Brain Stimulation Techniques in Psychiatry

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1 Newer Developments Brain Stimulation Techniques in Psychiatry Anju Gupta, Shri Niwash Jangir Psychiatrist, Senior Resident, Department of Psychiatry, Dr. Ram Manohar Lohia PGIMER Hospital ABSTRACT Some chronic patients remain resistant in spite of using well-advanced pharmacological and non pharmacological treatments. Some of the severe cases may benefit from treatment with neurosurgical interventions. Besides pharmacological, behavioral, and neurosurgical approaches, different brain stimulation methods-tran cranial magnetic stimulation, deep brain stimulation, and electro convulsive therapy-have been investigated in treatment-resistant patients with Depression and OCD. The work done in these areas till now, is quite limited in terms of sample size and study design, given the difficulty in conducting standard blinded trials for these procedures. This article is written to know the efficacy and tolerability of these procedures Key words - rtms, DBS and Stimulation. Introduction The mainstay of treatment of psychiatric disorders is pharmacological. However, a significant number of patients do not respond, in spite of using well advanced pharmacological and non pharmacological (psychological) interventions. ECT has been a good option for many of these patients. However, it is not acceptable to many patients due to associated stigma with it. Recently, new therapeutic tools have developed which are found to be effective in resistant cases of various psychiatric disorders specially depression and OCD. Most recently, vagus nerve stimulation therapy has obtained US Food and Drug Administration (FDA) approval for treatment-resistant depression. Other strategies, such as transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), and deep brain stimulation (DBS), are currently being researched for the treatment of resistant OCD and depression. Transcranial magnetic stimulation (rtms) Transcranial magnetic stimulation (TMS) a newer therapeutic tool in psychiatry. It is a non- invasive technique. It modifies the activity of specific brain areas without causing much serious side-effects. It is believed that rtms may have a place in the treatment of some mental illnesses especially in resistant depression. How it Works It works on the principle that when a current is passed through a coil, a magnetic field is generated perpendicular to the current flow. By rapidly changing the magnetic field near a conducting medium such as brain, a current is generated which is parallel but opposite in direction to the current in the coil. The magnetic energy is typically delivered as a series of pulses. When delivered in this manner the technique is called as repetitive TMS (rtms). Low frequency rtms (< 1 Hz) is said to reduce the excitability of cortical neurons. 1 Whereas high frequency rtms (>1 Hz) causes cortical excitability and increased cortical blood flow. 2,3 Its therapeutic effect is believed to occur by causing changes in cortical metabolism and blood flow. 4-6 or by influencing MHPG and brain-derived neurotrophic factors Delhi Psychiatry Journal 2008; 11:(2) Delhi Psychiatric Society 183

2 DELHI PSYCHIATRY JOURNAL Vol. 11 No.2 OCTOBER 2008 (BDNF). 7 The procedure can be carried out in outpatients setting and requires only fifteen minutes for the whole procedure. A magnetic coil is placed over the left or right prefrontal cortex. Both the patient and the operator use earplugs to protect against the loud clicking noise produced by the rapid change in magnetic pulse. The patient usually feels a tingling sensation over the scalp and occasionally a twitch over the muscles of the face or hand. Role in Mental disorder Various studies found rtms to be effective therapy in treatment resistant depression. Padberg et al treated 37 medication free depressed patients with rtms and found significant improvement after ten days of treatment. 8 Fitzgerald et al in 2003 reported treatment with left side high fr equency rtms as ideal in depression, taking into account safety, tolerability and efficacy. 9 Sequentially applying both highfrequency left-side rtms and low-frequency rtms to the right prefrontal cortex, is found to have substantial treatment efficacy in patients with treatment-resistant major depression. 10 Some studies support the efficacy of rtms in hastening the response to antidepressant drugs in patients with major depressive disorder. Like, High-frequency rtms over the left cortex is shown to be an add-on strategy of clinical significance in combination with escitalopram in patients with major depression resistant to non-tricyclic antidepressants. 11 Repetitive TMS at 5 Hz accelerated the onset of action and augmented the response to amitriptyline. 12 In contrast, Rossini et al found the effect of rtms to be unaffected by the specific concomitantly administered drug. 13 Though above studies support the efficacy of rtms in improving depr ession and hastening the r esponse of antidepressant drugs, there are various double blind, sham controlled studies finding rtms as ineffective antidepressant therapy. The effect of rtms has also been studied in depressed Bipolar Affective Disorder subjects and found to be safe with minimal risk of inducing mania. However, it failed to find statistically significant antidepressant effects with rtms greater than sham. 18 Low frequency rtms administered over the left dorso-lateral prefrontal cortex was not found to be effective in facilitating the effect of serotonin reuptake inhibitors in OCD patients. 19 Further studies are needed to fully investigate the potential role, if any, of TMS in Bipolar Affective Disorder depression and OCD. rtms verses ECT Janicak et al and Grunhaus et al reported similar rates of recovery with ECT and rtms in severely depressed patients in a randomized control trial. 20, 21 However, rtms appears to be safer than ECT. rtms causes no neuro cognitive deficits which often occur with ECT. No worsening of performance on any of the cognitive domains over the baseline-post rtms period was seen when tests were conducted on attention, working memory, executive function, objective memory and motor speed. 22 On the contrary, evidence of modest but statistically significant improvement in performance was seen in wor king memory, executive function, objective memory and fine motor speed domains over the rtms treatment period. Unlike ECT, It does not require anaesthesia and is a painless treatment. In ECT, the dose of current required is large due to the high resistance of the skull. The magnetic field used in TMS has the strength of two Tesla, the same intensity as in magnetic resonance imaging. The TMS magnetic field declines logarithmically with distance from the coil. This limits the area of depolarization to a depth of about two cm below the brain s surface. TMS appears to be more beneficial than ECT for severely depressed patients in terms of harmful effects and stigma associated with it. Application of TMS in research TMS allows researchers to test whether a given brain area is causally involved in producing a given behavior, even in normal healthy individuals. Traditionally, this was possible only in people with brain injury. The advantage with TMS is that, as soon as the current is turned off, the brain returns to normal. TMS is used currently clinically to measure activity and function of specific brain circuits in humans. The most widely-accepted use is in 184 Delhi Psychiatry Journal 2008; 11:(2) Delhi Psychiatric Society

3 measuring the connection between the primary motor cortex and a muscle (i.e. MEP amplitude, MEP latency, central motor conduction time). This is most useful in stroke, spinal cord injury, multiple sclerosis and motor neuron disease. Plasticity of the human brain can also be measured now with repetitive TMS (and variants of the technique, e.g. theta-burst stimulation, paired associative stimulation) and it has been suggested that this abnormality of plasticity is the primary abnormality in a number of conditions. Reported side-effects of rtms As it induces an electrical current in the human brain, TMS and rtms can produce a seizure. The risk of seizure is very low with TMS except in patients with epilepsy and patients on medications. Discomfort or pain from the stimulation of the scalp and associated nerves and muscles on the lying skin. Hearing problems from the loud click made by the rapid change in magnetic pulse. Deep brain stimulation Deep-brain stimulation (DBS) was first developed in France in 1987 and initially evolved as ablative, or lesioning, surgeries in which heat probes were used to burn and permanently damage small regions of the brain. Recently, a newer technique is developed for DBS, instead of destroying tissue, slender electrodes is implanted that pump steady pulses of electricity like a pacemaker for the brain. Deep brain stimulation is already FDA approved to treat Parkinson s disease, severe muscle spasms (dystonia), epilepsy and some forms of chronic pain. Research is ongoing to explore its use in epilepsy and cluster headaches. Research has just begun with patients diagnosed with severe, and resistant obsessive-compulsive disorder. The procedure hasn t been FDA approved for depression and OCD and is in only the early stages of research. Mechanism The exact neurobiological mechanism mediating clinical changes with DBS are unknown for any disorder. Electrophysiologic studies suggest both excitatory and inhibitory effects, depending on whether gray or white matter is targeted. Current evidence suggests that high-frequency DBS activates white matter, although the nature of the fibers being stimulated is critical to understanding whether the net effects are excitatory or inhibitory. Other data demonstrate that DBS results in inhibition of neurons. Change in network oscillations is an alternative possible mechanism. Some studies have observed chronic changes in regional blood flow using positron emission tomography (PET). Although this approach can identify which regions are affected by the chronic stimulation, it does not further elucidate the mechanisms mediating such changes. The converging evidence implicates a combination of local and remote chemical and electrophysiological effects. Procedure The deep brain stimulation system is a surgical procedure in which, a burr hole about 14 mm in diameter is drilled in the skull under local anesthesia and the electrode is inserted. The electrode is placed in the particular area of brain according to the type of symptoms to be addressed. The placement of the electrode is important, targeting different areas of the brain will have different results.the lead (or electrode ), is placed in the ventrointermedial nucleus of the thalamus for essential tremor and globus pallidus or subthalamic nucleus for dystonia and Parkinson s disease. This electrode is connected to the implanted pulse generator (IPG) by the extension (an insulated wire). IPG also called brain pacemaker, is usually placed under the skin below the clavicle.the IPG is a battery-powered neurostimulator which sends electrical pulses to the brain to interfere with neural activity at the target site. The installation of the IPG and electrode occurs under general anesthesia. The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa. The IPG can be calibrated by a physician, nurse or trained technician to optimize symptom suppression and control side effects. 23 Role in Depression and OCD Work in treatment-resistant Major Depressive Disorder (MDD) also suggests therapeutic potential in preliminary studies, generating cautious optimism for this indication. The hypothetically interesting site for DBS in Delhi Psychiatry Journal 2008; 11:(2) Delhi Psychiatric Society 185

4 DELHI PSYCHIATRY JOURNAL Vol. 11 No.2 OCTOBER 2008 depression is suggested to be nucleus accumbens as that region appears to be associated with pleasure and reward mechanisms. 24 Mayberg HS et al in 2005 conducted DBS on six patients suffering from clinical depression. Their symptoms were resistant to medication, psychotherapy and electroconvulsive therapy. The electrode was implanted at subgenual cingulate region (SCR or Brodmann area 25); this site seems to correlate with symptoms of sadness and depression. When the current was switched on, four of the patients reported feeling a black cloud lifting, and became more alert and interested in their environments. The changes reversed when the current was switched off. These patients were followed for next six months. The effects of continuous SCR stimulation have produced sustained remission from depression in the four patients for six months. 25 H. Johansen Berg et al also targeted the similar area (subgenual cingulate white matter) and reported dramatic remission of symptoms in some previously treatment-resistant depression patients 26.Similar result was also seen by Schlaepfer TE, The work had done till now, in obsessivecompulsive disorder (OCD), have shown consistently positive results across multiple smallscale studies. Various authors targeted various sites for patients with intractable and resistant OCD. Greenberg BD et al conducted deep brain stimulation (DBS) of the anterior limb of the internal capsule in eight patients with severe resistant obsessive-compulsive disorder (OCD) and found it to be beneficial in four out of eight patients. 28 Nuttin et al targeted capsule immediately rostral to the anterior commissure extending into adjacent ventral capsule/ventral striatum (VC/VS) in 10 severe and treatment resistance OCD patients. Eight patients were followed for at least 36 months. Four of eight patients were significantly improved in OCD and anxiety and also showed improvement in functional level. Surgical adverse effects observed were an asymptomatic hemorrhage, a single seizure, and a superficial infection. Psychiatric adverse effects wer e transient hypomanic symptoms, and worsened depression and OCD when DBS was interrupted by stimulator battery depletion. 29 In another study, DBS of the Nucleus Accumbence region found to alleviate OCD symptoms by reducing activity in subsets of Orbito frontal cor tex neurons in urethaneanesthetized rats. 30 DBS of the subthalamic nucleus in three patients with Parkinson s disease and refractory OCD reported positive results. 31 Okun MS in 2006 used active and sham programming to observe response of deep brain stimulation (DBS) in anterior limb of the internal capsule and nucleus accumbens in five patients with chronic and severe treatment-refractory OCD. A comparison of active to sham trials showed that sham stimulation was not associated with significant side effects or responses from patients. Acute stimulation resulted in either improved or worsened mood responses in both the dorsal and ventral regions of the anterior limb of the internal capsule. 32 Side-Effects Common side effects and adverse health problems associated with deep brain stimulation include: bleeding in the brain, infection, delirium, unwanted mood changes, movement disorders, lightheadedness and insomnia. Reports in the literature describe the possibility of apathy, hallucinations, compulsive gambling, hypersexuality, cognitive dysfunction, and depression. However, these may be temporary and related to incorrect placement and calibration of the stimulator and so is potentially reversible. 33 According to one trial about 9% of patients had psychiatric events, which ranged in severity from a relapse in voyeurism to a suicide attempt. But most patients in this trial reported an improvement in their quality of life and physical functioning following DBS. 34 Appleby BS et al, 2007 conducted a metaanalysis and reviewed 808 articles. The reported side effects were device or procedure related (e.g., infection and lead fracture). The prevalence of depression was 2-4%, mania %, emotional changes %, and the prevalence of suicidal ideation/suicide attempt was %. The completed suicide rate was %. There was a high rate of suicide in patients treated with DBS, particularly with thalamic and GPi stimulation. Because of the high suicide rate, patients should be prescreened for suicide risk prior to DBS surgery. Additionally, patients should be monitored closely for suicidal behavior post-operatively Delhi Psychiatry Journal 2008; 11:(2) Delhi Psychiatric Society

5 Conclusion Role of rtms and DBS remains investigational in neuropsychiatry. However, experience to date, though limited, suggests that techniques may offer a degree of hope to patients with severe and treatment-resistant neuropsychiatric illness. However, available data about the use of these techniques in neuropsychiatric illnesses are quite limited in terms of sample size and study design, given the difficulty in conducting standard blinded trials for these procedures. In addition, none of the mentioned treatments have received Food and Drug Administration approval. Nevertheless, promising findings regarding efficacy, tolerability, and noninvasiveness and/or reversibility of these techniques have increased interest in investigating their use in treatment-resistant. Reference 1. Chen R, Classen J, Gerloff C, Celnik P, Wasserman EM. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 1997; 48: Tergau F, Tormos JM, Paulus W. Effects of repetitive transcranial magnetic stimulation on corticospinal and cortic-cortical excitability. Neurology 1997; 48: A Speer AM, Kimbarell TA, Wasserman EM. Opposite effects of high and low frequency rtms on regional brain activity in depressed patients. Biol Psychiatry 2000; 48 : Wassermann EM, Kimbrell TA. Local and distant changes in cerebral glucose metabolism during repetitive tr anscranial magnetic stimulation (rtms) (abstract). Neurology 1997; 48:A107-A Fox P, Ingham R, George MS, Mayberg H, Ingham J, Roby J, Martin C, Jerabek P. Imaging human intra-cerebral connectivity by PET during TMS. Neuroreport 1997; 8: Paus T, Jech R, Thompson CJ, Comeau R, Peters T, Evans AC. Dose-dependent reduction of cerebral blood flow during rapid-rate transcranial magnetic stimulation of the human sensorimotor cortex. J Neurophysiol 1998; 79: Yukimasa T, Yoshimura R, Tamagawa A, Uozumi T, Shinkai K, Ueda N, Tsuji S, Nakamura J. High-fr equency repetitive transcranial agnetic stimulation improves refractory depression by influencing catecholamine and brain-derived neurotrophic factors. Pharmacopsychiatry 2006 Mar; 39(2): Padberg F, Zwanzger P, Thoma H, Kathmann N, Haag C, Greenberg BD, Hampel H, Möller HJ. Repetitive transcranial magnetic stimulation (rtms) in pharmacotherapyrefractory major depression: comparative study of fast, slow and sham rtms. Psychiatry Res 1999 Nov 29; 88(3): Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry 2003 Oct; 60(10): Fitzgerald PB, Benitez J, de Castella A, Daskalakis ZJ, Brown TL, Kulkarni J. A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression. Am J Psychiatry 2006 Jan; 163(1): Bretlau LG, Lunde M, Lindberg L, Undén M, Dissing S, Bech P.Repetitive transcranial magnetic stimulation (rtms) in combination with escitalopram in patients with treatmentresistant major depression: a double-blind, randomised, sham-controlled trial. Pharmacopsychiatry 2008 Mar; 41(2): Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F, Rosa MO, Mansur C, Myczkowski ML, Moreno RA, Marcolin MA. Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study. Biol Psychiatry 2005 Jan 15; 57(2): Rossini D, Magri L, Lucca A, Giordani S, Smeraldi E, Zanardi R. Does rtms hasten the response to escitalopram, sertraline, or venlafaxine in patients with major depressive disorder? A double-blind, randomized, shamcontrolled trial. J Clin Psychiatry 2005 Dec; 66(12): Hausmann A, Kemmler G, Walpoth M, Mechtcheriakov S, Kramer-Reinstadler K, Lechner T, Walch T, Deisenhammer EA, Kofler Delhi Psychiatry Journal 2008; 11:(2) Delhi Psychiatric Society 187

6 DELHI PSYCHIATRY JOURNAL Vol. 11 No.2 OCTOBER 2008 M, Rupp CI, Hinterhuber H, Conca A. No benefit derived from repetitive transcranial magnetic stimulation in depression: a prospective, single centre, randomised, double blind, sham controlled add on trial. J Neurol Neurosurg Psychiatry 2004 Feb; 75(2): Shajahan PM, Glabus MF, Steele JD, Doris AB, Anderson K,Jenkins JA. Left dorso-lateral repetitive transcranial magnetic stimulation affects cortical excitability and functional connectivity, but does not impair cognition in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: Loo CK, Mitchell PB, Croker VM, Malhi GS, Wen W, Gandevia SC, Sachdev PS. Doubleblind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychol Med 2003 Jan; 33(1): Miniussi C, Bonato C, Bignotti S, Gazzoli A, Gennarelli M, Pasqualetti P, Tura GB, Ventriglia M, Rossini PM. Repetitive transcranial magnetic stimulation (rtms) at high and low frequency: an efficacious therapy for major drug-resistant depression? Clin Neurophysiol 2005 May; 116(5): Nahas Z, Kozel FA, Li X, Anderson B, George MS. Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 2003 Feb; 5(1): Prasko J, Pasková B, Záleský R, Novák T, Kopecek M, Bares M, Horácek J. The effect of repetitive transcranial magnetic stimulation (rtms) on symptoms in obsessive compulsive disorder. A randomized, double blind, sham controlled study. Neuro Endocrinol Lett 2006 Jun; 27(3): Janicak PG, Dowd SM, Martis B, Alam D, Beedle D. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biol Psychiatry 2002; 15;52 : Grunhaus L, Schreiber S, Dolberg OT, Polak D, Dannon PN. A randomized controlled comparison of electroconvulsive therapy and repetitive transcranial magnetic stimulation in severe and resistant nonpsychotic major depression. Biol Psychiatry 2003; 53: Martis B, Alam D, Dowd SM, Hill SK, Sharma RP, Rosen C. Neurocognitive effects of repetitive transcranial magnetic stimulation in severe major depression. Clin Neurophysiol 2003; 114: Volkmann J, Herzog J, Kopper F, Deuschl G. Introduction to the programming of deep brain stimulators. Mov Disord 2002; 17: S Schlaepfer TE, Lieb K. Deep brain stimulation for treatment of refractory depression. Lancet 2005; 366(9495): Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH (March 3, 2005). Deep brain stimulation for treatment-resistant depression. Neuron. 45(5): PMID H. Johansen-Berg, D. A. Gutman, T.E.J. Behrens, P.M. Matthews, M.F.S. Rushworth, E. Katz, A.M. Lozano, Mayberg. Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment resistant depression. Cerebral Cortex Advance Access published online on October 10, Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M, Lenartz D, Sturm V. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2007 Apr Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, Salloway SP, Okun MS, Goodman WK, Rasmussen SA. Threeyear outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 2006 Nov; 31(11): Nuttin B, Cosyns P, Demeulemeester H, Gybels J, Meyerson B. Electrical stimulation in anterior limbs of internal capsules In patients with obsessive-compulsive disorder (letter). Lancet 1999; 354: McCracken CB, Grace AA. High-frequency deep brain stimulation of the nucleus accumbens region suppresses neuronal activity and selectively modulates afferent drive in rat 188 Delhi Psychiatry Journal 2008; 11:(2) Delhi Psychiatric Society

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