Posted by freedom2001 on November 3, 2002, at 8:33:04
New Methods of Brain Stimulation
(ECT, MST, TMS, VNS and DBS) Are Improving
OCD Research and Therapy
Mark S. George, M.D.
Dr. George is Professor of Psychiatry, Radiology and Neurology in the Departments of Psychiatry, Radiology and Neurology, Medical University of South Carolina (MUSC), and the Ralph H. Johnson Veterans Hospital, Charleston, SC. He directs the MUSC Functional Neuroimaging Research Division and the Brain Stimulation Laboratory.
Correspondence and reprint requests to Radiology Department, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425 (Dr George).
Dr. George’s telephone: (843) 792 7750; fax: (843) 792-9503; e-mail: georgem@musc.edu
From CNS Spectrums: The International Journal of Neuropsychiatric Medicine as an invited review article in an issue on The Proceedings of the 4th International Obsessive Compulsive Disorders Conference. From the plenary talk.
Potential Conflicts: Dr. George has research grants and collaborations with Neotonus, Dantec (Medtronic), and Cyberonics (VNS).
AbstractOver the past decade, new functional neuroimaging tools have enabled researchers to identify the specific brain regions involved in obsessive compulsive disorder (OCD). More recently, researchers have perfected several new techniques for stimulating the brain. With some exceptions, these new techniques are regionally specific and less invasive than older methods. As a class, these ‘somatic interventions’ build on prior neuroanatomic information about OCD. These new tools promise to revolutionize neuropsychiatry research and therapy over the next 10-20 years. This article reviews the past and current status of these brain stimulation methodologies. Because the brain circuits in OCD are becoming better understood, along with the pharmacology within those circuits, these brain stimulation techniques hold particular promise in helping to understand and perhaps treat OCD.
Educational Objectives
1) Know that OCD affects specific brain regions such as the orbitofrontal cortex, the basal ganglia and the anterior limbic system.
2) Be familiar with emerging brain stimulation methods in psychiatry that try and modify activity in these circuits in order to research or treat OCD.
IntroductionRecently, new functional neuroimaging techniques (PET, SPECT, fMRI) have allowed researchers to photograph the crucial brain regions involved in producing the symptoms of Obsessive-Compulsive Disorder (OCD). Several studies now consistently implicate the orbitofrontal cortex, cingulate gyrus, and basal ganglia as brain regions that operate abnormally in patients with OCD (for review see (1)).
In other work, clinicians interested in treating OCD have found that specific neurotransmitter systems are dysfunctional within these circuits (serotonin and dopamine, especially when tics are present). The pharmacological treatment advances of the last decade are important and not trivial. However, from a pure delivery standpoint, taking an oral medication is one of the least efficient ways to change activity in specific brain regions. Consider that the medication must be absorbed by the gut, and travel throughout the body, where a small portion of it is transported across the blood-brain barrier. There, within the brain the medication travels throughout, with only some of it reaching its intended target. Thus, there are potentials for side-effects in the periphery and in non-diseased parts of the brain through unintended exposure. The more discrete the placement of a drug or intervention, the more effective and fewer the side-effects. For example, some effective antidepressants, like thyrotropin releasing hormone (TRH), are marginally effective when given peripherally, but are profoundly effective when injected intrathecally directly into the CNS (2).
Moreover, currently available medications have not worked for all persons with OCD, and even in those where medications help, patients are rarely able to achieve remission, and tolerance is common. Viewed in this light, more aggressive somatic interventions for OCD seem plausible and even likely.
While the ability to image these abnormal circuits is an important first step, it is incomplete and limited from standpoint of therapy. One of the challenges squarely before the field of OCD is how to build on this imaging literature to create new treatments. That is, how does one translate this knowledge of anatomy and pharmacology into new treatments? Fortunately, there are several new methods available for stimulating the brain, either externally or directly, that now offer promise in this regard. These new somatic interventions, combined with functional imaging, promise to transform understanding and treatment of OCD in the next century.
Table - Somatic Interventions - Current and Evolving
The First Brain Stimulation Method -
Electroconvulsive therapy (ECT)
Electroconvulsive therapy (ECT) was first considered as a potential therapeutic treatment early in the last century following the likely faulty observation that patients with schizophrenia had few seizures, or that epileptic patients were not psychotic (subsequent work has shown that both of these statements are likely false). Thus generalized seizures were produced in patients with psychosis, some of whom improved (likely those with psychotic depression). Years of ECT use then allowed the clinical winnowing of applications to its current use profile of mood disorders, and occasional catatonia or Parkinson’s Disease (for reviews of the history of ECT see (3,4)). In fact the history of ECT can be seen as an initial broad application of a powerful brain intervention to many conditions, with clinical use narrowing both the clinical applications where it is effective, and the ways of application that affect efficacy (e.g. dose titration). Thus, 30 years of ECT use occurred before it was determined that prefrontal application of the electrodes, and not parietal, was necessary for therapeutic effect, regardless of whether a generalized seizure occurred (5). However, things will likely change rapidly within the next few years. Nobler and colleagues have found that those patients who go on to respond to ECT have a greater reduction in prefrontal blood flow immediately following ECT. There thus appears to be anatomic specificity to where the ECT stimulus is most needed and is most effective for the treatment of depression. Unfortunately, the skull acts as a large resistor when electrical current is applied to the scalp, so the bulk of the energy of an ECT pulse does not go directly into brain, and the electrical energy cannot be focused.
Perhaps due to the diffuse nature of the application of the current and the inability to focus the induced seizure, ECT has not proven effective for the treatment of primary OCD, although it is effective for comorbid depression symptoms.
A new form of convulsive therapy -
Magnetic Stimulation Therapy (MST) -
Recently Lisanby and Sackeim succeeded in using powerful alternating magnetic fields to induce a seizure in a primate (6). Unlike electricity, magnetic fields pass unimpeded through skull and soft tissue and can thus be applied in a much more focused fashion. This development opens up the possibility of inducing ECT-like seizures with a magnetic field, likely reducing greatly the cognitive side effects which are probably due to unnecessary passage of electrical current in ancillary brain regions. Thus, in this century, ECT may be further refined with a better ability to direct the origin of the seizure and spare other brain regions.
Although MST has yet to be performed in humans, if it is successful it might theoretically prove better than ECT for the treatment of OCD. MST, as compared to conventional ECT, is more focused in terms of the point of origin of the seizure (although the secondary general convulsion involves the entire brain). Unfortunately, MST, like ECT, would still require general anesthesia because of the induced seizure. More importantly, it remains to be demonstrated that a generalized convulsion, rather than constant stimulation or ablation, is important for the treatment of OCD. Although both convulsive (ECT) and subconvulsive stimulation (TMS, VNS, DBS) appear to have powerful antidepressant effects, it is unclear at present whether OCD, due to the nature of its pathology, requires constant, rather than episodic treatments.
Transcranial Magnetic Stimulation (TMS)
A different method for non-invasively modifying regional brain activity uses a powerful hand-held magnet to create a time-varying magnetic field (7,8). When held on the scalp, this strong magnetic field creates electrical currents in superficial cortex - a form of ‘electrodeless’ electrical stimulation. Transcranial magnetic stimulation (TMS) is thus able to depolarize cortical neurons and cause downstream changes in connected brain regions. (For recent reviews see (8,9)).
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Recently there has been enthusiasm about whether TMS can modify mood in health or disease. Initial studies in healthy, non-depressed adults found that left prefrontal TMS results in slight increases in subjective sadness whereas right prefrontal rTMS causes increased happiness (10-12). These initial studies need replication with larger samples before full acceptance, yet they raise the possibility that TMS can affect circuits that modulate mood.
There are now five randomized controlled studies of daily prefrontal TMS over two weeks as an antidepressant, with all but one showing that TMS has therapeutic effects greater than sham. Work in the next few years will begin to test the clinical utility of TMS as an antidepressant, and the role that many variables play in producing the antidepressant effect. Clinical trials will be refined and guided by findings combining TMS with imaging (13) and using TMS in animal models. The real potential of TMS will likely come when critical studies are performed to determine if TMS at a given region or circuit might be able to effect long-term changes in the circuit. If this were to be the case, then TMS at specific regions, intensities and frequencies might serve as a new treatment option for a host of conditions.
TMS to test circuits in OCD - As a first foray of using TMS in OCD, Greenberg and colleagues administered single sessions of high-frequency stimulation to the left and right dorsolateral prefrontal cortex and to a parieto-occipital control site, in a randomized design (14). The prefrontal locations were defined as the site 5cm anterior and 2cm inferior to the hand area of primary motor cortex on each side. Twelve OCD patients were studied; they had on average moderately severe symptoms (a mean baseline Yale-Brown Obsessive-Compulsive Scale score of about 20), even though eight of them were treated with antiobsessional serotonin-reuptake inhibiting medications. Each site was stimulated, 2 days apart, with 20 Hz trains of 2 seconds each, once per minute for 20 minutes (800 pulses total per session) with an eight-shaped focal coil attached to a Cadwell High Speed Magnetic Stimulator. rTMS intensity was 80% of abductor pollicis brevis twitch threshold. Right lateral prefrontal rTMS was followed by a significant reduction in compulsive urges, lasting at least eight hours, in this group of OCD patients who were mainly moderately affected but included two severely ill individuals. This effect was not seen after left prefrontal or parieto-occipital stimulation. These OCD patients, who were not clinically depressed at baseline as a group, also reported significant mood elevation for 30 minutes after right prefrontal stimulation.
This study suggests that a single rTMS session might reduce compulsive urges by changing neuronal activity well beyond the period of acute stimulation. However, the study had a number of limitations including the possibility of placebo effects, the relatively crude anatomical localization, and, importantly, the lack of independent measures of cortical or subcortical function. In work that builds in this same area, Menchon and colleagues from Spain presented an abstract at this meeting using daily TMS in 20 OCD patients in a parallel double-blind trial. They found an improvement over time in compulsions (specifically checking) in the group with active TMS, with no effect on compulsions.
OCD has many phenomenological and epidemiological overlaps with Tourette Syndrome (TS) or tics. Karp, Wassermann, Porter and Hallett (1997) were the first group to use TMS as a challenge tool to investigate tic circuits in 6 patients with motor tics. Each patient in Karp et al.’s study received 800 total stimuli per site in 30-s trains of 1 Hz TMS, with 15-s rest between trains. The figure-8 stimulus paddle was positioned on the scalp over the primary motor cortex (M1) (both contralateral and ipsilateral to the most active tic), the vertex, occipital lobe, and held above the scalp over the M1 site (sham). There was a 44% decrease in tic activity when TMS was delivered over the contralateral motor cortex (19% decrease over the ipsilateral motor cortex; 2% decrease over occipital and during sham). There was also a 37% decrease during vertex stimulation, which the investigators attribute to the effects of TMS on the supplementary motor area (SMA). No CBF or other measures were reported to determine the effects of TMS on neural activity, but the obtained differential ipsilateral-contralateral effect likely relates to the neural source of tic activity. Karp et al. speculated that TMS action on M1 might inhibit the action of the basal ganglia, which has also been implicated in TS and OCD. The known connectivity between basal ganglia and SMA might be an additional reason why vertex stimulation resulted in reduced tic activity during TMS.
TMS to Test Electrophysiological Evaluations of Cortical Inhibition in OCD: Recently, Ziemann, Paulus and Rothenberger (1998) (15) used paired pulse TMS to test the theory that TS patients display deficient inhibitory control through the cortical-striatal-thalamic-cortical motor loop. With paired pulse TMS, one delivers a normal TMS pulse preceded by a brief pre-pulse. This pre-pulse, depending on its intensity and timing relative to the later pulse, can either abolish of augment the normal motor response elicited by TMS. Paired pulse TMS is thus thought to be a tool for investigating local inhibition and excitation paths within motor cortex (see (16)). This group used paired pulse TMS to measure levels of motor cortex excitability using TMS delivered to the hand area of left motor cortex and documenting the right abductor digiti minimi muscle response via surface EMG. Twenty TS patients and 21 controls, all right handed adults, were investigated for the effect of a single pulse of stimulation delivered to the left motor cortex. Motor threshold and peripheral motor excitability were normal in the TS subjects, but their cortical silent period and intracortical inhibition were reduced relative to the controls.
Greenberg and colleagues used a similar technique of paired pulse TMS and asked whether deficient intracortical inhibition also exists in Obsessive-Compulsive Disorder (OCD) (17). They studied 12 adult patients with OCD and 11 healthy volunteers and found that OCD patients, like those with GTS, had markedly decreased intracortical inhibition on paired-pulse TMS. In contrast to the findings in GTS patients, the duration of the cortical silent period (CSP) was not different between OCD patients and healthy individuals. Interestingly, their healthy control group was rigorously screened for the lack of psychopathology and, as a group, had much greater intracortical inhibition than did the controls from the Ziemman study, who were drawn from members of an academic neurology department and their relatives, and who might have subclinical symptoms of TS or OCD. In further work this group has studied a new cohort of 16 adults with OCD and 11 healthy volunteers (18). Again, OCD subjects had less intracortical inhibition than volunteers, as measured by paired pulse TMS. However, if the OCD subjects were divided into those with or without a history of motor tics, those with ‘tic-related’ OCD showed the most profound deficit in intracortical inhibition. Additionally, OCD subjects had lower resting and active motor thresholds than volunteers (Greenberg, personal communication).
Most recently the Gottingen group partially replicated their earlier finding in 21 children with GTS compared to 25 healthy controls (19). At the highest intensity of stimulation (140% MT) the GTS children had a shortened cortical silent period (CSP). There was no difference between the two groups on excitability as measured by the I/O curves. Many of the GTS children were taking medications.
Taken as a whole, these initial studies are consistent with an impaired inhibitory system in TS patients, and perhaps in OCD. Further studies are warranted in this promising area.
Newer Therapies - Vagus Nerve Stimulation
Another new somatic intervention involves stimulating the vagus nerve with electrical current (for review see (20,21)). In 1992 Zabara first demonstrated the anticonvulsant action of vagus nerve stimulation (VNS) on experimental seizures in dogs (22). Although the vagus is an autonomic nerve, he hypothesized that VNS could prevent or control the motor and autonomic components of epilepsy. This hypothesis built on previous research identifying extensive projections of the vagus nerve via its connection in the nucleus tractus solitarius to many areas of the brain. Thus, VNS could reach areas of brain epileptic activity. Now vagus nerve stimulation (VNS) is FDA approved for the treatment of epilepsy and about 7000 people worldwide have these generators implanted. Most epilepsy patients using VNS have failed many medication trials and have considered using VNS prior to brain surgery. In these clinical studies, the efferent peripheral effects of VNS have been minimal without significant GI or cardiac side effects (23,24).
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Within the last century, many anticonvulsants have been found to have mood stabilizing effects (carbamazepine (25,26), valproic acid (27,28), lamotrogine (29)). In the VNS clinical trials, many clinicians noted that their epilepsy patients had improved mood. This and other unpublished data led to a multisite open pilot study of VNS in patients with treatment resistant mood disorders (21,30). The results were generally positive in this difficult to treat group. VNS effects on comorbid anxiety symptoms were as significant as the antidepressant effects.
It is unclear whether VNS might have anti-obsessional effects in either its current form or in modifications in the future. If VNS actions were limited to locus ceruleus and norepinephrine effects, then current thinking would predict only a minimal effect of VNS on OCD symptoms. Yet, sleep studies and animal CSF studies have shown that VNS has effects on serotonin systems and thus a trial of VNS in OCD appears warranted.
Newer Therapies - Deep Brain Stimulation
The most anatomically discrete, and also the most invasive, method of stimulating deep brain structures is called deep brain stimulation (DBS). In this technique, a thin electrode is inserted directly into the brain and then different currents are applied at varying depth levels until the proper effects are found. This technique was used by some researchers in the US (31-33) as well as extensively by Russians. High frequency (>80Hz) electrical stimulation of the subthalamic nucleus has recently been shown to be effective in treating Parkinson’s Disease (34) and is now an FDA approved treatment. It has the clear advantage over brain surgery (pallidotomy) of being reversible. Direct comparisons of DBS with conventional brain surgery for PD show that DBS is more effective and has fewer side effects. Mood effects of DBS have been reported. For example, in one Parkinson’s patient who had never suffered from depression in her life, during the testing of stimulation, she noted the acute onset of tearfulness, sadness and despair, which immediately remitted when the surgeons moved the stimulator out away from the substantia nigra, directly below the subthalamic nucleus ( (35) and P. Damier, personal communication).
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Parkinson’s Disease leads the neuropsychiatric field in terms of understanding the pathological circuitry and it is thus natural that deep brain stimulation be used first in PD. However, as the neuroanatomy of OCD becomes better understood, DBS may be used in OCD as well. For example, recently Nuttin and colleagues from Europe reported an open case series of DBS in OCD. The researchers implanted DBS electrodes at the internal capsule bilaterally, and used high frequency stimulation to effectively ‘ablate’ information flowing through this region. Three of the 4 patients showed improvement after several weeks of therapy (36). Further studies are warranted.
Ablative Surgery
Cingulotomies and orbito-frontal leukotomies have been an effective treatment option for treatment resistant OCD for several decades now (37,38). Surgery in this manner is irreversible, and sham studies to establish efficacy are difficult to perform. The explosion of other less invasive techniques described above are likely to replace traditional surgery for OCD. Thus the new somatic interventions may obviate the need for surgery much as DBS is challenging pallidotomy for the treatment of Parkinson’s Disease.
Conclusions
Lagging behind the pharmacological expertise of modern psychiatry, knowledge of the regional neuroanatomic deficits of OCD is rapidly catching up. This knowledge is serving as the background for the development of several new somatic interventions that will likely change the way clinicians think about and treat OCD in the next century. One can envision a day when an OCD patient may have a resting and activated brain scan for diagnosis. There would then be a host of anatomically discrete options available for correcting the dysfunctional circuits both to treat the immediate disease state, and also to strengthen the circuitry so that relapse might be prevented.
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