TMS: Neurocircuitry-Part 2

Considering how important it is, the dorsolateral prefrontal is surprisingly small. And because everybody's brain is a little different, its precise location can vary slightly from one person to the next. But in TMS, precise location of the stimulus is essential along with intensity, frequency, and duration. By altering these parameters in different ways, TMS can be used for different purposes.


For example, fast, excitatory TMS applied to the left dorsolateral prefrontal cortex has been approved by the FDA as a treatment for depression, but slow, inhibitory TMS applied to the same region has no effect on mood. On the other hand, recent studies have shown that fast, excitatory TMS applied to the right dorsolateral prefrontal cortex is an effective treatment for depression and slow, inhibitory TMS once again appears to be an effective treatment for depression.


TMS has been used experimentally to treat refractory epilepsy. In this situation, slow, inhibitory TMS is applied directly to the epileptogenic focus, the site in the brain where the seizure originates. When this is done repeatedly, over time, it has the effect of quieting down the focus.


TMS has also been used experimentally to aid in recovery from stroke, but here a different approach is used. Fast, excitatory TMS can be applied directly to the site of the lesion in an effort to stimulate damaged brain cells to function more effectively. But better results come from stimulating the corresponding site of the opposite, undamaged hemisphere. When this is done repeatedly, over time, it has the effect of stimulating neuroplasticity and regeneration at the site of the lesion.


And this is really the essence of how TMS works--by stimulating neuroplasticity.


www.tmsnewengland.com

TMS: Neurocircuitry-Part 1

TMS was developed at the same time functional brain imaging was being perfected. Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have allowed us to map cortical function with unprecedented detail and accuracy. For example, in the right cerebral cortex, we have separate circuits that allow us to tell the difference between pitch, rhythm, and harmony whenever we hear music. And in the left cortex, we have separate circuits which allow us to recognize a word if we see it written and the same word if we happen to hear it spoken or sung.


TMS can be combined with various forms of brain imaging. Studies like this have not only allowed us to map brain function but also brain circuitry--and not only in the cortex--but deep inside the brain as well. 


The part of the brain responsible for the antidepressant effects of TMS is the left dorsolateral prefrontal cortex. This is a small but important area concerned with executive function.

This part of the cortex is involved with high level organization and planning. You're using this part of your cortex right now to focus your attention and to hold new information in your working memory while you process it and incorporate it into what you already know. This is the same part of your brain that allows you to watch what you're doing so you don't make a fool of yourself in public.

The dorsolateral prefrontal cortex has extensive connections throughout the cortex as well as with deep, sub-cortical nuclei. And by modulating the circuits connecting them, TMS alleviates the symptoms of major depression.

One way to think about it is like this: antidepressants work their way up the ladder of the central nervous system. By altering neurotransmitter levels at the synaptic cleft, they alter communication between individual neurons, which changes the firing pattern in larger circuits, which, in turn, modulates the activity of entire networks.

In TMS, the therapeutic sequence moves in the opposite direction--from network...to circuit...to neuron...to synapse.

TMS: Neurochemistry

For over 40 years now, there's been a lot of talk about neurotransmitters, which has given rise to the popular notion that depression is caused by some sort of chemical imbalance in the brain. According to this popular "neuro-mythology", depression is caused by a deficiency of one or more neurotransmitters and treating depression is simply a matter of restoring these neurotransmitter levels to normal.


There is some truth to this, but it's a lot more complicated. Neurotransmitters play just one role in a much larger and more complex scenario. After all, we have a number of different antidepressants to choose from, some of which act on different neurotransmitter systems in different ways. But all effective treatments for depression have several things in common:

• They all affect regional blood flow and glucose metabolism
• They all modulate neuronal excitability
• They all have cumulative effects over time
• They all act in some manner through gene expression
• And all of them affect serotonin, dopamine, and to a lesser extent, norepinephrine levels

TMS produces all of the same neurotransmitter effects as antidepressant medications. But there are also some obvious differences between antidepressants and TMS. Antidepressants are molecules so they have to be ingested. In order to reach the brain they have to travel through the bloodstream. Along the way, they pass through every organ system of the body, which is why they can sometimes cause side effects. When they reach the brain, they attach to receptors in the cell membrane, altering neurotransmitters at the synaptic cleft, triggering a whole cascade of intracellular events. 

Even if TMS does all of these same things, it has to work by some different mechanism since the deep limbic mood circuits are simply too deep for the TMS pulse to reach directly. 


www.tmsnewengland.com
klanocha@tmsnewengland.com

TMS: Clinical Benefit Is Long-lasting

The fact that TMS is a very effective acute treatment for depression has long been established, but one lingering question has remained: how long do the effects last? In a study to determine the durability of the effects of TMS, a consortium of psychiatric researchers has found it to be an effective, long-term treatment for depression.

Results of the study, led by Philip G Janicak, MD, a professor at Chicago's Rush University Medical Center, were published in the October issue of the Journal of Brain Stimulation.

“This is the only prospective, maintenance, follow-up study which assesses the durability of acute TMS benefit in patients with major depression,” said Dr. Janicak.

In the study:

• 301 patients suffering from major depression were randomly assigned to receive active or sham TMS in an acute, six-week, controlled trial. 

• Patients who responded then underwent a three-week transition period where they were tapered off of active or sham TMS treatment and started on a standard antidepressant for maintenance. (After any successful acute treatment for depression, whether it is TMS, antidepressant medications, or electroconvulsive therapy, it is standard practice in most cases to introduce maintenance medication to lessen the chance of relapsing).

• Of those patients who received active TMS therapy and responded, 99 agreed to be followed for an additional 24-week period, during which only 10 patients relapsed.

In addition, TMS was successfully used as an intermittent rescue strategy to preclude impending relapse in 32 of 38 patients.

This means that:

• The therapeutic effects of TMS are long-lasting in the majority of acute responders, and

• Reintroduction of TMS is effective in preventing relapse.

“These results further support TMS as a viable treatment option for patients with major depression who have not responded to conventional antidepressant medications,” said Janicak.


This is an important study that underscores the fact that TMS produces long term improvement. Even so, the study looks at outcomes only for a period of 6 months. The TMS Center of New England is part of a multi-site, longitudinal outcomes study that aims to assess the durability of TMS over the course of 2 years.

TMS: Biophysics

In order to understand how TMS works, it's important to know a little bit about the biophysics underlying the technology. The earth is surrounded by a magnetic field which shields us from harmful cosmic rays. The magnetic field strength of TMS is 30,000 times greater than the earth's magnetic field and is about the same strength as a standard MRI machine. But you could lie in one these all day and you wouldn't be very happy.


Magnetic resonance imaging uses a static or unchanging magnetic field. TMS uses what is called a time-varying magnetic field, first discovered by the British physicist, Sir Michael Faraday, in 1839. The question Faraday asked was, "If electricity can create magnetism, why can't magnetism create electricity?" The answer is: it can--as long as the magnetic field is moving. 


So we could move the magnet, but an easier and more effective way of generating this kind of magnetic field is to rapidly turn an electrical current on and off. This current flows through a thick copper wire tightly coiled around a piece of solid iron, which becomes a magnet every time the current flows through the coil. In the most common form of TMS used to treat depression, this happens 10 times every second. So what we're really talking about is rTMS--repetitive transcranial stimulation--as opposed to single pule or paired pulse TMS which are used in research.


rTMS can be fast or slow. In slow rTMS the magnetic pulses come at a rate of one every second. Anything more rapid is considered to be fast rTMS. The speed of the magnetic pulses determines how TMS affects the brain. Slow pulses decrease the excitability of brain cells while fast pulses increase the excitability of brain cells and can excite them so much that they continue to fire even long after the magnetic stimulation ceases. This is the basic underlying mechanism by which TMS acts to treat depression.

TMS: Side Effects

Unlike antidepressants, where the list of side effects can go on for several pages, with TMS there is actually little to say. The only side effect from TMS is a mild, localized tingling sensation caused by direct stimulation of sensory neurons in the scalp. Most people adapt to this quickly and it's not unusual for patients to fall asleep during a treatment.


The only contraindication is the presence of a ferromagnetic foreign object, such as an aneurysm clip, somewhere in the head. Pacemakers and defibrillators are not a problem since they lie outside the magnetic field. TMS can be safely used in pregnant women. And it has also been used in children, where it's been used mostly for treatment medication resistant epilepsy.

TMS: History

As a treatment for depression, TMS has a unique mechanism of action. But it has something in common with every other breakthrough treatment in psychiatry--it was discovered by accident.


The first TMS device was invented by Dr. Anthony Barker in Sheffield, England in 1985 and it was intended solely for research purposes. It was originally used as a brain mapping tool where it has a time resolution ranging from milliseconds up to about an hour and a spatial resolution down to the level of the cell column or cerebral cell layer. 


One thing that TMS is especially good at is stimulating the motor cortex, which controls voluntary movement, so a lot of the early research was focused on movement disorders. By the mid 1990s, several investigators had made the same interesting observation: patients with Parkinson's disease, who were being studied with TMS, reported significant improvement in mood.


At first the papers just trickled in. Then they began pouring in from all over the world. Before long many researchers agreed that TMS was probably an effective treatment for depression, The question was: how effective? Different researchers were using very different protocols at the time which made it hard to compare one study to another. But there was another question too: is it safe?


It seemed to be pretty safe. The only thing that anybody complained about was minor scalp irritation at the stimulus site and this usually went away after a few treatments. But every once in a while, somebody had a seizure. It didn't happen very often, but the fact that it happened at all was bad news, and clearly there were still some questions to be answered.

• How strong should the magnetic pulses be? 
• How rapidly should they be delivered? 
• For how long? 
• And to what part of the brain?

Eventually all of these questions were answered. Guidelines were published in 1998 and since then the risk of having a seizure from TMS has been reduced even further.

TMS vs ECT

So how is TMS different from ECT? Both treatments use some form of electricity to stimulate the brain. But apart from this similarity there are a number of important differences. For one thing ECT is always given under general anesthesia. TMS is always given while a person is awake. A course of TMS is a bit longer than an average course of ECT, but it's a lot more convenient since it's always done as an outpatient procedure. And because there's no anesthesia used, patients can drive themselves to and from treatment. It's also a lot less expensive. But the most important difference is that TMS is virtually free of side effects.

ECT always causes temporary confusion. And it often causes temporary--but sometimes significant--memory problems. Plus, it has significant effects on the cardiovascular system which can be an issue for some patients. TMS causes none of these problems.

These different side effect profiles are due to the different ways in which these two treatments act upon the brain.

ECT stimulates the entire cerebral cortex. TMS stimulates only a small part of the cortex. And whereas ECT stimulates the entire brain, from the cortex all the way to the brainstem, TMS stimulates only the outer layers of the cortex and primarily the pyramidal cells in layer 5. But these pyramidal cells communicate with other cells. Although the magnetic field doesn't penetrate deeply, ultimately TMS treats depression by acting on the deep limbic mood circuits.