Posts tagged deep brain stimulation

Findings could help guide clinicians in selecting stimulation sites and improve treatment for neurological and psychiatric disorders

Over the past several decades, brain stimulation has become an increasingly important treatment option for a number of psychiatric and neurological conditions.

Divided into two broad approaches, invasive and noninvasive, brain stimulation works by targeting specific sites to adjust brain activity. The most widely known invasive technique, deep brain stimulation (DBS), requires brain surgery to insert an electrode and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Parkinson’s disease and essential tremor. Noninvasive techniques, including transcranial magnetic stimulation (TMS), can be administered from outside the head and are currently approved for the treatment of depression. Brain stimulation can result in dramatic benefit to patients with these disorders, motivating researchers to test whether it can also help patients with other diseases.

But, in many cases, the ideal sites to administer stimulation have remained ambiguous. Exactly where in the brain is the best spot to stimulate to treat a given patient or a given disease?

Now a new study in the Proceedings of the National Academy of Sciences (PNAS) helps answer this question. Led by investigators at Beth Israel Deaconess Medical Center (BIDMC), the findings suggest that brain networks – the interconnected pathways that link brain circuits to one another— can help guide site selection for brain stimulation therapies.

"Although different types of brain stimulation are currently applied in different locations, we found that the targets used to treat the same disease are nodes in the same connected brain network," says first author Michael D. Fox, MD, PhD, an investigator in the Berenson-Allen Center for Noninvasive Brain Stimulation and in the Parkinson’s Disease and Movement Disorders Center at BIDMC.

"This may have implications for how we administer brain stimulation to treat disease. If you want to treat Parkinson’s disease or tremor with brain stimulation, you can insert an electrode deep in the brain and get a great effect. However, getting this same benefit with noninvasive stimulation is difficult, as you can’t directly stimulate the same site deep in the brain from outside the head," explains Fox, an Assistant Professor of Neurology at Harvard Medical School (HMS). "But, by looking at the brain’s own network connectivity, we can identify sites on the surface of the brain that connect with this deep site, and stimulate those sites noninvasively."

Brain networks consist of interconnected pathways linking brain circuits or loops, similar to a college campus in which paved sidewalks connect a wide variety of buildings.

In this paper, Fox led a team that first conducted a large-scale literature search to identify all neurological and psychiatric diseases where improvement had been seen with both invasive and noninvasive brain stimulation. Their analysis revealed 14 conditions: addiction, Alzheimer’s disease, anorexia, depression, dystonia, epilepsy, essential tremor, gait dysfunction, Huntington’s disease, minimally conscious state, obsessive compulsive disorder, pain, Parkinson disease and Tourette syndrome. They next listed the stimulation sites, either deep in the brain or on the surface of the brain, thought to be effective for the treatment of each of the 14 diseases.

"We wanted to test the hypothesis that these various stimulation sites are actually different spots within the same brain network," explains Fox. "To examine the connectivity from any one site to other brain regions, we used a data base of functional MRI images and a technique that enables you to see correlations in spontaneous brain activity." From these correlations, the investigators were able to create a map of connections from deep brain stimulation sites to the surface of the brain. When they compared this map to sites on the brain surface that work for noninvasive brain stimulation, the two matched.

"These results suggest that brain networks might be used to help us better understand why brain stimulation works and to improve therapy by identifying the best place to stimulate the brain for each individual patient and given disease," says senior author Alvaro Pascual-Leone, MD, PhD, the Director of the Berenson-Allen Center for Noninvasive Brain Stimulation at BIDMC and Professor of Neurology at HMS. "This study illustrates the potential of gaining fundamental insights into brain function while helping patients with debilitating diseases, and provides us with a powerful way of selecting targets based on their connectivity to other regions that can be widely applied to help guide brain stimulation therapy across multiple neurological and psychiatric disorders."

"As we’re trying different types of brain stimulation for different diseases, the question comes up, ‘How does one relate to the other?’" notes Fox. "In other words, can we use the success in one to help design a trial or inform how we apply a new type of brain stimulation? Our new findings suggest that resting-state functional connectivity may be useful for translating therapy between treatment modalities, optimizing treatment and identifying new stimulation targets."

(Source: eurekalert.org)

Available research evidence supports the use of deep brain stimulation (DBS) for patients with obsessive-compulsive disorder (OCD) who don’t respond to other treatments, concludes a review in the October issue of Neurosurgery, official journal of the Congress of Neurological Surgeons (CNS). The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

Based on evidence, two specific bilateral DBS techniques are recommended for treatment of carefully selected patients with OCD, according to a new clinical practice guideline endorsed by the CNS and the American Association of Neurological Surgeons. While calling for further research in key areas, Dr. Clement Hamani of Toronto Western Hospital and coauthors emphasize that patients with OCD symptoms that don’t respond to other treatments should continue to have access to DBS.

Deep Brain Stimulation for OCD—What’s the Evidence?

Dr. Hamani led a multispecialty expert group in performing a systematic review of research on the effectiveness of DBS for OCD. Deep brain stimulation—placement of electrodes in specific areas of the brain, followed by electrical stimulation of those areas—has become an important treatment for patients with Parkinson’s disease and other movement disorders.

Although many patients with OCD respond well to medications and/or psychotherapy, 40 to 60 percent continue to experience symptoms despite treatment. Over the past decade, a growing number of reports have suggested that DBS may be an effective alternative in these “medically refractory” cases.

Dr. Hamani and colleagues were tasked with analyzing the supporting evidence and developing an initial clinical practice guideline for the use of DBS for patients with OCD. The review and guideline development process was sponsored by the American Society of Stereotactic and Functional Neurosurgery and the CNS. Out of more than 350 papers, the reviewers identified seven high-quality studies evaluating DBS for OCD.

Based on that evidence, they conclude that bilateral stimulation (on both sides of the brain) of two brain “targets”—areas called the subthalamic nucleus and the nucleus accumbens—can be regarded as effective treatments for OCD. In controlled clinical trials, both techniques improved OCD symptoms by around 30 percent on a standard rating scale.

While Research Proceeds, well-selected treatment-resistant severe OCD Patients Should Have Access to DBS

That evidence forms the basis for a clinical guideline stating that bilateral DBS is a “reasonable therapeutic option” for patients with severe OCD that does not respond to other treatments. The guideline also notes that there is “insufficient evidence” supporting the use of any type of unilateral DBS target (one side of the brain) for OCD.

The review highlights the difficulties of studying the effectiveness of DBS for OCD—because most patients respond to medical treatment, studies of this highly specialized treatment typically include only small numbers of patients. Dr. Hamani and coauthors identify some priorities for future research: particularly to identify the most effective brain targets and the subgroups of patients most likely to benefit.

Despite the limited evidence base, DBS therapy for OCD has been approved by the Food and Drug Administration under a humanitarian device exemption. Dr. Hamani and coauthors note that various safeguards are in place to ensure appropriate use, and prevent overuse, of DBS for OCD.

While research continues, they believe that functional neurosurgeons should continue to work with other specialists to ensure that patients with severe, medically refractory OCD continue to have access to potentially beneficial DBS therapy.

(Source: wolterskluwerhealth.com)

Although deep brain stimulation can be an effective therapy for dystonia – a potentially crippling movement disorder – the treatment isn’t always effective, or benefits may not be immediate. Precise placement of DBS electrodes is one of several factors that can affect results, but few studies have attempted to identify the “sweet spot,” where electrode placement yields the best results.

Researchers led by investigators at Cedars-Sinai, using a complex set of data from records and imaging scans of patients who have undergone successful DBS implantation, have created 3-D, computerized models that map the brain region involved in dystonia. The models identify an anatomical target for further study and provide information for neurologists and neurosurgeons to consider when planning surgery and making device programming decisions.

“We know DBS works as a treatment for dystonia, but we don’t know exactly how it works or why some patients have better, quicker results than others. Patient age, disease duration and other underlying factors have a role, and we believe electrode positioning and device programming are critical, but there is no consensus on ideal device placement and optimal programming strategies,” said Michele Tagliati, MD, director of the Movement Disorders Program in the Department of Neurology at Cedars-Sinai.

“This modeling paves the way for the construction of practical therapeutic and investigational targets,” added Tagliati, senior author of an article now available on the online edition of Annals of Neurology.

Medications usually are the first line of treatment for dystonia and several other movement disorders, but if drugs fail – as frequently happens – or side effects are excessive, neurologists and neurosurgeons may supplement them with deep brain stimulation. Electrical leads are implanted deep in the brain, and a pulse generator is placed near the collarbone. The device is later programmed with a remote, hand-held controller.

To calm the disorganized muscle contractions of dystonia, doctors generally target a brain structure called the globus pallidus, but studies on precise positioning of electrode contacts and the best programming parameters – such as the intensity and frequency of electrical stimulation – are rare and conflicting. Finding the most effective settings can take months of fine-tuning.

In this retrospective study, investigators examined a database of 94 patients with the most common genetic form of dystonia, DYT1, who had been treated with DBS for at least a year. They selected 21 patients who had good responses to treatment, compiled their demographic and treatment information, and used magnetic resonance imaging scans to create 3-D anatomical models with a fine grid to show exact location of relevant brain structures.

The investigators then simulated the placement of electrodes as they were positioned in the patients’ brains and input the actual stimulation parameters into a computer program – a “volume of tissue activation” model – which calculated detailed information specific to each patient and each electrode. The model draws on principles of neurophysiology – the way nerve cells respond to DBS – the biophysics of voltage distribution from electrodes, and the anatomy of the globus pallidus and surrounding structures.

“We found that clinicians were applying relatively large amounts of energy to wide swaths of the globus pallidus, but the area in common among most individuals was much smaller. We interpret this as being the potential ‘target within the target,’ and if our results are validated in further research and clinical practice, computer modeling may offer a physiologically-based, data-driven, visualized approach to clinical decision-making,” Tagliati said.

(Source: newswise.com)

Stimulation of a certain population of neurons within the brain can alter the learning process, according to a team of neuroscientists and neurosurgeons at the University of Pennsylvania. A report in the Journal of Neuroscience describes for the first time that human learning can be modified by stimulation of dopamine-containing neurons in a deep brain structure known as the substantia nigra. Researchers suggest that the stimulation may have altered learning by biasing individuals to repeat physical actions that resulted in reward.

"Stimulating the substantia nigra as participants received a reward led them to repeat the action that preceded the reward, suggesting that this brain region plays an important role in modulating action-based associative learning," said co-senior author Michael Kahana, PhD, professor of Psychology in Penn’s School of Arts and Sciences.

Eleven study participants were all undergoing deep brain stimulation (DBS) treatment for Parkinson’s disease. During an awake portion of the procedure, participants played a computer game where they chose between pairs of objects that carried different reward rates (like choosing between rigged slot machines in a casino). The objects were displayed on a computer screen and participants made selections by pressing buttons on hand-held controllers. When they got a reward, they were shown a green screen and heard a sound of a cash register (as they might in a casino). Participants were not told which objects were more likely to yield reward, but that their task was to figure out which ones were “good” options based on trial and error. 

When stimulation was provided in the substantia nigra following reward, participants tended to repeat the button press that resulted in a reward. This was the case even when the rewarded object was no longer associated with that button press, resulting in poorer performance on the game when stimulation was given (48 percent accuracy), compared to when stimulation was not given (67 percent).

"While we’ve suspected, based on previous studies in animal models, that these dopaminergic neurons in the substantia nigra - play an important role in reward learning, this is the first study to demonstrate in humans that electrical stimulation near these neurons can modify the learning process," said the study’s co-senior author Gordon Baltuch, MD, PhD, professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania. “This result also has possible clinical implications through modulating pathological reward-based learning, for conditions such as substance abuse or problem gambling, or enhancing the rehabilitation process in patients with neurological deficits.”

(Source: uphs.upenn.edu)

Experimental studies have shown that deep brain stimulation (DBS) within the subcallosal cingulate (SCC) white matter of the brain is an effective treatment for many patients with treatment-resistant depression. Response rates are between 41 percent and 64 percent across published studies to date. One of the proposed mechanisms of action is through modulation of a network of brain regions connected to the SCC. Identifying the critical connections within this network for successful antidepressant response is an important next step.  

A new study using MRI analysis of the white matter connections examined the architecture of this network in patients who demonstrated significant response to SCC DBS. Researchers found that all responders showed a common pattern defined by three distinct white matter bundles passing through the SCC. Non-responders did not show this pattern.

The study is published online in the journal Biological Psychiatry, with the title “Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.”

"This study shows that successful DBS therapy is not due solely to local changes at the site of stimulation but also in those regions in direct communication with the SCC," says Helen Mayberg, MD, senior author of the article, professor of psychiatry, neurology and radiology and the Dorothy C. Fuqua Chair in Psychiatric Imaging and Therapeutics at Emory University School of Medicine.

"Precisely delineating these white matter connections appears to be very important to a successful outcome with this procedure. From a practical point of view, these results may help us to choose the optimal contact for stimulation and eventually to better plan the surgical placement of the DBS electrodes."

Led by researchers at Emory University, Case Western Reserve University and Dartmouth University, the study included 16 patients with treatment-resistant depression who previously received SCC DBS at Emory. Computerized tomography was used post-operatively to localize the DBS contacts on each electrode. The activation volumes around the active contacts were modeled for each patient. Sophisticated neuroimaging combined with computerized analysis was used to derive and visualize the specific white matter fibers affected by ongoing DBS.

Therapeutic outcome was evaluated at six months and at two years. Six of the patients had responded positively to DBS at six months, and by two years these six plus six more patients responded positively. All shared common involvement of three distinct white matter bundles: the cingulum, the forceps minor and the uncinate fasciculus.

The conversion of six of the patients who were not responding at six months to being responders at two years was explained by the inclusion of all three bundles due to changes in stimulation settings. Non-responders at both six months and two years showed incomplete involvement of these three tracts. 

"In the past, placement of the electrode relied solely on anatomical landmarks with contact selection and stimulation parameter changes based on a trial-and-error method," says Patricio Riva-Posse, MD, Emory assistant professor of psychiatry and behavioral sciences and first author of the paper. "These results suggest that clinical outcome can be significantly influenced by optimally modulating the response network defined by tractography. This obviously will need to be tested prospectively in additional subjects here and by other teams exploring the use of this experimental treatment."

This new information will allow us to develop a refined algorithm for guiding surgical implantation of electrodes and optimizing the response through fine tuning of stimulation parameters,” notes Mayberg. “That said, improving anatomical precision alone doesn’t account for all non-responders, so that is an important next focus of our research.”

The researchers now plan to study DBS therapy in a prospective protocol of similar treatment-resistant depressed patients, using presurgical mapping of an individual patient’s network structure, precisely targeting the three SCC fiber bundles, and systematically testing the stimulation contacts.

(Source: news.emory.edu)