the first interval, “Right Shift” button when stimulus is in the second interval Adaptive staircase to identify detection threshold in 30 trials Stimulus: plaid (2 x ±450 Gabor) Stimulus duration: 40 ms Method

Method Single-pulse TMS to occipital pole 100 ms after stimulus onset Stimulation intensities: Varied from 80% - 120% of phosphene threshold Control: no TMS or stimulation at Cz Plaid was positioned where phosphene was located Method

Preliminary Results Individual data EA HP EL EL Individual data Average detection threshold by condition These are individual results from three participants, which are based on the average of 3-5 data points. Preliminary Results

Result seem to support the hypothesis that subthreshold TMS can act as a pedestal It is contended that the noise injection, as a results of stimulation, acts as a pedestal which improves the stimulus detection threshold We are devising a final protocol for more systematic testing and data collection Manipulating levels of subthreshold stimulation Manipulating the timing of the TMS pulse Conclusions

Acknowledgements Justin Harris Colin Clifford Ehsan Arabzadeh Irina Harris Alexandra Murray Participants: Evan Livesey Hannah Pincham Acknowledgements

Thank you [4]

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24. http://www. wpclipart. com 25. http://www. physics. lsa. umich 24. http://www.wpclipart.com 25. http://www.physics.lsa.umich.edu/zochowski/images/Neurons.jpg 26. http://www.boneclones.com/BC-092-Set.htm 27. http://www.medcat.nl/Research/softaxic.htm 28. http://www.ant-neuro.com/products/visor 29. http://www.youtube.com/watch?v=NQG-ml4aZ_s 30. http://medicine.mercer.edu/Research/safety 31. Barker, A.T., Jalinous, R., and Freeston, I. Non-invasive magnetic stimulation of the human motor cortex. Lancet 1:1106-1107, 1985. 32. Wassermann, E.M., Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol, 1998. 108(1): p. 1-16. 33. Ueno, S., Tashiro, T. & Harada, K. Localised stimulation of neural tissue in the brain by means of a paired configuration of time-varying magnetic fields. J. Appl. Phys. 64, 5862–5864 (1988). References

Questions

Improving phosphene threshold identification Motor or phosphene thresholds are established using a manual staircase procedure Improving phosphene threshold identification

Finding a threshold using a computer