Read a review on the use of deep brain stimulation (DBS). Wrote a lot of posts about this new treatment on this blog, mostly for treatment resistant depression. As with most new treatment options the new treatment is tried with other severe diseases. You can probably find some on this blog or down this post in the related posts section. The use of DBS in Alzheimer’s disease drew my attention. Stimulating certain brain regions in a disease with a neurodegenerative character seems almost impossible.
This review was written by members of the Canadian group who also published about the use of DBS in treatment resistant depression. They stimulated certain brain regions serving cognitive and memory functions (the fornix, part of the Papez memory circuit) in six patients with Alzheimer’s disease.
After 1 year of chronic high-frequency stimulation, glucose hypometabolism within the temporoparietal cortex that is characteristic of the diseased brain was largely reversed
Two patients improved on the Mini Mental State Examination, three others declined and one was unchanged. The average decline on points of the MMSE suggest a delay of this cognitive decline for these patients.
It was just a pilot study and needs further research. The authors have started a large multicenter trial
J. Schouenborg, M. Garwicz and N. Danielsen (Eds.)
Progress in Brain Research, Vol. 194
Deep brain stimulation: emerging indications
Travis S. Tierney, Tejas Sankar and Andres M. Lozano
New long term data on efficacy of deep brain stimulation for treatment resistant depression are available. The first follow up data up to 1 year were already promising. Published research about deep brain stimulation for treatment resistant depression showed that six months after surgery, 60% of patients were responders and 35% met criteria for remission, benefits that were largely maintained at 12 months.
The average response rate to DBS after two and three years were 46,2% and 75%. More than one-third of patients were in remission at year 3. But what’s more convincing functional impairment in the areas of physical health and social functioning progressively improved up to the last follow-up visit.
The Mayberg group published a follow up for 6 patients after 6 months and they subsequently reported on 12 month outcomes in an expanded sample of 20 patients. The last report at 3 years of follow-up as summarized above were also with 20 patients. The report on the extended follow-up of these 20 patients results from data from 3 to 6 years (mean=3.5 years) after DBS implantation. The mean duration of follow-up of the 20 patients was 42,1 months. In general patients required less medication after DBS implantation.
Two patients died by suicide during depressive relapses. This is of concern but stipulates the severity of the illness and it’s consequences. From the editorial:
One issue arising from this study requires special attention—that of suicide. Two of the 20 patients in this extended follow-up study committed suicide, and two others made suicide attempts. There is no evidence suggesting that DBS was related to these deaths. Rather, these suicides reflect the severity and seriousness of treatment resistant depression. In one of these patients there had been periods of sustained remission, but the patient relapsed and required a course of ECT prior to her suicide. The other patient had persistent suicidal ideation. These results underscore the high mortality in patients with treatment-resistant depression, even with careful and frequent monitoring by experienced and competent providers. It should serve as an impetus for us to continue to strive to develop new strategies to treat this patient population.
The first year three of the first six patients had hardware infections, no device related adverse events occurred after those three. Eight battery replacement surgeries were required during follow-up (mean time to battery replacement, 43.3 months).
Over the course of follow-up, eight patients were hospitalized for medical reasons on a total of 12 occasions. Half of these admissions were for psychiatric reasons (worsening depression, N=3; suicidal ideation, N=3), and the other half were for nonpsychiatric reasons
Other scarce reports on efficacy and follow up with DBS targeting other areas also show comparable results. Limitations of this study:
Open label, selected group of nonpsychotic unipolar depressed patients which leaves it unclear whether other forms of depression will also respond favorably.
Kennedy SH, Giacobbe P, Rizvi SJ, Placenza FM, Nishikawa Y, Mayberg HS, & Lozano AM (2011). Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. The American journal of psychiatry, 168 (5), 502-10 PMID: 21285143 Hirschfeld RM (2011). Deep brain stimulation for treatment-resistant depression. The American journal of psychiatry, 168 (5), 455-6 PMID: 21536698
According to this neurosurgeon, the strongest evidence exists for Broadman Area 25 in the subcallosal cingulate gyrus (SCG) as target for deep brain stimulation in treatment resistant depression.. This area in the brain is depicted in the figure above and is from the most important publication about DBS and depression in Neuron march 2005 by Helen Mayberg. Functional neuroimaging as well as antidepressant treatment effects suggest that this area plays an important role in modulating negative mood states. A decrease in activity is reported with clinical response to antidepressants and electroconvulsive therapy (ECT).
But depression is not a disease of a single brain region nor neurotransmitter system. It is now generally viewed as a systems-level disorder affecting integrated pathways linking select cortical, subcortical, and limbic brain regions with their related neurotransmitter systems.
In a recent study done by the “Mayberg group”, Toronto, Canada, the autors compared the location of the electrode contacts in responders and nonresponders to DBS of the subcallosal cingulate gyrus (SCG) and correlated the results with clinical outcome to help in identifying the optimal target within the region.
On postoperative MRI scans the researchers did complicated mapping procedures to pin point the locations of the active contacts on the implanted electrodes. There was no difference when the right and left electrodes were compared in patients. So both electrodes were exactly placed on each side (hemisphere). The only significant difference they found between responders and nonresponders was that electrodes in patients who responded were in a slightly more ventral position relative to the anatomical landmarks used in the medial prefrontal lobe. This difference between responders and nonresponders did not exceed 1,5 mm. The authors is not likely to be of clinical significance, according to the authors. This small difference is probably unimportant compared to the clinical features of the patient for the outcome of the DBS procedure in depression. Another limiting factor on this research is the small sample size, in larger groups these results might differ.
What we can conclude based on our findings is that within the small targeted region of the SCG, the location of the electrode contacts did not determine outcome.
This article also describes a detailed method for a more standardized method for targeting the SCG with DBS for depression. This is to technical to reproduce in this post but those working with DBS for depression should have a look at this procedure. From this study it is still not clear whether DBS of other brain areas might be more superior in efficacy. And is brain area more important than clinical features of the patient or do the areas differ for different types of depression? All very interesting questions and topic for more research on DBS.
Hamani, C., Mayberg, H., Snyder, B., Giacobbe, P., Kennedy, S., & Lozano, A. (2009). Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting Journal of Neurosurgery, 111 (6), 1209-1215 DOI: 10.3171/2008.10.JNS08763
A new neurosurgical procedure may prove helpful for patients with treatment-resistant depression. Bilateral epidural prefrontal cortical stimulation (EpCS) was found generally safe and provided significant improvement of depressive symptoms in a small group of patients
The location for Brain Stimulation in EpCS targets electrical stimulation to the anterior frontal poles and the lateral prefrontal cortex. Two different places on both hemispheres, resulting in four separate paddle leads which are connected to two small generators surgically implanted in the upper chest area of the patient. The leads are placed through a burr hole in the skull but above the dura mater and thus remain separated from the underlying cortical region by the arachnoid space. ECS is more direct than transcranial magnetic stimulation (TMS) and or vagus nerve stimulation (VNS) and potentially safer than deep brain stimulation (DBS), which involves passing the electrodes through brain tissue.
Of five patients three reached remission. Overall after seven months, the average improvement was 54.9 percent based on the Hamilton Rating Scare for Depression.
Advantages according to the team:
“Cortical stimulation has several advantages provided that it shows efficacy in treating depression. It is reversible, non-destructive and potentially safer than other forms of invasive brain stimulation since the stimulating paddles don’t come in direct contact with the brain.”
Deep Brain Stimulation (DBS) is mostly used for Parkinson’s Disease. DBS for Obsessive Compulsive Disorder and Depression is just starting to be used. It is unclear how DBS works for Parkinson’s Disease.
A great step forward, patients don’t have to be awake during the procedure. This video shows a clear description of the old and new procedure for deep brain stimulation (DBS). In the old procedure a frame has to applied after which a brain mapping procedure has to follow, up to 6-8 hours while the patient has to be awake. At the end the patient has to undergo a MRI to see whether the electrodes are in the right place. All very tedious and time consuming. The new procedure takes place in the MRI with anesthesia and takes less time (50%). Have a look at this new procedure in the video.
Is there new hope for Parkinson’s patients? Imaging scientist, Alastair Martin, and neurosurgeon, Dr. Paul Larson, have teamed up to develop a way to perform Deep Brain Stimulation surgery that’s more comfortable for the patients, more accurate and cuts the regular procedure time in half to 3 1/2 hours. The pair, working at the University of California in San Francisco perform DBI surgery while the patient is inside the MRI . The advantage to the procedure is that the patient does not have to be awake, it detects complications on the spot and allows for precise placement of the electrodes in the brain.
Deep Brain Stimulation (DBS) should only be used when there is a high change that the lives of patients will be improved by its use and when all other possible interventions have been tried
Patients must be fully informed and informed consent must be obtained
The whole procedure should be done by teams of appropriate specialists like neurosurgeons, neurologist, psychiatrist and other health professionals that can help the patient before during and after the operation and who will continuously monitor the patient
The procedure should help restore (but not augment) normal function, should provide relief from pain and distress, and should never be used for law enforcement or for political or social purposes
It is important to provide follow-up for every patient enrolled in a trial if at all possible and to report the outcomes in scientific journals
These ethical guidelines were recently published in the JAMA and I fully agree with these guidelines. The article starts with a brief description of DBS, it’s complications and a short history of the lessons from past errors of psychosurgery.
Important lessons from the abuses of psychosurgery in the last century make it imperative to have solid hypotheses with strong scientific support and appropriate safeguards (eg, interdisciplinary review boards) before proceeding to treat patients using DBS.
Using these guidelines with the recent technological advances DBS can perhaps help a lot of patients in the near future.
Kringelbach, M., & Aziz, T. (2009). Deep Brain Stimulation: Avoiding the Errors of Psychosurgery JAMA: The Journal of the American Medical Association, 301 (16), 1705-1707 DOI: 10.1001/jama.2009.551
Deep Brain Stimulation (DBS) is mostly used for Parkinson’s Disease. DBS for Obsessive Compulsive Disorder and Depression is just starting to be used. It is unclear how DBS works for Parkinson’s Disease. With DBS an electrical probe is inserted into the brain and it stimulates an area known as the subthalamic nucleus. This can help people with Parkinson’s disease overcome the disorder’s neurological block on movement.
But how does this stimulation work. Some researchers think the technique stimulates neurons that initiate movement. Others say it blocks inhibitory neurons, allowing brain signals to resume. And yet another theory holds that it influences the flow of information along axons — fibers that connect neurons to each other.
A recent study published in Science shows that deep brain stimulation exerts its effect on axons, specifically those that feed into the subthalamic nucleus, rather than on the neurons in the structure.
This is the experiment:
For the Science study, the team genetically engineered mice that have a condition that mimics Parkinson’s disease to produce light-responsive proteins only in certain cells in the brain. Then, the researchers inserted fiber optic threads into the mice’s brains. The team used a pulse of blue laser light to increase activity of the cells, or a burst of yellow laser light to quiet the cells. The scientists also used electrical probes to measure activity of the neurons.
When the researchers turned on the light in cells in the subthalamic nucleus nothing happened. But light stimulation of incoming axons improved the mice’s movements. Quieting activity of the axons made the movement disorder worse.
These findings sugests that to stimulate parts of the brain closer to the surface might be an alternative to deep brain surgery. This is a less invasive procedure than DBS.
In yet another Science publication the stimulation of the spinal cord in mice and rats could restore movement to rats and mice with Parkinson’s–like problems.
It’s good news for patients,” says Feng, who was not involved in either study. “Of course, it is not a cure.”
He says that the light-responsive techniques may help uncover the neural circuitry that leads to other psychiatric diseases, such as depression and obsessive-compulsive disorder, which are also sometimes treated with brain stimulation. And spinal cord stimulation or other minimally invasive therapies may offer psychiatric patients an alternative to deep brain surgery.
This will be continued but it will not stop the use of DBS for Parkinson’s disease and why should it, we don’t know how antidepressants work or ECT for that matter.
Gradinaru, V., Mogri, M., Thompson, K., Henderson, J., & Deisseroth, K. (2009). Optical Deconstruction of Parkinsonian Neural Circuitry Science DOI: 10.1126/science.1167093 Fuentes, R., Petersson, P., Siesser, W., Caron, M., & Nicolelis, M. (2009). Spinal Cord Stimulation Restores Locomotion in Animal Models of Parkinson’s Disease Science, 323 (5921), 1578-1582 DOI: 10.1126/science.1164901
This is an important question. until now all medication for Parkinson’s disease relieved the symptoms of this disease for a while. The medication couldn’t prevent the progression of the disease resulting in lack of efficacy of the medication. Increasing the dosage until side-effects or adding another therapeutic temporarily resolved the symptoms until the progression again decreased their efficacy.
Hundreds of putative neuroprotective agents have been tested in clinical trials over the past two decades, but none of these agents has been successful at preventing the progression of PD.
We believe that DBS will be the first therapy proven to slow PD progression, and that it must be applied in the earliest stages of the disease to have such an effect.
They base their opinion on the results of animal research. From these animal models it was learned that high frequency deep brain stimulation can be neuroprotective. The animals received DBS during ongoing neurodegeneration, which more accurately represents clinical practice and DBS at high frequency has inhibitory effects on this neurodegeneration.
Results from clinical trials are contradictory. In some trials no significant clinical deterioration during 4 years of DBS therapy could be found, while many trials have noted clinically and statistically significant deterioration of motor symptoms after initiation of DBS therapy.
The authors have stron arguments for these conflicting results:
First, continued functional decline does not eliminate the possibility of positive disease modification—it only eliminates the possibility that DBS might result in a complete halt in progression. Furthermore, none of the studies so far has included a control group that was treated with standard drug therapy, and, thus, progression rates between the two groups have not been compared.
An additional limitation is that all studies to date have been in patients with features of advanced PD, including motor complications of therapy. Currently, patients do not receive DBS therapy until they have developed intractable symptoms and motor complications of therapy; electrode implantation both in clinical trials and in standard of care takes place at an average of 11 years after diagnosis, at which point considerable cell death has occurred, and potentially neuroprotective strategies are unlikely to demonstrate a clear benefit.
The authors have started a pilot clinical trial (ClinicalTrials.gov identifier NCT00282152) to study the neuroprotective effects of DBS in Parkinson’s Disease. They will test the hypothesis that DBS slows the progression of early stage PD.
Hope they will succeed in confirming their hypothesis for such a debilitating disease.
Charles, P., Gill, C., Davis, T., Konrad, P., & Benabid, A. (2008). Is deep brain stimulation neuroprotective if applied early in the course of PD? Nature Clinical Practice Neurology, 4 (8), 424-426 DOI: 10.1038/ncpneuro0848
New data are being published about deep brain stimulation and treatment resistant depression. Especially longer follow up is of importance. In recent published research about deep brain stimulation for treatment resistant depression, six months after surgery, 60% of patients were responders and 35% met criteria for remission, benefits that were largely maintained at 12 months. Moreover, there was no significant loss of effect requiring dose adjustments over time. So once a good stimulus dose, high change that it will remain that way over a long period of time.
With DBS for TRD symptoms typically return rapidly if the device is turned off, if a lead breaks, or if the battery dies. From other areas of neuroscience it is learned that intermittent stimulation of brain areas could provoke longer-term neuroplastic brain changes in these circuits (LTD or LTP), thus moving brain circuits into a more resilient and healthy mode, making symptom recurrence less likely if stimulation is stopped or withdrawn. Exciting trials with intermittent DBS are underway testing these new hypotheses and probably after some time it is probable that the devices can be switched of for good or until recurrence.
In this study twenty patients with TRD underwent serial assessments before and after Subcallosal Cingulate Gyrus DBS. They determined the percentage of patients who achieved a response (50% or greater reduction in the 17-item Hamilton Rating Scale for Depression or remission (scores of 7 or less) after surgery. They also examined changes in brain metabolism associated with DBS, using positron emission tomography.
Results from PET scans. The results indicate that SCG DBS produces striking changes in cognitive and limbic brain areas and they provide a biological basis for the observed improvements in depression in these patients. There is a direct activation of the white matter at target that can lead to either metabolic activation or inhibition in distinct remote brain areas. Antidepressant medications, cognitive behavioral therapy, and electroconvulsive therapy produce similar changes in many of these same brain regions.
Wound Infection and Hardware removal 3 patients
Reinsertion of DBS Hardware 1 patient
Wound Infection Managed with Antibiotics Alone 1 patient
Perioperative Seizure 1 patient
Worsening Mood/Irritability 2 patients
Perioperative Headache 4 patients
Pain at Pulse Generator Site 1 patient
No Adverse Effects 7 patients
Limitation of this study is the open label assessment of outcomes
A LOZANO, H MAYBERG, P GIACOBBE, C HAMANI, R CRADDOCK, S KENNEDY (2008). Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression Biological Psychiatry, 64 (6), 461-467 DOI: 10.1016/j.biopsych.2008.05.034