The Past and Future of Brain Circuit-Based Therapies for OCD

By Darin D. Dougherty MD and Benjamin D. Greenberg MD, PhD

Darin Dougherty, MD is Associate Professor of Psychiatry at Harvard Medical School, Clinical Associate at Massachusetts General Hospital (MGH), Director of the Division of Neurotherapeutics in the Department of Psychiatry at MGH, Visiting Scientist at Massachusetts Institute of Technology and serves on the MGH Psychiatric Neurosurgery Committee. Dr. Dougherty is also an attending psychiatrist at the OCD Institute (OCDI) at McLean Hospital outside of Boston, MA.

Benjamin Greenberg, MD, PhD, is Professor of Psychiatry and Human Behavior at the Warren Alpert Medical School of Brown University. Based at Butler Hospital (Providence, RI) and the Center for Neurorestoration and Neurotechnology at the Providence VA Medical Center,  Dr. Greenberg’s work focuses on development of neuromodulation (deep brain stimulation, transcranial electrical and magnetic stimulation) for OCD and other conditions.

This article was initially published in the Winter 2016 edition of the OCD Newsletter

As part of the IOCDF newsletter series covering OCD treatments from the past 50 years to the present, we present the article below on “brain circuit-based” treatments. These methods aim to improve OCD symptoms and functioning of people not by a behavioral intervention or using medications, but by intervening to change the functioning of brain networks. In noninvasive methods either magnetic or electrical energy is delivered across the scalp and skull and into the brain. In invasive interventions, devices are directly implanted into the brain itself or lesions are made there. Such specific neurosurgical procedures are considered only for carefully-selected individuals with severe OCD who are not helped enough by conventional treatments, whereas non-invasive techniques could be applied to a larger number of people. Some invasive methods (lesion procedures) actually appeared over 50 years ago, though they have undergone considerable refinement since then. Here, we begin with noninvasive methods, which are generally earliest. It is important to note that any of these methods is most likely to be useful when added to conventional behavioral and medication approaches, so they would be delivered as part of a team approach where clinicians with different kinds of expertise all work together for the benefit of OCD sufferers who do not respond adequately to traditional treatments alone.

Transcranial Magnetic Stimulation (TMS)

Since one of us (BDG) and colleagues introduced TMS as a research tool in OCD, studies have increased, although at a slower pace than for major depression, where TMS is now standard of care, with hundreds of clinics offering this therapy across the U.S. and hundreds more worldwide. However, and fortunately, the pace of TMS research in OCD has recently picked up. Briefly, TMS uses an electromagnet to send pulses of magnetism into the brain (the scalp and skull are transparent to magnetism). Keep in mind that the it is a brain network being affected, or modulated, which is why TMS is one of a group of methods also known as “neuromodulation.” All such methods can affect areas that are functionally connected to the part of the brain being directly stimulated. Depending on the device used, TMS can directly affect brain structures from several centimeters under the surface of the magnetic coil to somewhat farther away. In general, the deeper the stimulation goes, the less “focal” it is, that is, the more parts of the brain get stimulated (see the excellent summary of TMS in OCD by Joan Camprodon MD PhD in the Fall/Winter 2015 edition of this newsletter for more details). As of this writing, stimulation targeting a part of the brain called the pre-Supplementary Motor Area (pre-SMA) looks to be the most promising. The pre-SMA can be accessed via a TMS coil placed on the midline on top of the head, slightly toward the front, and also via larger coils producing TMS more deeply (and also more widely) in the brain. There is evidence to suggest that pre-SMA TMS, might also reduce abnormal brain excitability seen in OCD. Other brain targets for TMS in OCD include orbitofrontal cortex, and dorsolateral prefrontal cortex (which is the TMS stmimulation site used for major depression). This is an outpatient procedure, involving multiple daily sessions which are delivered usually on weekdays, and usually over a period weeks. TMS is generally very well-tolerated, though scalp discomfort can occur during and after stimulation pulses, and precautions need to be taken to reduce the (extremely small) risk that the stimulation might induce an unwanted seizure. TMS research studies for OCD, ongoing or soon to begin, often now involve brain imaging to investigate how brain networks change after a course of this investigational therapy.

Transcranial Direct Current Stimulation (tDCS)

As the name implies, in tDCS (and related kinds of electrical stimulation), electrical current is passed across the scalp and skull into the brain. Since electrical resistance to current flow is relatively high, only weak electric currents are produced in the brain during tDCS. Unlike TMS, which can make neurons in the brain fire off nerve impulses, tDCS does not deliver enough energy for that to happen. What tDCS is thought to do instead is “bias the system,” meaning it influence brain activity by increasing or decreasing the chance that activity already going on in the brain will shift the functioning of a brain network in a particular direction. While the amount of research using tDCS across many clinical conditions has increased truly dramatically in recent years, as of now this has been the least studied of noninvasive neuromodulation methods for OCD.

Some of the targets for stimulation most actively investigated n OCD are similar to those being used in studies of TMS, like the pre-SMA discussed above. Compared to TMS, tDCS is generally less focal (less specific in where it is thought to act).  However, there are ways to use software to model current flow in the brain, and different kinds of devices that may allow current flow to be shaped to be more specific. This method in general is very well-tolerated, and is, unlike TMS, suitable to eventually be developed for portable or even home use. Examples of current tDCS research in OCD include two studies in our group at Butler Hospital, one where tDCS is combined with exposure-based behavior therapy testing the idea that benefit from behavior therapy might occur faster or be greater in combination with tDCS (see ClinicalTrials.gov NCT02329587). Another study (NCTNCT02704117) is part of a wider NIMH-funded Conte Center effort focused on mapping the brain circuitry involved in OCD and on how to use noninvasive methods to modulate it for therapeutic purposes.

Neurosurgical Interventions for Intractable OCD

As we note above, most patients with OCD eventually respond to treatment with medication and/or behavioral therapy. But a small minority do not improve following all conventional treatments. For this small minority, one remaining viable option is neurosurgery, including lesion procedures (cingulotomy or capsulotomy) or deep brain stimulation (DBS).

Anterior cingulotomy

Neuroimaging studies aimed at seeing what parts of the brain are involved in OCD have found that the anterior cingulate cortex, is repeatedly involved in the pathophysiology of OCD (Deckersbach et al. 2006). Starting in the 1960s, anterior cingulotomy has been used to treat refractory patients with OCD and/or major depression. The procedure involves a craniotomy (drilling holes through the skull) followed by placing an electrode in the brain which is then heated in order to burn away a small amount of brain tissues. After the procedure, the electrode is removed. Patients are typically awake during the procedure and return home after a few days in the hospital. Studies examining the outcome for patients following anterior cingulotomy for treatment-resistant OCD have shown that up to 69% of patients who did not respond to conventional treatment achieve some benefit from the procedure (Sheth et al. 2013). Side effects are relatively minimal. There is a small risk of infection or seizure after any craniotomy. Before and after cognitive testing has not revealed any changes in thinking abilities following the procedure.

Anterior capsulotomy

Another neurosurgery procedure that has been used for treatment resistant OCD is called anterior capsulotomy. This procedure is named after another structure in the brain, the anterior limb of the internal capsule. Again, this procedure was first used in the 1960s and also involves making lesions (holes) in a part of this brain structure (technically this is an “ablative” or lesion procedure). Positive outcomes following an anterior capsulotomy for OCD are approximately 50-60% (Greenberg et al. 2003; Ruck et al. 2008). While the original anterior capsulotomy procedure also involved a craniotomy, the use of the “gamma knife” has more recently allowed for anterior capsulotomy procedures that do not require opening the skull. The gamma knife ventral anterior capsulotomy involves passing multiple gamma rays through the skull. No single gamma ray poses any danger to brain tissue. However, where the gamma rays intersect, the energy level is high enough to destroy (or ablate) the targeted tissue. The most recent version of this procedure is called gamma ventral capsulotomy in which the lesions are limited to the ventral (bottom) half of the anterior capsule. Responses to this procedure appear to be seen in up to 60% of patients (Greenberg et al. 2003; Lopes, et al. 2014). Another significant advantage of the gamma ventral capsulotomy is that it is associated with fewer side effects than an anterior capsulotomy that involves a craniotomy. Current research includes mapping the brain changes associated with clinical improvement after gamma knife ventral capsulotomy (ClinicalTrials.gov NCT01849809).

Deep Brain Stimulation

Another important development for treatment-resistant OCD is deep brain stimulation (DBS). DBS has been used since the mid-1980s to treat movement disorders such as severe tremor or Parkinson’s disease. DBS involves placing electrodes in targeted areas of the brain. In Parkinson’s disease electrical stimulation of the targeted brain region (such as the subthalamic nucleus) usually results in a significant decrease in some of the disabling symptoms of the illness, such as tremor. Once the electrodes are in place they are connected by wires under the skin to pulse generators under the skin (usually just below the collarbone). The pulse generator or “implantable neurostimulator” contains a battery for power and a microchip to regulate the stimulation. The treating physician uses a hand-held wand and small computer to communicate with the pulse generator through the skin. In doing, so the treating physician can determine how much electrical stimulation is delivered in which manner through the stimulating electrodes. These pulse generators are very similar to those implanted under the skin (also usually just below the collarbone) for patients with cardiac pacemakers. The treating physician even uses a similar device to communicate with the pulse generator through the skin. The biggest difference is that in DBS the electrodes are in the brain instead of in the heart (as is the case with cardiac pacemakers).

Given the encouraging response rates following capsulotomy for highly treatment refractory OCD, investigators decided to test DBS in this area of the brain and first implanted electrodes in the anterior capsule in patients with treatment-resistant OCD in the late 1990s (Nuttin et al. 1999). The early results were promising, as three of these first four patients experienced benefit. Since then, larger scale trials have been conducted and the target site has moved slightly to an overlapping part of the brain called the ventral capsule/ventral striatum (VC/VS). A recent report by Greenberg (2008) describes the current world wide experience with DBS for OCD. For the 26 patients with treatment-resistant OCD described in the Greenberg manuscript, 61.5% were considered responders to DBS. This response rate is comparable to or slightly higher than the response rates for the other neurosurgical options described above (cingulotomy and capsulotomy), but comparisons must be tentative since the numbers of patients treated with DBS are still relatively small. In addition, it must be noted that these data are open label (meaning both the patient and the doctor knew they were receiving treatment). A controlled trial (were both the patient and the doctor don’t know if the patient is receiving treatment has just completed; results are currently being analyzed. Lastly, while DBS does require opening the skull it does not require destroying any brain tissue. Lastly, DBS allows for a wider range of stimulation parameters (different amounts of electrical charge) than an ablative procedure.

Based on these open label results the FDA in 2009 approved DBS for highly treatment-resistant OCD under a Humanitarian Device Exemption (HDE). The HDE approval assumes that a relatively small number of patients will receive the treatment. Because DBS for treatment-resistant OCD is a very specialized procedure, it is recommended that treatment be rendered at institutions that have experience with this intervention. Appropriate patient selection is vitally important. Typically, patients eligible for DBS will have had minimal or no response to all currently available medication and behavioral treatments for OCD. It is also critically important that a neurosurgeon with expertise in “Stereotactic and Functional Neurosurgery” perform the procedure. Of course, treatment begins after electrode placement. Determination of optimal stimulation parameters and longitudinal treatment are crucial. It is crucial that a psychiatrist with expertise in DBS be directly involved in a patient’s care over the months and years following surgery. At this point, it appears that DBS needs to continue indefinitely for continued benefit. One of the most interesting clinical observations after lesion procedures (capsulotomy or cingulotomy) or DBS, is that behavior therapy may become effective for a patient who was unable to improve with such treatment before surgery (Greenberg et al. 2006).

While the field of neurosurgery for treatment-resistant OCD has advanced considerably in recent years, further research is needed to both optimize DBS treatment and to better understand how DBS works (which areas of the brain are affected and how). While these are exciting times for OCD treatment there is still much to be learned.

 

References

  1. Deckersbach T., Dougherty DD, Rauch SL, “Functional neuroimaging of mood and anxiety disorders,” J. Neuroimaging, 2006; 16:1-10.
  2. Sheth SA, Neal J, Tangherlini F, Mian MK, Gentil A, Cosgrove GR, Eskandar EN, Dougherty DD, “Limbic system surgery for treatment-refractory obsessive-compulsive disorder: a prospective long-term follow-up of 64 patients,” Journal of Neurosurgery, 2013;118(3):491-7.
  3. Greenberg BD, Price LH, Rauch SL, Jenike M, Malone D, Friehs G, Noren G, Rasmussen SA, “Neurosurgery for Intractable Obsessive-Compulsive Disorder and Depression Critical Issues,” Neurosurgery Clinics of North America, 2003; 14(2) 199-212.
  4. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, Salloway SP, Okun MS, Goodman WK, Rasmussen SA, “Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder,” Neuropsychopharmacology, 2006; 31 2384–93.
  5. Greenberg BD, Gabriels LA, Malone DA, Jr, Rezai AR, Friehs GM, Okun MS, Shapira NA, Foote KD, Cosyns PR, Kubu CS, Malloy PF, Salloway SP, Giftakis JE, Rise MT, Machado AG, Baker KB, Stypulkowski PH, Goodman WK, Rasmussen SA, Nuttin BJ, “Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder worldwide experience,” Mol Psychiatry, 2008 May 20 [Epub ahead of print]
  6. Lopes AC, Greenberg BD, Canteras MM, Batistuzzo MC, Hoexter MQ, Gentil AF, Pereira CA, Joaquim MA, de Mathis ME, D’Alcante CC, Taub A, de Castro DG, Tokeshi L, Sampaio LA, Leite CC, Shavitt RG, Diniz JB, Busatto G, Noren G, Rasmussen SA, Miguel EC, “Gamma ventral capsulotomy for obsessive-compulsive disorder: a randomized clinical trial,” JAMA Psychiatry, 2014; 71(9):1066-76..
  7. Nuttin B, Cosyns P, Demeulemeester H, Gybels J, Meyerson B, “Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder,” Lancet, 1999 Oct 30;354(9189):1526.
  8. Rück C, MD, Karlsson A, Steele JD, Edman G, Meyerson BA, Ericson K, Nyman H, Asberg M, Svanborg P, “Capsulotomy for obsessive-compulsive disorder. Long-term follow-up of 25 patients,” Arch Gen Psychiatry, 2008; 65(8):914-922.