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Arq. Neuro-Psiquiatr. vol.68 no.3 São Paulo June 2010
VIEW AND REVIEW
Estratégias de neuromodulação para o tratamento da depressão maior: desafios e recomendações de uma força-tarefa
André Russowsky BrunoniI; Chei Tung TengI; Claudio CorreaII; Marta ImamuraIII; Joaquim P. Brasil-NetoIV; Raphael BoechatIV; Moacyr RosaV; Paulo CaramelliVI; Roni CohenVII; Jose Alberto Del PortoVIII; Paulo Sergio BoggioIX; Felipe FregniX
IDepartment and Institute of Psychiatry, University of São Paulo, São Paulo SP, Brazil
IIPain Center and Functional Neurosurgery, Hospital 9 de Julho, São Paulo SP, Brazil
IIIDepartment of Physical Medicine and Rehabilitation, University of Paulo, São Paulo SP, Brazil
IVLaboratory of Neurosciences and Behavior, University of Brasília, Brasília DF, Brazil
VColumbia University, New York, NY
VIDepartment of Internal Medicine (Neurology Unit), Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte MG, Brazil
VIICentro Brasileiro de Estimulação Magnética, São Paulo SP, Brazil
VIIIDepartment of Psychiatry; Federal University of São Paulo, São Paulo SP, Brazil
IXUniversity Mackenzie, São Paulo SP, Brazil
XLaboratory of Neuromodulation, Spaulding Rehabilitation Hospital, Harvard Medical School and Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
The use of neuromodulation as a treatment for major depressive disorder (MDD) has recently attracted renewed interest due to development of other non-pharmacological therapies besides electroconvulsive therapy (ECT) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS).
METHOD: We convened a working group of researchers to discuss the updates and key challenges of neuromodulation use for the treatment of MDD.
RESULTS: The state-of-art of neuromodulation techniques was reviewed and discussed in four sections:  epidemiology and pathophysiology of MDD;  a comprehensive overview of the neuromodulation techniques;  using neuromodulation techniques in MDD associated with non-psychiatric conditions;  the main challenges of neuromodulation research and alternatives to overcome them.
DISCUSSION: ECT is the first-line treatment for severe depression. TMS and tDCS are strategies with a relative benign profile of side effects; however, while TMS effects are comparable to antidepressant drugs for treating MDD; further research is needed to establish the role of tDCS. DBS and VNS are invasive strategies with a possible role in treatment-resistant depression. In summary, MDD is a chronic and incapacitating condition with a high prevalence; therefore clinicians should consider all the treatment options including invasive and non-invasive neuromodulation approaches.
Key words: comprehensive review, major depressive disorder, ECT, TMS, clinical guidelines.
O uso de técnicas de neuromodulação para o tratamento do transtorno depressivo maior (TDM) tem despertado um renovado interesse nos últimos anos com o desenvolvimento de outras intervenções não-farmacólogicas além da eletroconvulsoterapia (ECT), como a estimulação magnética transcraniana (EMT), a estimulação transcraniana por corrente continua (ETCC), a estimulação cerebral profunda (DBS) e a estimulação de nervo vago (VNS).
MÉTODO: Nós organizamos um grupo de trabalho com vários pesquisadores para discutir os avanços recentes e os principais desafios para o uso da neuromodulação no tratamento do TDM.
RESULTADOS: O estado-da-arte da neuromodulação foi revisado e discutido em quatro seções:  epidemiologia e fisiopatologia do TDM;  uma revisão das técnicas de neuromodulação;  o uso das técnicas de neuromodulação na depressão que ocorre associada ou em virtude de condições não-psiquiátricas;  os principais desafios da pesquisa na neuromodulação e alternativas para superá-los.
DISCUSSÃO: ECT é o tratamento de primeira linha para depressão grave. EMT e ETCC são estratégias com um perfil benigno de efeitos adversos; contudo, enquanto os efeitos da EMT são comparáveis ao das drogas antidepressivas para o tratamento da TDM, a eficácia da ETCC ainda precisa ser estabelecida por mais pesquisas clínicas. DBS e VNS são intervenções invasivas com um papel possível para a depressão refratária. Em resumo, TDM é uma condição crônica, incapacitante e de alta prevalência; portanto na prática clínica todas as opções de tratamento possíveis, incluindo as farmacológicas e não-farmacológicas, devem ser consideradas.
Palavras-chave: artigo de revisão, transtorno depressivo maior, eletroconvulsoterapia, estimulação magnética transcraniana, recomendações para a prática clínica.
Although the field of neuromodulation with electromagnetic stimulation is not new - dating back to the beginning of the last century with electroconvulsive therapy (ECT), followed by the invasive techniques such as deep brain stimulation in the 1960s - it recently attracted further interest due to development of novel methods of noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Techniques of neuromodulation have been tested for a variety of neuropsychiatric conditions such as major depression, schizophrenia, stroke, chronic pain and Parkinson's disease. To date, the condition that was most studied on this field is major depressive disorder (MDD).
The development of alternative non-pharmacological methods of treatment for MDD is essential as this disorder has a high lifetime prevalence (between 8-16%)1,2 and is challenging to treat as many patients fail to achieve complete remission of symptoms or have moderate to severe adverse effects with antidepressants. Therefore, updated guidelines for diagnosing and treating depression are needed.
Specific guidelines from different countries, such as Canada3, the UK4; the US5 and Brazil6, have been published. In fact, novel treatments need to be regularly updated and incorporated to the therapeutic arsenal of the physician, such as neuromodulation therapies. We therefore convened a working group of established clinical researchers in major depression and experts in techniques of neuromodulation on August 18th, 2009 to discuss the updates and main challenges of neuromodulation use for the treatment of major depression. In this article we [I] summarize the state-of-art of neuromodulation therapies, focusing on pathophysiology, efficacy, safety and tolerability; [II] discuss opportunities of using such therapies in relatively unexplored contexts of major depression and; [III] critically discuss the main challenges and future directions of brain stimulation.
A task force meeting was set with active researchers in the fields of major depression and/or neurostimulation therapies at the Universidade Presbitariana Mackenzie, in São Paulo, Brazil, in August 18th, 2009. Participants from the working group were asked to previously submit material to the working group coordinator (FF). During the consensus meeting each participant presented his/her designated topics with input and discussion by all working group participants. The meeting lasted 3 hours and was video-recorded. After the initial meeting, the first author (ARB) added the suggestions to the initial drafts and prepared a preliminary manuscript that was initially edited by the last author (FF) and then reviewed, edited and rectified by each co-author.
The present paper is divided in four sections: the first one overviews the epidemiology and pathophysiology of major depression; the second discusses the mechanisms of action and the clinical evidence of using each neuromodulation technique; the third section considers using neuromodulation therapies in other clinical and neurological contexts in which MDD as a comorbidity is common; finally, in the fourth section we discuss current challenges of neuromodulation research and alternatives to overcome them. One key consideration here is that the rTMS section is the longest due to the large number of studies in this area as compared to other techniques except ECT - that was less explored due to the fact that there are excellent reviews in this area and is an already established treatment for MDD with specific guidelines.
Major depressive disorder
MDD is a common condition that is widely frequent in population: community-baseed surveys conducted in several countries using ICD-10 criteria showed a lifetime prevalence ranging from 6-12%, with an annual prevalence of 3-11%1,2,6,7. Current data show that MDD is an incapacitating condition: it is predicted that MDD will be the second cause of incapacitating disease in 20208. In addition, depression is a chronic, recurrent disorder, as nearly 80% of patients relapse after the treatment of an episode4. Finally, about one third of patients have treatment-resistant depression (TRD), which is defined as the failure to achieve adequate response of symptoms after two or more antidepressant treatment trials9,10. In fact, the high prevalence of TRD, associated with failure to antidepressant response, is an important concern when managing major depression.
In this context, the National Institute of Mental Health (NIMH) sponsored the Sequenced Treatment Alternatives to Relieve Depression trial. STAR*D confirmed that the cumulative response and remission rates after two failed antidepressant treatments are 73% and 47%, respectively11,12. After four failed treatments, response and remission rates decay to 19% and 13%11. STAR*D confirmed the need for developing novel therapeutic strategies when patients fail to respond to antidepressants.
In Brazil, Andrade and colleagues2 observed a lifetime prevalence and an annual incidence of depression of 16.8% and 7.1%, respectively, in a catchment area of two boroughs in São Paulo; while Almeida-Filho et al.13 observed an annual incidence of 12% in an urban sample of Bahia. In 2003, a larger survey conducted by the World Health Survey showed a 15% of 30-day prevalence of depression14 in Brazil. The prevalence of major depression in Brazil is likely to be similar to other countries2,15. Other studies showed, in Brazil, the prevalence of acute depressive disorder in pediatric patients, geriatric patients and in the postnatal period to be 8.7%, 22% and 20.7%, respectively16-18.
Finally, there is a high association between MDD and other psychiatric disorders, especially anxiety disorders, impulse control disorders and substance use/abuse disorders1, as well as with chronic medical illnesses - for instance, the prevalence of MDD in emergency departments in Latin America ranges from 23 to 35%19; while it has been detected on average in 26% in hospitalized patients20. These numbers confirm the need to develop novel therapeutic strategies for MDD in order to offer alternatives to patients who fail to antidepressants or those who have contraindication to these drugs.
There are several hypotheses to explain the pathophysiology of depression. It is important to review the mechanisms underlying MDD in order to understand the mechanisms of action of neuromodulation techniques.
One important and usually highly cited hypothesis of MDD is the "monoamine hypothesis". The development of antidepressant drugs in the 1960s and the following finding that such drugs had synaptic activity in circuits controlled by the neurotransmitters norepinephrine, dopamine and serotonin led to the "monoamine hypothesis" which suggests that MDD symptoms are related to low concentrations of monoamines in the synaptic cleft21. Although such view generally agrees with the pharmacological activity of antidepressant drugs (e.g. MAO inhibitors act by stopping monoamine metabolism in the pre-synaptic neuron; while serotonin selective reuptake inhibitors act by increasing serotonin concentration at the synaptic site), it is not sufficient to explain other observations - for example, the time lag of antidepressants for therapeutic action, and that symptoms of MDD do not directly relate with monoamine synaptic levels22. Other mechanisms need then to be entertained.
One interesting and increasingly discussed hypothesis is the neuroplastic hypothesis. Several animal and clinical studies showed that the Brain Derived Neurotrophic Factor (BDNF) serum levels are decreased in patients with major depression and normalized after antidepressant treatment23. BDNF expression is associated with neuronal survival and differentiation24; while lack of BDNF leads to neuronal apoptosis25. In addition, BDNF plays a key role in long-term potentiation (LTP) - a feature of neurons to facilitate the synaptic transmission in areas whose neurons are constantly demanded (on the other hand, low BDNF expression is related to Long-Term Depression (LTD) - i.e., the slowdown of neuronal activity with decreased cortical activity)26. The neurotrophin hypothesis complements the monoamine hypothesis as synaptic activity is enhanced when monoamine levels increase - and also suggests there is a "final common pathway" of different antidepressant treatment modalities that ultimately lead to BDNF levels increasing. If the neuroplastic hypothesis is relevant to MDD, then it can be hypothesized that patients with MDD have decreased plasticity that might be accentuated in some neural circuits; therefore obstructing the creation of new synapses in areas associated with positive emotional processing.
These two previous hypotheses have lead to another one: the neural system hypothesis. The advancement of neuroimaging techniques showed that specific brain areas, such as the amygdala and the hippocampus, have a lower volume in depressed patients when compared to controls27,28. In addition, functional studies suggest a high level of activity in the ventro-medial prefrontal cortex (vmPFC) and a low level of activity in the dorso-lateral prefrontal cortex (DLPFC). It seems that patients with major depression have lower excitability in the left motor cortex29, in the left hemisphere30 and a higher brain activity in the right cortex31. These findings suggest a "differential activity" of certain brain areas in patients with MDD, which can explain some symptoms of depression: for instance, psychomotor retardation and executive function impairment (related to the DLPFC), feelings of guilt and hopelessness (related to hippocampus and amygdala dysfunction), anhedonia (related to nucleus accumbens) and negative emotional judgment (related to left-right imbalance)32-34.
Another important theory lies in the influence of the hypothalamic-pituitary-adrenal (HPA) axis and its main end-product (cortisol) in cortical activity. Cortisol receptors are widely distributed in the brain, especially in the hippocampus, amygdala and hypothalamus35 - areas that are also impaired in MDD. In fact, there is convincing evidence from basic and clinical studies of overactivity of HPA axis among depressed subjects - e.g., high cortisol serum levels in depressed subjects36; and exaggerated cortisol increasing after the dexamethasone supression test37. Along these lines, recent evidence suggests a moderate role for steroid hormones in the antidepressant efficacy of TMS; i.e., cortisol and other hormones can impair cortical activity in the brain (especially in those areas with high levels of steroid receptors) thus leading to a more severe, "endogenous" depression38.
Taken together, the integrated view of these hypotheses supports the notion that MDD is a disorder associated with dysfunction in critical areas related to mood regulation. In fact, two major pathways can be determined here: the cognitive-executive pathway, in which a hypoactive DLPFC fails to regulate areas related to executive functioning; and the affective-somatic pathway, in which a hyperactive vmPFC modulates erratically areas related to negative affect and self-awareness39. The rationale in using different neurostimulation therapies is based on their mechanisms of inhibiting or enhancing activity in these pathways, as we discuss below.
The neurostimulation therapies
Electroconvulsive therapy (ECT)
ECT is the first and most studied brain stimulation therapy to date. In fact, Cerletti and Bini, in 1938, conducted the first descriptions of using electric stimuli to induce therapeutic seizures40. Although its mechanisms of action are still incompletely known, accumulated evidence points that its antidepressants effects are related to several mechanisms, such as restoring hemispheric balance41, increasing BDNF serum levels42, enhancing neurogenesis through a series of electrical shocks43 and, long-term up-regulation of serotonin activity and down-regulation of muscarinic activity44. Nevertheless, several guidelines support the role of ECT as a first-line treatment of severe major depressive disorder, especially in psychotic and/or suicidal patients, or those with catatonia or treatment-resistant depression3,5,6.
In recent years, several systematic reviews and meta-analyses of ECT efficacy have been published45-47. The UK ECT Review Group45 reviewed the efficacy of ECT vs. simulated (sham) ECT (6 trials, 256 patients), ECT vs. drug therapy (18 trials, 1144 subjects), bilateral vs. unilateral (28 trials, 1408 participants), and low vs. high dose ECT (7 trials, 342 patients). Compared to sham ECT, active ECT was significantly more effective, with a mean difference in endpoint Hamilton scores of 9.7 (95% CI 5.7- 13.5). The pooled analysis of ECT comparisons against amitriptyline, imipramine, phenelzine, or others favored ECT with a mean Hamilton difference of 5.2 (95% CI 1.4-8.9). Bilateral ECT was more effective than unilateral (mean Hamilton reduction of 3.6 points - 95% CI ranging between 2.2-5.2). Finally, treatment with high doses of ECT led to a greater reduction in depressive symptoms with a mean change of Hamilton scores of 4.1 (95% CI 2.4-5.9) when compared to placebo. This meta-analysis did not identify significant differences between brief pulse vs. sinewave ECT and ECT delivered two vs. three times a week. These results were confirmed by following meta-analyses46,47.
The negative cognitive effects of ECT were explored by Sackeim et al.48 who performed an observational, naturalistic study with 751 patients who underwent ECT for MDD. These patients went through a comprehensive neuropsychological battery at pre-ECT (baseline), after completing ECT (post-ECT) and at 6-month follow-up, which measured cognitive status, psychomotor function, attention, and several aspects of memory. They observed an important decrease in performance in almost all neuropsychological tests at post-ECT. At 6-month follow-up, patients treated with sine wave stimulation continued to have slower reaction times; while those treated with bilateral ECT had inferior performance on the global cognitive status, reaction time, Stroop effect and some memory tasks. Multi-linear regressions showed that bilateral ECT, sine wave ECT, older age, lower premorbid cognitive function, and female gender were associated with greater cognitive effects.
In summary, despite being a very effective treatment for MDD, ECT is also associated with important cognitive deficits, especially in subgroups of patients and in specific protocols.
Repetitive transcranial magnetic stimulation (rTMS)
Mechanisms of action
TMS uses the principle of electromagnetic induction to focus induced current in the brain49. When applied transiently, the effects last only a few minutes; however, when applied repetitively, rTMS (repetitive TMS) can modulate cortical excitability for several minutes beyond the train of stimulation50. There are two types of rTMS according to the frequency of stimulation:  low-frequency rTMS (<5 Hz) that is applied over the right DLPFC to induce a decrease in cortical excitability, and  high-frequency rTMS that is applied on the left DLPC to increase cortical excitability. Both approaches induce neuroplastic changes in the targeted areas - in fact, it has been suggested that high-frequency rTMS is associated with LTP and low-frequency rTMS with LTD51: Chen and colleagues52 used a protocol (0.1 Hz for 15 minutes) similar to one that induced LTD in cortical slice preparations to stimulate the motor cortex of volunteers, showing a decrease in the motor evoked potential that persisted for several minutes, in a LTD-like phenomenon; while a TMS/EEG study showed LTP-like changes in EEG activity after high-frequency (5Hz) rTMS53. However, there is an important variability associated with these effects and in fact subjects might respond differently to high and low-frequency rTMS according to other factors such as baseline cortical activity54.
Thus, it is hypothesized that high-frequency TMS acts by increasing activity in the left DLPFC area, thus ameliorating depression symptoms. Low-frequency rTMS, on the other hand, might act by modifying interhemispheric imbalance - i.e., as MDD might be associated with an imbalance in prefrontal cortex activity, decreasing the right DLPFC activity "releases" left DLPFC, which was being inhibited via transcallosal connections55.
Efficacy of rTMS in acute MDD
RTMS has been tested for several neurological and psychiatric conditions, but none has had the same number of studies and positive results than MDD: in fact, although the first meta-analyses published in 2003 and 2005 showed that rTMS studies were of low quality to date56,57, more recent meta-analyses published in 2007 and 2008 showed the trial design, as well as other parameters of stimulation, improved in five years, and that rTMS had the same efficacy of pharmacological drugs for MDD58,59, with also similar rates of response and remission rates for TRD (25% and 17%), respectively, which interestingly is similar to the STAR*D results of 19% and 13%11,60. Currently, rTMS has been approved for use in Brazil, Canada, Israel, and some European countries and also in the US. Here it should be underscored that rTMS was only approved in the US to treat patients who failed to respond to at least one antidepressant trial as a pivotal rTMS study performed in 2007 with 301 patients with various degrees of refractoriness showed positive results only after a post-hoc analysis61; however, a subsequent analysis of patients failing to at least one adequate trial found a robust positive result, with an effect size of 0.83 and a drug-placebo difference of 5 points62.
To date, most rTMS trials tested its use as a combination therapy, i.e., the combination of rTMS with a pharmacological treatment - usually an antidepressant that has failed however not tapered off63. A few studies tested the use of rTMS as an accelerating therapy, i.e., the use of rTMS to hasten an antidepressant response - in this type of trial, active or sham rTMS starts simultaneously with a pharmacological treatment - 3 of 4 studies showed that the active rTMS fastened drug response. The drugs tested were venlafaxine, escitalopram or sertraline64; amitriptyline65; escitalopram66; mirtazapine or venlafaxine67 - the last trial, however, showed a negative response.
Finally, Bares and colleagues68 compared low-frequency rTMS vs. venlafaxine ER in TRD patients in a double-blind, randomized design, finding that both therapies had similar response and remission rates (rTMS: 33% and 19%, venlafaxine ER: 39% and 23%, respectively) as well as drop-out rates. To date, this is the first double-blinded, randomized clinical trial that directly compared rTMS against a pharmacological treatment for MDD.
Efficacy of rTMS as a maintenance
treatment (relapse prevention)
Currently, there is limited data concerning using rTMS as a maintenance treatment for MDD. There are no randomized, controlled trials assessing rTMS maintenance therapy to prevent relapse as this type of trial would have some practical issues as it is not possible to randomize patients that received active treatment previously to sham treatment without compromising blinding. Therefore, the efficacy of rTMS as a maintenance treatment is better assessed through naturalistic studies. Along these lines, Fitzgerald et al.69 followed a sample of 19 patients previously treated with rTMS and observed a mean time of 10 months for relapsing, and also most of the patients were successfully treated with rTMS after relapse. Demirtas-Tatlidede et al.70 accompanied 16 medication-free patients with TRD who responded to rTMS until relapse, when they were treated again with rTMS. Importantly, these patients continued receiving rTMS weekly or two times a week. The authors observed a medication-free period ranging from 26-43 months and that approximately 65% of patients individually sustained a clinically significant response to retreatment with rTMS. Finally, Cohen and colleagues71 followed 204 patients who remitted with rTMS assessing the time to relapse; they observed that 75% of patients had relapsed after 6 months of treatment, and a long duration of rTMS effects was negatively associated with age and positively with the number of rTMS sessions during acute treatment.
Thus, although there is little evidence on using rTMS as a maintenance treatment for MDD, initial studies showed encouraging results - further studies should assess whether different protocols (e.g. weekly, bi-weekly, monthly rTMS applications) are better to sustain response without using antidepressant drugs. On the other hand, it is important to notice that patients who responded to a prior rTMS treatment are likely to respond again to rTMS whether they relapse.
Safety and tolerability
Loo and colleagues72 recently reviewed all published rTMS trials for side effects. They found that rTMS is a treatment virtually absent of serious side effects: in fact, only 16 patients presented seizures (the most severe side effect reported)- most of them having prior neurological disorders or using parameters outside of the recommended guidelines. In addition, they showed that rTMS did not induce cognitive impairments; in fact, some studies showed that active groups improved neuropsychological assessments. Regarding hearing loss, it has been shown that rTMS can transiently increase auditory threshold, thus wearing earplugs is recommended. Common side effects are headache that responds readily to oral analgesia and facial pain due to muscular twitches. Finally, regarding on treatment-emergent (i.e., during or after rTMS treatment) mania/hypomania, another meta-analysis showed that the risk rates are low and similar for active (0.84%) and sham (0.73%) groups73. However, 9 of 13 patients who presented treatment-emergent mania/hypomania were suffering from bipolar depression.
Parameters of stimulation
Several variables should be considered when delivering rTMS treatment, such as site of stimulation, frequency of trains, intensity of stimulus, frequency of sessions, and duration of treatment. Regarding left vs. right stimulation, the accumulated evidence favors the former as more studies were performed stimulating the left DLPFC74; and the evidence for low-frequency right DLPFC is mixed75-77. However, low-frequency rTMS seems to be better tolerated78 and might be an interesting approach in selected cases. Considering the frequency of trains, most low-frequency protocols use 1 Hz or less; while high-frequency stimulation ranges from 5 to 20 Hz79.80 with more recent studies favoring the 10Hz-frequency61,67,81,82. Along these lines, although the intensity of stimulus (indexed to the motor threshold - MT) can vary from 80-120% MT, there is a tendency of more recent studies in using intensities >100%, when compared to the first studies that used intensities <100% - perhaps due to safety concerns59.
rTMS is usually delivered daily in weekdays (i.e. 5 sessions per week) although other studies used different protocols such as three times a week or two times per day83. Finally, several studies have shown that a larger number of sessions is associated with a better response59,62 as well as a larger time period to relapse71. Nevertheless, this number can range from 10 to 30 sessions (i.e. 2 to 6 weeks, as sessions are not usually delivered in weekends).
Finally, one point that needs to be underscored is that parameters of stimulation have not been compared systematically and they reflect much more the personal decision of the group of researchers conducting the trial; therefore readers should consider this carefully when choosing the parameters of stimulation in clinical practice and research. Finally, individual parameters also play an important role - for instance, baseline cortical activity, medications being used by the patients. These factors can have an important interaction with the effects of rTMS.
rTMS in depressed patients with bipolar disorder
Although the clinical manifestations of bipolar depression and MDD might be quite similar, recent evidence shows that their clinical management is different, as bipolar depression is better managed with either mood stabilizers (lithium, anticonvulsants or some atypical antipsychotics) in monotherapy or a combination of mood stabilizers and antidepressant drugs (lithium/divalproex and selective serotonin reuptake inhibitors)84. Thus, one important question is whether rTMS for bipolar depression is as effective as for MDD. However, there are only a few studies on the topic: Nahas and colleagues79 enrolled 23 patients with bipolar depression; randomizing them to receive either high-frequency rTMS or placebo. They failed to show difference between groups. Subsequently, Dolberg and colleagues85 recruited 20 patients to receive active or sham intervention, finding mixed results - although a significant difference was observed at week-2, no difference between groups was found at the final endpoint (week-4). In 2004, Cohen et al.86 used low-frequency rTMS as an adjunctive therapy in refractory bipolar depression. In an open-label study, 22 patients received 15 sessions of rTMS - after 3 weeks, 16 showed response. Tamas and colleagues87 compared four patients on active rTMS and one on placebo, obtaining a difference between groups only at week-6. Finally, in 2009, Dell'Osso and colleagues88 performed an open-label study using low-frequency rTMS in 11 patients, showing significant reductions in all rating scales.
In conclusion, although many initial rTMS controlled trials enrolled a few depressed patients with bipolar disorder while studying major depressive disorder, the specific use of rTMS in this condition has been insufficiently explored. Thus, considering the prevalence and severity of bipolar disorder, further well-designed sham-controlled rTMS studies on this topic are needed.
A recent study addressed the cost-effectiveness of rTMS in major depression: using data from previous multi-center studies and of the STAR*D trial, the authors modeled the cost-effectiveness of rTMS considering different scenarios in which rTMS was combined to antidepressants after one, two or more than two drug trials failure, and comparing such association with different augmentation pharmacological strategies (antidepressant with mood stabilizers or atypical antipsychotics). Considering a base cost of US$300 per treatment session for rTMS, the authors demonstrated that rTMS is cost-effective considering QALY criteria and might be more cost-effective than certain psychopharmacological combinations (especially those combining newer antidepressants with mood stabilizers and atypical antipsychotics)89.
Transcranial direct current stimulation
Transcranial direct current stimulation (tDCS) is a renewed method of non-invasive brain modulation. It is based on a transcranial application of weak direct currents (usually up to 2mA) via scalp electrodes in a non-invasive, simple and painless manner. Other advantages are the low cost of the device and the possibility of a reliable sham control. The effects are polarity-dependent: while anodal stimulation induces an enhancement on cortical excitability, cathodal stimulation decreases it. These effects are explained as related to shifting on membrane resting potential (depolarization or hyperpolarization, respectively). Finally, the effects are also related to the stimulated area90.
The investigation on the effects of tDCS as an antidepressant therapy dates from the 1960s. However, the lack of methodological rigor on some parameters such as the target area, current strength, electrode size, reference electrode position, number of sessions, and duration of each session might explain some contradictory findings between the studies. For instance, Arfai et al.91 did not find significant effects on depression in a randomized, double-blinded, sham controlled study where tDCS (i=0.25mA) was applied on frontal cortex with the reference on the thigh; on the other hand, Redfearn et al.92, in an open pilot study, found a reduction of depressive symptoms after tDCS (i=0.02 to 0.25 mA) over frontal areas with the reference electrode on the knee (for extended reviews see93 and94).
This scenario began to change in the last decade with new tDCS protocols in which the parameters of stimulation were well-defined. Also, the emergence of other techniques of brain stimulation, such as TMS, allowed a better understanding of the effects of tDCS effects on cortical excitability. In the recent years, some randomized, double-blinded, sham controlled clinical trials on the effects of tDCS on depression have been conducted.
Table 4 summarizes some parameters and the observed effects of each recent protocol. As it can be observed, all recent studies targeted anodal tDCS over the left DLPFC. The only difference regarding electrodes montage is the position of cathodal electrode. Ferrucci et al.95 applied this electrode over the right DLPFC whereas the other protocols used it over the contralateral supraorbital area. Besides this difference, the protocols differ with respect to number of sessions, time and intensity of stimulation current. In addition, patients of each protocol had different degrees of depression severity. Still, tDCS had antidepressant effects for patients with mild to moderate and for those with severe symptoms. In addition, it appears that the effects of repeated sessions of tDCS can prolong its therapeutic effects after the end of treatment.
A critical point to consider is the concomitant use of antidepressants - there is a difference between the studies in this respect and this may explain differences in relation to the effect size observed in each study. For instance, Nitsche et al.96 found that citalopram increased and prolonged the facilitatory effects of anodal tDCS showing that further studies should be done investigating the association of antidepressant pharmacotherapy with tDCS.
Finally, all studies showed only mild adverse effects and those, in general, were no different from those observed in the control group.
Deep brain stimulation
Although DBS was first developed in the 1950s and was initially used for treatment of chronic pain, it has been used for MDD only recently97. When using DBS, electrodes connected to implantable pulse generators (IPG) are implanted in specific brain areas98-100. For individuals suffering from depression, electrodes may be implanted into the following regions of the brain: subthalamic nucleus, internal globus pallidus, ventral internal capsule, ventral striatum, or the subgenual cingulate101-104.
DBS is the most invasive therapy option for treatment-resistant depression. It was observed in preliminary studies that in these patients the subgenual region of the cingulate region (Broadmann area 25) is overactive-providing a rationale for implantation of deep brain stimulation devices with the aim of reducing this increased activity as stimulation in DBS has the goal to interrupt local activity.
Mayberg et al investigated the use of DBS in 6 patients with treatment-resistant depression; specifically, such patients had failed in four different medication strategies and 5 of 6 also to ECT104. After 6 months of treatment, four responded to DBS and three had full or almost full remission of depressive symptoms; while two patients had to have their DBS devices removed due to persistent infections104. This group recently published a follow-up study of these same 6 patients in which they underwent neuropsychological testing at baseline (before surgery), 3, 6, and 12-months post-surgery105. Cognitive function was evaluated and they found that DBS caused minimal to no neuropsychological adverse effects105. One interesting aspect of this study is that parameters of stimulation needed to be adjusted individually in order to provide beneficial results104.
Because the data is still scarce with this condition, several questions then need to be addressed, such as: whether DBS might be the long-term solution to patients who respond to noninvasive brain stimulation or whether it will be possible to develop portable techniques of noninvasive brain stimulation. Another important question is how to localize the optimal site of stimulation - and whether neuroimaging is enough to localize such area as it may vary across patients.
Vagus nerve stimulation (VNS)
VNS was developed relatively recently in the 1990s106-108. It works by having an electrode attached from a pacemaker implanted on the left side of the chest to the left vagus nerve in the neck106,107. Although its mechanism of action remains elusive, it has been suggested that impulses from the vagus nerve are transmitted to the following regions: locus ceruleus, raphe nuclei, and nucleus tractus soliarious, which then project to other regions of the brain, ultimately affecting the limbic system109-113. Therefore, this may be a less focal method of electrical stimulation. In fact, the lack of focality of this technique might be associated with the limited clinical results and might favor the use of other techniques such as rTMS or DBS. In addition, it might also be used in combination with another focal method of brain stimulation. Finally, VNS is used intermittently with trains of stimulation 24 hours per day108,114.
VNS is approved in the US for treating chronic or refractory depression in patients not showing an adequate response after four antidepressant treatments. In a recent systematic review, Daban and colleagues115 could only identify one randomized clinical study, the others being open-label studies and series of cases, i.e., studies of lower methodological quality. In fact, the only blinded trial was inconclusive. Therefore, VNS may be seen as a new promising form of treatment; however the present evidence supporting its use is still limited.
Other neurostimulation approaches
Given the remarkable effects of transcranial stimulation with low-intensity constant direct current (tDCS), the use of low-intensity non-constant current (alternate current or intermittent direct current) may also prove to be an attractive option. Non-constant current can be delivered with pulses of unidirectional current in rectangular waves (intensity rapidly increased to a certain amplitude, held at the peak without change, and then interrupted by zero current) or sinusoidal waves (intensity and direction constantly varies as a function of time). In fact, non-constant current can be delivered with unidirectional current (in which pulses share the same polarity) or alternating current (in which the pulses of current alternate with opposite amplitude). Indeed, pulsed stimulation is the method used for most of brain stimulation therapies previously discussed. Of the variety of methods of low-intensity non-constant current that have been explored, here we will discuss the few specific methods of AC stimulation that have been shown to have clinical effects: cranial electrotherapy stimulation (CES), transcutaneous electrical stimulation (TCES) with Limoge's current, transcranial electrical stimulation (TES) with Lebedev's current, and transcranial alternating current stimulation (tACS).
Cranial electrotherapy stimulation (CES) is a form of AC stimulation that involves the application of current to infra- or supra-auricular structures (e.g. the ear lobes, mastoid processes, zygomatic arches, or maxillo-occipital junction). CES is a non-standardized and often indistinct method of delivering cranial AC stimulation; indeed many studies cite the method of stimulation simply as "cranial electrotherapy stimulation" without identifying the specific site or other parameters of stimulation (e.g. duration, current density, intensity, electrode size) calling into question existing reviews of this method. Additionally, CES has been suggested to be effective in the treatment of anxiety, depression, stress, and insomnia116, and the following parameters of stimulation have been reported: frequency (0.5 Hz to 167 kHz), intensity (100 uA to 4 mA), duration of stimulation (5 min to up to 6 consecutive days). Of note, although alternating current is applied to the head in these circumstances, the current may or may not be delivered directly to the underlying brain structures and thus the term "transcranial" may not apply; we therefore select the term "cranial" AC stimulation to include applications of low-intensity AC in this context. Indeed, CES might more accurately be considered a form of peripheral nerve stimulation.
Exploring brain stimulation for treating
MDD in different contexts
The presence of a chronic clinical diseases increases the life-long prevalence of mood disorders from 8.9% to 12.9% and the recent prevalence (last 6 months) from 5.8% to 9.4% - in fact, more severe illnesses are associated with higher rates of depressive symptoms (Table1), a condition referred as "mood disorder due to a general medical condition"117.
Fibromyalgia - a somatic disease characterized by chronic widespread pain, allodynia in specific points, joint stiffness and fatigue - is highly associated with depression118. There are a few studies using neurostimulation techniques for treating this overlapping depression-pain condition: Carretero et al.119 reported an improvement in pain and depression after active low-frequency rTMS, but such improvement was not statistically different than sham rTMS. Passard et al.120 randomized 30 patients to receive either active or sham rTMS; they were able to demonstrate a significant improvement in pain, without any positive effect on depression or anxiety. Another brain stimulation technique that has been tested for this condition was tDCS, Fregni et al.121 reported a decreased efficacy of this technique for the treatment of depressive symptoms when patients with fibromyalgia were compared to those with major depression, suggesting differences in the mechanisms of depression underlying these diseases. In addition, brain stimulation in these studies was aimed at decreasing pain and not depression symptoms; therefore it is unclear whether brain stimulation would have a positive clinical effect on depression in fibromyalgia.
Finally another issue that needs to be considered is that, in some cases, depression in some clinical conditions might be associated with changes in neural circuits that also are responsible for sustaining the clinical manifestation of disease. For instance, hypothyroidism is an example of such situation. It is well known that hypothyroidism is linked to behavioral disturbances, cognitive deficits and psychiatric illnesses122. Rizzo et al.123 studied cortical excitability to transcranial magnetic stimulation (TMS) in 10 patients with hypothyroidism, comparing them to 10 healthy volunteers. They found a few abnormalities in cortical excitability in the patients. After hormone replacement therapy with thyroid hormone over a period of 3 to 6 months, it was seen that cortical excitability parameters were back to normal. Because rTMS has been shown to induce hormonal changes, it needs to be investigated whether rTMS for depression in this condition would induce hormonal changes that might not be necessarily beneficial.
For the clinician, the cause-effect relationship between medical illness and depression is often not clear: it is not known whether depressive symptoms are a risk factor favoring the appearance of a medical ailment, or just a consequence of the latter (in fact both conditions are possible). Neurostimulation techniques will act upon specific brain areas known to be associated with the pathophysiology of depression, such as the prefrontal cortex, without acting upon areas that may be linked to the pathophysiology of the concurrent clinical illness. In this case, there is a question of whether neurostimulation would induce an improvement of depression symptoms given that mechanisms underlying MDD might be different than those of secondary depression.
Depression is a common finding in patients with neurological diseases: in fact, its prevalence is up to 50%, especially in chronic conditions such as dementia, epilepsy, migraine, multiple sclerosis, Parkinson's disease and stroke. In these conditions, depressive symptoms are associated with increased burden, poor quality of life, impaired therapeutic response and, hence, to poor prognosis124-129. On the other hand, depressive symptoms associated with neurological diseases usually display a good response to pharmacological interventions, with the same drugs used in MDD, although patients may experience more adverse events depending on the nature of their neurological diagnosis130. Thus, new treatment approaches are still necessary in order to provide better care to this subset of patients. We discuss here the use of some of the techniques of brain stimulation for treatment of depression in neurological diseases.
RTMS has been shown to be effective and safe in treating depression in patients with stroke. A controlled study compared sham and active rTMS on the left prefrontal cortex in patients with refractory post-stroke depression found that a series of ten sessions of active high frequency rTMS was associated with a significant reduction of depressive symptoms, with mild adverse events131.
In MDD associated with Parkinson's disease, several open and controlled studies have been published, showing consistent improvement of depressive symptoms as well as motor symptoms after prefrontal stimulation132-136. Two randomized controlled trials showed that the efficacy of rTMS is similar to fluoxetine in patients with this condition, but with less adverse events133,135.
Potential use of rTMS in epileptic patients with depression has also been suggested137, although specific studies in this indication are still lacking, but are particularly important due to safety issues as in this case low-frequency rTMS that has a significant anti-epileptic effect can be used and therefore a combined treatment of epilepsy and depression might be possible. VNS, another related technique, has shown to be effective not only in reducing seizure frequency but also in improving depressive symptoms in epileptic patients138.
Similar opportunities might be applicable to tDCS. Because no trial with this technique has been conducted yet, this is another interesting area of future research especially due to the portability characteristics of tDCS.
MDD in the rehabilitation setting
Depressive disorders are common in the rehabilitation settings. In fact, approximately 30 to 40% of stroke survivors will experience clinically significant depression during the first year after stroke139 and at some point following a stroke140,141. Over half of these patients will develop major or minor depression in the acute care rehabilitation settings142. In fact, depression is considered to be the strongest predictor of quality of life in this patient population143,144 and is associated with reduced rehabilitation treatment efficacy, poor functional recovery, poor social outcomes, increased cognitive impairment and increased mortality145.
Antidepressants, psychostimulants, counseling and psychotherapy are the most commonly prescribed interventions. However, despite showing some beneficial effects146,147, pharmacological management of depression may be contraindicated due to their cardiovascular and anticholinergic adverse effects131. Some trials have demonstrated that selective serotonin reuptake inhibitors are no more effective than placebo in treating depression among stroke survivors148. ECT may be an alternative for refractory patients; however, caution should be exercised in stroke patients due to the risk of provoking or aggravating cognitive dysfunction.
Therefore, other safe treatment modalities are needed to effectively address this common clinical condition. RTMS may be an alternative treatment for stroke patients either with refractory depression or who are unable to use antidepressant medications. A recent study showed that ten to 15 sessions of rTMS applied on the left DLPFC at a frequency of 10Hz, and an intensity of 110% MT was associated with significant reduction of depressive symptoms by 30% and a remission rate of 10% as compared to placebo intervention. Mild and few adverse effects such as headache were reported131-149. Another advantage of the use of rTMS is the improvement in executive functions by rTMS150,151. Preliminary data suggests that better responses to magnetic stimulation are obtained in patients with higher frontal volumes. For patients with severe frontal atrophy, higher intensity and prolonged stimulation might be required. Finally, because of the positive effects of rTMS for motor recovery and reduction of spasticity, it is conceivable that patients might receive combined treatment for these conditions, being the parameters adjusted for either mood or motor symptoms, for instance.
MDD and cognition
In addition to the symptoms usually observed in MDD, there is also change in some cognitive domains such as verbal memory, working memory, and selective attention152. Moreover, according to depression severity and cognitive performance, some patients present a pattern of the so-called pseudodementia153,154. Also, pharmacological strategies in the management of MDD can result in negative effects on cognition - tricyclic antidepressants, for instance, have been associated with cognitive impairments in attention, memory and executive function155. These adverse effects indicate the need for new therapeutic strategies with fewer adverse cognitive effects and, in this scenario, neuromodulation techniques are beginning to be investigated.
Vanderhasselt et al.156 assessed attentional control and depressive symptoms before and after rTMS over the left DLPFC. The authors observed improvement in attentional control in responders at the first rTMS session. Fitzgerald et al.157 tested the antidepressant effects of high-frequency rTMS over the left DLPFC and low-frequency over the right DLPFC. Besides the improvement of depressive symptoms in both strategies of stimulation, an improvement in immediate verbal memory and verbal fluency was also observed.
Regarding tDCS, a preliminary study by Fregni et al.158 showed that 5 days of anodal stimulation over the left DLPFC did not result in deleterious effects on functions such as memory, attention, language and executive functions. Instead, an improvement in working memory was found.
Cognitive/affective information processing is also altered in MDD. Bermpohl et al.159 investigated the effect of rTMS over the DLPFC of depressed patients in a go/no-go task with emotional content, finding that low-frequency rTMS resulted in improved performance in the task when applied to the right DLPFC. Likewise, Boggio et al.160 investigated the effects of anodal tDCS applied over the left DLPFC of MDD patients during the same go/no-go task, observing an improvement in performance during the tDCS session in comparison to sham or occipital stimulation.
Such observations can also be extended to depression-related neurological diseases, such as observed in Parkinson's disease. Fregni et al.161 found that high-frequency rTMS applied over the left DLPFC daily for ten days resulted in reduction of depressive symptoms. Boggio et al.162 found that this improvement extended to cognitive functions such as verbal fluency and executive functions. The same authors found that anodal tDCS (2 mA) applied over the left DLPFC of patients with Parkinson's disease resulted in an improvement in working memory task163.
With respect to DBS, some studies have shown that this technique is also associated with gains in memory164,165. Parameters such as amplitude and pulse width are associated with improvement in cognitive performance166. On the other hand, some authors have shown negative effects related to functions such as verbal fluency and attention165,167.
In addition, two key factors for assessing the cognitive effects of neuromodulation techniques used as tools for the treatment of depression are: 1) neural network underlying this disorder integrates structures such as prefrontal cortex, amygdala, cingulate and thalamus, and 2) cascading effects resulting from stimulation (top-down and bottom-up regulation according to the type of neuromodulation)168.
Thus, it was observed that from the point of view of cognitive functions, neuromodulation techniques appear as promising tools associated with low cognitive adverse effects and might also improve cognitive functions. New studies are mandatory to disentangle the effects of each brain stimulation technique for each specific cognitive domain.
Clinical research in brain stimulation
To date, brain stimulation trials have produced mixed results. Despite the difficulties inherent in the technical aspects of the intervention (i.e., site of stimulation, amount of energy delivered, validation in animal studies, lack of deep understanding in its mechanisms of action), the methodology of brain stimulation trials also faces important issues that might preclude the achievement of significant results.
In a recent review, Brunoni and Fregni83 reviewed 31 brain stimulation trials published from 2002-2008 and identified some issues that could be arranged in three main topics:
 Issues inherent to small, exploratory studies - The small sample size of almost all trials could have produced false negative results (due to underpower) as well as false positive results (due to multiple hypothesis testing). Such caveats could be minimized in future trials by determining a priorithe main hypothesis of the study and, consequently, by estimating the sample size necessary to prove the main hypothesis. For instance, the authors identified that only 20% of studies estimating sample size had negative results, while 33% not estimating had negative results. Moreover, the authors observed the statistics of the studies are very sophisticated, which is a natural alternative to overcome the lack of power. On the other hand, the use of complex models can violate statistical assumptions and thus produce false findings.
 Issues inherent to MDD trials - Here the problems identified were of construct validity and reliability of the instruments used to diagnose and quantify depression. An important topic is the definition of treatment resistant depression - 30% provided no definition, 55% defined it as when at least one antidepressant trial in adequate dose and duration failed, and 15% required at least two failed trials. In addition, the issue of using categorical (remission) or continuous (score change) outcomes is under debate, both approaches have their pros and cons: categorical outcomes produces more clinically meaningful results but generally demands larger sample sizes; on the other hand, continuous outcomes produces more statistically meaningful results but demands smaller sample sizes.
 Issues specific no NIBS trials - A specific issue is blinding. In rTMS trials, the most common methods of blinding do not guarantee double-blinding, an issue that might bias results in two ways: by increasing response in the active group (by increased staff care and positive enforcement) and decreasing it in control group. Also, some authors raised the issue that angled coil - a method used in sham groups of numerous rTMS trials - might still induce cortical changes thus not being a "real" sham. On the other hand, a recent meta-analysis of sham responses showed angled vs. sham coils produce similar effect sizes169. In tDCS trails, blinding vulnerability is a minor problem as; accordingly to the set of parameters specified, both groups will suffer no adverse events, thus providing a more reliable blinding. Another issue is the target sample of brain stimulation studies - focusing on treatment resistant depression per se favors smaller effect sizes.
Therefore, future directions in brain stimulation research could be:  to use alternative designs - after regulatory approval of some brain stimulation techniques, the use of naturalistic, follow-up studies can help to find predictors associated with better outcomes, such as age, gender, degree of refractoriness, use of concomitant medications and comorbid psychiatric diagnostics as well as endophenotypes - for instance, neuroimaging, genetic polymorphisms, BDNF baseline serum levels and neuropsychological and psychophysiological testing;  to recruit alternative populations - since rTMS is a safe, non-invasive technique with at least comparable effect sizes with antidepressant drugs, its use could be extended in patients not able or not ideally indicated to use medications, for example, breast-feeding women, elderly patients with polypharmacy, patients taking drugs with unfavorable pharmakocinetics (e.g. chemotherapy, immunosuppressant drugs) or even those not wanting to take pills;  to set a collaborative network - since most clinical studies in brain stimulation are developed in university setting with limited, public funding, the design of large trials is often unfeasible. An alternative would be to set an international collaborative network in which data are gathered from different centers - such approach could be used to do multicenter trials as well as to build a databank to perform exploratory, post-hoc analyses and identify predictors of treatment- if blood samples are collected and stored, biochemical endophenotypes could also be researched. Finally, such network would be especially important for safety issues as to identify the prevalence of side effects associated with brain stimulation;  to design head-to-head comparisons against pharmacological treatments - although the effect size of rTMS in recent meta-analyses is comparable to the effect size of antidepressant trials, it is not straightforward to claim such approaches have similar efficacy, as pharmacological and non-pharmacological trials are methodologically different. Therefore, direct head-to-head comparisons are necessary to evaluate this issue - along these lines, a recent trial compared low-frequency right-sided rTMS (20 sessions)+placebo vs. venlafaxine ER (mean dose 256mg/day)+sham rTMS for TRD and found both interventions to have similar efficacy in ameliorating depressive symptoms68;  to research optimal parameters of stimulation: the optimal number of applications (10 vs. 20 sessions), train frequency (low frequency, 5 Hz, 10 Hz, 20 Hz high-frequency), session parameters (low-frequency right-sided vs. high-frequency left-sided, concomitant application, potency in relation to motor threshold) and site of application (direct measurement for targeting DLPFC vs. neuronavegation). On the other hand, the amount of variables to combine would require several clinical trials - an alternative would be to use adaptive designs, starting with several combinations and dropping weaker treatments during the trial.
In the current review, we convened a group of experts in the field to review and synthesize the available evidence for using neuromodulation interventions in major depressive disorder - a chronic, relapsing disorder that is associated with significant prevalence and morbidity that also accompanies many non-psychiatric conditions. In agreement with the literature, we found that ECT and rTMS are viable alternatives for treating the acute depressive episode: ECT has been widely recognized for the treatment of refractory and/or severe depression and is somewhat limited in other conditions due to adverse cognitive events and difficulty of using it in clinical practice (e.g. anesthesia, an accompanying person is needed, post-ECT amnesia); while rTMS might have a broader range of use as currently established by some guidelines (e.g., the FDA), however more studies are needed as the optimal parameters have not been established. DBS, VNS and tDCS are possible strategies for major depressive disorder that demand more controlled trials in order to assess their role in the realm of depressive disorders - however, while the invasiveness of DBS and VNS will naturally limit their use to the most severe spectrum of depressive disorder, the "user-friendly" approach of tDCS (i.e., low cost, absence of side effects, portable device, can be built to be operated by the patient or relative) is a promising alternative to treat a wide range of depressed patients, if such technique is proven to be effective in the near future. Along these lines, novel, non-invasive brain stimulation modalities (such as rTMS and tDCS) could be better explored when managing depressive symptoms in non-psychiatric disorders, as hazardous pharmacokinetic interactions are possible when antidepressants are associated with other drugs, and also because these novel treatments might also have positive "cognitive side effects". In summary, while to date only ECT has robust efficacy for major depressive disorder, the continuous research of novel neuromodulation techniques is showing promising results and therefore the attending physician should consider them as alternatives when treating a depressed patient.
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Laboratory of Neuromodulation Spaulding Rehabilitation Hospital & Center for Non-invasive Brain Stimulation Beth Israel Deaconess Medical Center Harvard Medical School
330 Brookline Ave - KS 452
Boston, MA 02215, USA
Received 24 September 2009
Accepted 29 September 2009