By Sarah Baldauf

Medicine has long gone straight to the master organ, the brain, in an attempt to heal various psychiatric, neurodegenerative, and movement disorders.

In recent years, attention has been focused heavily on the potential of brain stimulation therapies, which interrupt misbehaving brain signals. The therapies -- including electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS) -- work to rejigger the brain's electrical circuitry and provide relief from debilitating symptoms that don't respond to medications. And the list of disorders these techniques could target is lengthening. Depression and Parkinson's disease have been the subject of a considerable body of brain stimulation research, and clinical trials are now investigating the therapies to treat pain, epilepsy, Tourette's syndrome, tinnitus, obsessive-compulsive disorder, headache, and other conditions.

Brain stimulation, also known as neuromodulation, can come in several forms.

Implanted pacemakerlike devices can zap at deep parts of the brain using DBS. Strong magnets can be pressed onto a patient's head to influence the brain's circuitry via TMS. And controlled, seizure-inducing electrical currents can be applied to the head with ECT; intentionally causing seizures has long been used to alleviate symptoms of some mental illnesses. All those treatments offer alternatives to medications that are meant to tip the balance of neurochemicals in such a way that a tremor is controlled, say, or mania or depression is alleviated. And brain stimulation is a less-invasive choice than the scalpel, which is sometimes used by neurosurgeons to remove an offending section believed to be causing debilitating seizures, for example. Such surgery requires removing a portion of the brain.

The main question at the heart of therapeutic brain stimulation research has been: Can medicine and technology manipulate neurological circuits to inhibit or excite specific areas of the brain that are causing trouble? Clinicians and researchers have, in some cases, been able to answer, yes.

The brain is essentially a buzzing web of neural circuitry. Turning its electrical circuits on and off, researchers have found, has the potential to control the symptoms of diseases that emanate from the brain, says Brian Litt, whose lab at the University of Pennsylvania studies the intersection of brain network disorders and electrical engineering. (Litt is a neurologist and electrical engineer by training.) In particular, benefit has been seen with psychiatric diseases, like severe depression, and movement disorders, like Parkinson's, in cases in which patients don't improve on medications.

But successfully manipulating the brain's circuitry is no simple task. It is estimated that the brain has about 100 billion neurons that send electrical signals to one another through a web of about 100 trillion connections called synapses. In addition to being complex, that organ inside our heads is extremely dynamic. Unlike other organs, it is continually transforming itself.

"The [brain's] circuits change all the time," Litt says. "Every time you store a new memory there is a physical change." Yet amid the chaotic webs of circuitry is order--albeit an extremely complex order. Among other things, the Litt Lab is working to map some of the dysfunctional circuitry involved in disease processes, including epilepsy, in order to better understand brain disease and to guide and refine the stimulation treatments.

Medical interest in brain stimulation treatments exists partly because they offer some significant advantages over alternatives, say some practitioners. One hugely attractive gain is that brain stimulation is reversible. Neurosurgery is not. "No one likes to be making lesions in a brain that is already injured," explains Frederick Lenz, neurosurgeon and director of epilepsy surgery at Johns Hopkins Hospital in Baltimore.

Removing or intentionally damaging portions of the brain has historically been a part of the practice of neurosurgery, and those methods are still used. But now Lenz, who has practiced neurosurgery for decades, uses what's called deep brain stimulation, or DBS, as well. In DBS, he implants electrodes into patients' brains--typically those who have movement disorders--that serve as something of a neural pacemaker. Similarly, vagus nerve stimulation involves implanting a pulse generator in a patient's chest. VNS taps the vagus nerves that run down either side of the neck, which in turn stimulates key portions of the brain. VNS is most often used in depression and epilepsy cases that don't respond to drug treatment.

Another benefit of the stimulation therapies, experts argue, is their deft aim.

"They get to the brain more directly than medications," says Mehmet Dokucu, a psychiatrist who is director of the Cancer Psychiatry Service at the Feinberg School of Medicine at Northwestern University. He administers transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) to treat patients with severe depression. He also administers ECT to Parkinson's patients and people with mania that is followed by a catatonic state. Current medications, he adds, "hit a very broad swath of the body and the brain"--a fact that can make for side effects, including dry mouth, lethargy, diminished libido, agitation, or suicidal thoughts. But brain stimulation therapies are not without their own side effects, which can range from headache to memory loss to death. (Death is always a risk--though a relatively small one--with surgical procedures, too.)

To be sure, patients shouldn't expect a doctor to be flip about recommending a brain stimulation therapy. "Typically, we address [a patient's illness] first with medications, psychotherapy, exercise, dietary changes," Dokucu explains. "Neurostimulation is a second-, third-, or fourth-line treatment." And sometimes drugs might be used in combination with brain stimulation, even though they may not have worked previously, to maintain gains from the stimulation.

Getting treated with ECT or TMS involves a series of visits to get the therapy -- a few times per week, say, for three to five weeks.

That is not the case with the implanted devices used in DBS and VNS, though several separate procedures are required for DBS.

While arguably less invasive than surgery, a series of treatments with TMS or ECT can provide only temporary results and, even when covered by insurance, may cost several hundred dollars in copays per treatment.

While no one knows the limits of brain stimulation's therapeutic potential, research on neuromodulation is certainly exploding.

That's partly because of the potential financial upside for successful device-makers.

No matter how optimistic researchers may be, patients seeking relief through relatively new or experimental applications of brain stimulation need to have measured expectations and exercise caution.


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