Thursday, October 12th, 2017 at 6:49 pm
Originally Published at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492646/
Major depression is often difficult to diagnose accurately. Even when the diagnosis is properly made, standard treatment approaches (eg, psychotherapy, medications, or their combination) are often inadequate to control acute symptoms or maintain initial benefit. Additional obstacles involve safety and tolerability problems, which frequently preclude an adequate course of treatment. This leaves an important gap in our ability to properly manage major depression in a substantial proportion of patients, leaving them vulnerable to ensuing complications (eg, employment-related disability, increased risk of suicide, comorbid medical disorders, and substance abuse). Thus, there is a need for more effective and better tolerated approaches. Transcranial magnetic stimulation is a neuromodulation technique increasingly used to partly fill this therapeutic void. In the context of treating depression, we critically review the development of transcranial magnetic stimulation, focusing on the results of controlled and pragmatic trials for depression, which consider its efficacy, safety, and tolerability.
Depression is a major contributor to disability worldwide. Further, its management can be a challenge for even experienced clinicians. Problems begin with recognizing and properly diagnosing patients who suffer from this disorder. For example, it is estimated that about half of the individuals in the US who experience a major depressive episode annually are not diagnosed correctly. Of those who are identified and receive treatment (eg, psychotherapy, medications, or various combinations of these therapies), only about half benefit.1 This is because many patients frequently do not receive an adequate trial of therapy to achieve sufficient symptom reduction, initially benefit but then lose this effect over time, or do not tolerate standard approaches. This problem is highlighted by the results of the National Institute of Mental Health (NIMH)-sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.2 This large (n=4,040), seminaturalistic clinical trial found that after up to four aggressive treatment strategies, about one-third of patients still had not achieved remission. In summary, there is a critical need to improve the identification of depression in clinical practice and to develop alternate therapies to better manage this disorder.
In terms of alternative treatment approaches, one option is therapeutic neuromodulation, which involves the use of various devices to alter electrical activity in the central nervous system.3 This approach is based on the premise that the brain is an electrochemical organ and therefore can be modulated by electrical as well as pharmacological means. While the therapeutic application of neuromodulation has primarily focused on depression, other neuropsychiatric disorders (eg, bipolar disorder, schizophrenia, pain disorders) may also benefit from this strategy.4,5
In the context of depression, various neuromodulation devices appear to impact areas of the brain (eg, mesocortical limbic mood circuit) implicated in its pathophysiology. The prototypic example is electroconvulsive therapy (ECT) which has been available for 75 years. Its use, however, is limited by several disadvantages, including the lack of access in many areas, adverse cognitive effects, substantial relapse rates after a successful acute treatment course, and a negative public image.6 Further, it is usually reserved for the most severely ill patients encountered in clinical practice. Thus, there are a substantial proportion of depressed patients who are inadequately responsive to first- and second-line treatment approaches and are not ideal candidates for ECT or refuse to consider it as an option. Partly in response to this dilemma, a number of neuromodulation approaches are in development. Two such options presently cleared by the US Food and Drug Administration (FDA) for the treatment of depression are vagus nerve stimulation (VNS) and transcranial magnetic stimulation (TMS). Although available since 2005, to date VNS is not widely utilized. This is in part because of the need for a surgical procedure to implant the device and the need for prolonged exposure over months to achieve the optimal results.7 Furthermore, in the US, most insurance companies do not reimburse for this process, and eligible patients usually need to pay out of pocket, with the cost typically exceeding $25,000. In contrast, TMS, which has been clinically available since 2008, is a noninvasive procedure with over 35 randomized, sham-controlled trials supporting its benefit for the treatment of an acute major depressive episode.8 Of note, TMS produces very few adverse effects and is usually better tolerated than medications or other therapeutic neuromodulation approaches.9 In addition, relative to VNS and ECT, the cost of an acute treatment course in the US is lower (typically in the $10–$12,000 range); and unlike VNS, insurance companies are increasingly providing coverage.10
This review considers the developmental history of TMS as a treatment strategy, its basic principles, purported mechanism(s) of action, and the results of clinical trials for acute and maintenance management of major depression.
Galvani first performed electrical stimulation of muscles and nerve fibers in the late 18th century.11Subsequently, Michael Faraday discovered the principles of electromagnetic induction in 1831, giving rise to the possibility of using magnetic fields in lieu of electrical currents to stimulate nervous tissue.12 There were, however, few attempts in the 19th century to study their effect on the brain, largely due to technological limitations that prevented the reliable generation of powerful and rapidly alternating electromagnetic fields. Thus, there was limited use of this technique in research or clinical settings until the mid-1970s. At that time, Anthony Barker started a research program at the University of Sheffield using ultrabrief magnetic pulses to stimulate the nervous tissue. In 1985, Barker et al13 designed and built the first practical electromagnetic stimulation device for human use. The initial intention was to stimulate the spinal cord, since these researchers were concerned about the unpredictable effects of TMS on memory (personal communication, George MS. 2013). Nevertheless, TMS was eventually found to be well-suited for exploring cortical function and gained widespread use for this purpose. Mark George, who was a visiting scholar in England, first applied TMS for the treatment of depression after he moved to the National Institutes of Health (NIH) (personal communication, George MS. 2013). In 1995, the first pilot clinical trial was published reporting the results of TMS in six highly treatment-resistant depressed (TRD) patients.14 This was followed by multiple preliminary and two large trials ultimately leading to FDA clearance of the first TMS device for the treatment of major depression in 2008.15 A subsequent large trial with a “deep TMS” device led to its clearance in 2013.16
Based on the principle of electromagnetic induction, TMS modulates the brain’s electrical environment using magnetic fields, which pass through the scalp and skull unimpeded. These fields are produced by passing rapidly alternating electrical currents through a coil with a ferromagnetic core (ie, an electromagnet in lieu of a permanent magnet). The magnetic field strength produced by TMS varies from 1.5 to 3 T and is comparable to an MRI device, except that it focuses on a limited area of the cortex using a circular, figure-eight, conical, or helmet-like coil design (eg, H-coil). TMS can be administered in single pulses or as a brief series of pulses, called a train, for research, diagnostic, and therapeutic purposes. When used clinically, several thousand pulses are usually applied over a period of minutes to hours. This is called repetitive transcranial magnetic stimulation or “rTMS”. These pulses can be delivered in a rapid (ie, >1–20 Hz) repetitive fashion, enhancing cortical activity; or in a slow (ie, <1 Hz) repetitive fashion, inhibiting cortical activity. For this review, we will use the term TMS.
Stimulation parameters for major depression
There are several important parameters which can be adjusted when delivering TMS. This includes coil location, which is typically over the left or right dorsolateral prefrontal cortex (DLPFC). Motor threshold (MT) is the intensity of the magnetic field required when the coil is placed over the primary motor cortex to activate skeletal muscles. This threshold has been extensively studied as a basic neurophysiological parameter, and its determination enables practitioners to vary stimulation intensities across individuals with the aim of optimizing efficacy and minimizing adverse effects (eg, seizures).
The magnetic pulses are delivered in stimulation trains that are typically 1–5 seconds in duration. The frequency (Hz) of pulsations over this time period typically varies (eg, <1–20 Hz), with lower frequencies inhibiting and higher frequencies facilitating neuronal depolarization. An intertrain interval is utilized to allow cooling of the coil, recharging of the capacitors for the next train, and decreasing the probability of inducing a seizure.
As the safety of various TMS parameters used for treatment purposes was better understood over time, practitioners have increased the total number of pulses, the duration of the treatment, and stimulation intensities relative to the MT.17,18 Table 1 lists the most commonly applied parameters that vary based on the specific TMS device and intended impact on neuronal activity.
Mechanism of action
The basic physical principles of TMS and its effect on the brain at molecular, electrophysiological, and neuroimaging levels are extensively studied, and its application in experimental and diagnostic paradigms is well documented.19 This body of research provides a plausible biological basis for the use of TMS to treat various neuropsychiatric disorders. For example, in the context of depression, there are many similar biological effects associated with response to TMS and response to ECT or antidepressant medications, suggesting that their mechanism of action is similar. As with these other treatment modalities, and in spite of the clinical evidence for efficacy, TMS’ mechanism of action in depression is not clearly understood. This gap is largely due to the lack of robust pathophysiological theories of depression as a psychiatric disorder. Further, the validity of the Diagnostic and Statistical Manual of Mental Disorders’ criteria for major depressive disorder has been questioned.20 As a result, the heterogeneity in diagnosing depression contributes significantly to our limited understanding of its underlying cause(s).
The pathophysiology of depression is conceptualized at the levels of neurotransmitter action and cortical and subcortical circuits in the brain.21 For example, animal and human studies demonstrate that increased dopaminergic transmission occurs in cortical and subcortical areas of the brain after TMS.22,23 The current hypothesis, that led to the application of high-frequency, excitatory TMS over the DLPFC presumes an unbalanced connection between limbic regions (eg, hippocampus, amygdala, anterior cingulate, and insula) and the prefrontal cortex (PFC).24 Brain imaging of depressed patients demonstrates decreased activity in the DLPFC, an area implicated in the dysregulation of behaviors consistent with depression (eg, appetite changes, sleep–wake cycle disruption, decreased energy level).21 In addition, neurophysiological and positron emission tomography (PET) studies of stroke patients generated the “valence theory of emotion”. Although later refuted, this hypothesis suggested a lateralization of depression-related emotions to the left hemisphere (happiness, joy, anger) and was influential in the choice to stimulate over the left PFC with high-frequency, excitatory TMS pulses.25
The depolarization of cortical neurons with rapid, repetitive TMS temporarily increases blood flow and metabolism in the local area under which the coil is placed. In addition, transynaptic connections impact other cortical and deeper areas of the brain. For example, when higher frequency TMS is applied over the left DLPFC, the mesolimbic “mood neurocircuit” can be modulated. This may be accomplished through entrainment of cerebral oscillatory rhythms necessary for appropriate regional neuronal activity based on environmental demands. In contrast, selective stimulation of inhibitory interneurons and subsequent hyperpolarization with lower frequency TMS over the right DLPFC could lead to a decrease in local neuronal activity and may also produce antidepressant effects. In this scenario, it is possible that inhibition of linked cortical and subcortical networks may alter blood flow to limbic structures such as the amygdala, an area often implicated in the modulation of anxiety and fear, which are prominent features of many depressive episodes.
More recent research utilizing both brain imaging and TMS points to the connection between the anterior cingulate cortex and the DLPFC.26 These areas are strongly “anticorrelated” in depression, where overactivity of the anterior cingulate and hypoactivity of the DLPFC occur. In this context, a positive response to treatment with TMS was predicted by this correlation and holds the promise of using imaged-based, individualized treatment parameters in the future.27
A comprehensive and detailed review of neurobiological changes observed in animal and human brains caused by TMS is beyond the scope of this article. A recent, systematic review of biological markers in TMS and depression can be found in Fidalgo et al’s paper.28 The authors reviewed more than 50 studies, over half of which utilized neuroimaging methods in addition to clinical outcome measures of depression. They found that neuroimaging studies using various techniques (eg, fMRI, PET, SPECT, MTS) showed the most robust correlations with clinical outcomes, followed by the brain-derived neurotropic factor and cortical excitability studies. Such correlations were not as consistent for other markers such as thyroid stimulating hormone or electroencephalogram (EEG) activity. Contrary to changes observed in TMS animal studies, this review found no significant clinical correlations involving dopamine, serotonin, and saccadic eye movements.
TMS clinical trials for treatment of major depression
Types of trials
Initial studies of TMS for major depression included promising case reports, case series, and small open-labeled trials. This led to more definitive, larger sham-controlled trials with TMS as either a monotherapy or augmentation therapy. The latter is particularly important since a combined approach using different modalities is often required for TRD. In addition, there are several, nonblinded, randomized, and nonrandomized studies which compare the acute effects of TMS versus ECT. Finally, there are a number of pragmatic outcome studies which consider the acute and long-term efficacy of TMS in real-world situations.
TMS sham-controlled monotherapy trials
There are now several sham-controlled trials that vary in terms of their quality, which consider TMS monotherapy in the management of TRD. Multiple systematic reviews and meta-analyses have summarized their results (Table 2). Most recently, Gaynes et al29identified 18 trials (n=1,970) which met their criteria for good or fair quality. They reported that active TMS was superior to the sham procedure on all three of their major outcomes: severity of depressive symptoms; response rate; and remission rate. Thus, active TMS averaged more than a 4-point greater decrease in Hamilton Depression Rating Scale (HDRS) scores compared with the sham procedure. Further, those receiving active TMS were three times more likely to achieve response and five times more likely to achieve remission compared with the sham group. The authors concluded that for patients with major depression who have failed two or more adequate antidepressant medication trials, TMS represents a reasonable, effective alternative. They also recommend comparative studies with alternate treatments such as ECT or medication combinations to further clarify the role of TMS in TRD. Finally, they recommend longer maintenance trials to assess the durability of acute TMS benefit.
TMS sham-controlled augmentation trials
Liu et al30 also recently published the first meta-analysis of studies that used TMS as an augmentation strategy in TRD. They identified seven randomized sham-controlled trials which met their criteria for inclusion. The total sample size was 279 (171 in the TMS group; 108 in the sham group). The pooled response rates for active TMS compared with the sham procedure were 46.6% and 22.1%, respectively (OR =5.12; 95% CI =2.11–12.45; z =3.60; P<0.0003). Active TMS was also superior to the sham procedure in terms of change in baseline HDRS scores (ie, pooled standardized mean difference was 0.86; P<0.00001). The authors concluded that TMS augmentation was significantly superior to a sham condition for TRD. However, given the small number of studies and heterogeneity in subgroup analyses, they suggest more rigorously designed trials are needed to confirm this observation.
Among the randomized sham-controlled studies, four stand out due to their size and clinical implications. The first two studies used a research version of the Neuronetics device and included 491 patients (301 and 190, respectively). Both involved only nonmedicated TRD patients who were randomized to either active or sham TMS.31,32 These studies also differed from others in their use of more aggressive treatment parameters based on the safety record obtained from previous trials and earlier analyses suggesting that these parameters improved clinical outcomes. The most relevant of these parameters were coil placement over the left DLPFC; a frequency of 10 Hz; stimulation intensity at 120% MT; 4-second pulse trains; 26-second intertrain intervals; and up to 90,000 pulses delivered over 30 sessions. Moreover, blinding was improved in both the studies by designing and using more convincing sham treatments. For instance, the NIH-sponsored study also included electrical stimulation of the scalp to mask any differences in sensations produced by the active and sham TMS procedures.32 The results of the two trials aligned surprisingly well. For example, based on improvement in the HDRS-24 scores, rates of remission were approximately 5% for the sham procedure and 15% for active TMS in both trials. Further, tolerability and safety were comparable between the two studies (eg, no suicides, no seizures, no cognitive adverse effects, low dropout rates due to adverse effects).
The third large (n=212) RCT utilized a novel coil design (ie, H-coil) coupled to a Magstim stimulator.33This system produces strong magnetic fields that penetrate deeper into the brain.34 The results of this study were presented to the FDA which cleared this system for the treatment of major depressive disorder in patients who failed at least one adequate antidepressant medication trial.16 In this double-blind, sham-controlled study, coil placement was over the medial and lateral PFC and treatment parameters included an 18 Hz frequency, stimulation intensity of 120% MT, 1,980 pulses per session given over a 20.2 minute duration, and administration 5 days a week with a total of 20 sessions. The sham procedure involved the use of inverse currents, which produced negligible magnetic fields. After the acute treatment phase, patients were treated twice weekly for an additional 12 weeks during a maintenance phase. Based on HDRS-21 change scores, TMS significantly separated from the sham procedure (ie, a 6.39- versus a 3.28-point decrease; P<0.008). Further, the response rates (37.0% versus 27.8%; P<0.03) and remission rates (30.4% versus 15.8%; P<0.016) were significantly different between active and sham coil treatments. Common adverse effects were stimulation-site pain and jaw pain. One seizure (confounded by heavy alcohol use) was reported, and no cognitive adverse effects were observed.
Finally, the fourth large (n=170) multicenter sham-controlled trial conducted at 18 sites in France compared low-frequency TMS to venlafaxine (VEN) for TRD.35 The study included three arms: active TMS plus VEN, active TMS plus placebo tablets, and sham TMS plus VEN. The active TMS group received daily stimulations over the right DLPFC at 1 Hz frequency; 120% MT intensity; 8.5 minute durations; and a total of 360 pulses per day for 2–6 weeks. The mean VEN dose was 179.0 (±36.6) mg per day. Based on the primary outcome, all groups achieved a comparable number of remitters. Since TMS alone was comparable to the combination and VEN-only groups, the authors suggested it may be a useful alternative in this population.
TMS versus ECT
ECT is considered the most effective treatment available for more severe episodes of depression. There are, however, a number of limitations associated with ECT, including a lack of availability in many areas, significant short-term cognitive adverse effects, poor durability of effect in a substantial proportion of acute responders, patients’ reluctance to accept this treatment, and its cost. In this context, TMS is often considered as a potential substitute for or a complementary treatment with ECT.
There are several trials directly comparing these two approaches, primarily for patients deemed clinically appropriate for ECT (Table 3). In this context, two recent systematic reviews and meta-analyses considered the randomized trials comparing the relative benefit of TMS with ECT for the acute management of more severe depressive episodes.
Micallef-Trigona36 reported the first meta-analysis of such a comparison which included nine trials (n=384). The author found that this primarily treatment-resistant group of patients experienced significant reductions in depressive symptoms from baseline as measured by the HDRS. Specifically, the TMS group had an average reduction of 9.3 points and the ECT group, an average reduction of 15.4 points. When comparing the two treatment modalities, however, the ECT group experienced a significantly greater point reduction (P<0.011). Overall, the mean effect size was 1.33 for TMS and 2.14 for ECT. The authors concluded that while ECT was superior to TMS, at least some patients who might otherwise be referred for ECT could potentially benefit from TMS as an alternative. Further, they opined that the ultimate role for TMS in more severe depression depends in part upon technological and logistical advances in its administration.
A second systematic review and meta-analysis by Ren et al37 included nine trials (n=425). The authors reported that ECT was superior to high-frequency TMS when psychotic depressed patients were included, both in terms of response (P<0.03) and remission (P<0.006); but that ECT and high frequency TMS were comparable in the nonpsychotic depressed group. Of note, overall discontinuation rates were low (ie, ∼9%) and did not differ between the two treatment groups. Adverse cognitive effects (eg, visual memory, verbal fluency) were more common in the ECT group. The authors called for more good quality trials to assess the long-term outcome between these two treatments, especially in terms of cognitive effects. They also noted that more work is needed to optimize the stimulus delivery with TMS.
One positive, pilot study also found TMS in combination with ECT (versus ECT alone) for acute treatment of depression reduced the number of ECT sessions required, thus minimizing adverse effects (eg, cognitive).38 Preliminary data and increasing clinical experience also suggest a potential maintenance role with TMS after a successful acute trial of ECT.39
TMS outcomes studies
These trials were conducted to assess the durability of antidepressant benefits after a successful, acute TMS course. They can be divided into follow-up studies after response to acute TMS in controlled trials or follow-up studies after response to acute TMS in clinical practice settings. Of note, these studies employed reintroduction of TMS sessions when required, in addition to standard maintenance therapies involving medication and psychotherapy.
The first, large-scale, semi-controlled outcome study involved patients who were considered at least partial responders (ie, at least a 25% decrease in their baseline HDRS scores) after acute treatment in the pivotal trial that led to FDA clearance of the first TMS device for treatment of depression.40 In this study, patients (n=99) were initially tapered from their 5-day-per-week TMS schedule over a 3-week period, while simultaneously being titrated up on a single antidepressant medication for maintenance purposes. Over the next 6 months, they were regularly assessed for early signs of depression relapse. If this occurred, they then received additional TMS treatments to regain mood stability. At the end of the 6-month trial, 10 (13%) of the patients had relapsed. Thirty-eight (38%) met criteria for symptom worsening and were retreated with reintroduction TMS sessions (mean ∼14 additional treatments). Thirty-two (84%) of this pending relapse group were able to reachieve symptomatic stability. In a second follow-up study, 50 patients who had achieved remission during the acute phase of the NIH-sponsored optimised TMS trial were then followed for 3 months.41 After TMS taper and either continued pharmacotherapy or naturalistic follow-up, 29 (58%) maintained remission; two (4%) maintained partial response; and one (2%) relapsed.
The results of a recent controlled maintenance trial is reported only in abstract form presently.42 A medication-free TRD group (n=67) received an acute course of TMS. Responders were then randomized to 12 month follow-up assessments with or without a scheduled prophylactic TMS session at each visit. Patients in either group could also receive acute reintroduction TMS treatments if they met predefined criteria for worsening. About two-thirds of these patients achieved remission during the acute TMS treatment phase. After 1 year, based on the proportion of patients without symptomatic worsening, there was a trend favoring the monthly TMS prophylactic treatment group. These preliminary results indicate that TMS monotherapy for both acute and maintenance purposes may be a viable strategy in some patients.
Several studies report the outcome in depressed patients who received an acute trial of TMS in routine clinical practice and were then assessed after varying periods of time for ongoing benefit. For example, one trial (n=59) followed TRD patients who benefited from an acute course of TMS for 20 weeks.43 Thirty-seven of these patients received maintenance TMS and 22 received no additional TMS treatments. At the end of this period, 82% of patients without TMS maintenance treatment had relapsed versus only 38% who received maintenance TMS (P<0.004). In another retrospective report, the authors assessed 42 patients who initially responded or remitted after an acute trial of TMS for their unipolar or bipolar depressive episode.44 In this group, 62% experienced continued benefit over a 6-month period while receiving adjunctive maintenance TMS.
In the largest pragmatic study to date, Dunner et al reported the outcome in 257 TRD patients who successfully completed an acute TMS course and agreed to follow-up over 52 weeks.45–47 Patients received ongoing maintenance medication as per clinician’s discretion and also had the option to receive reintroduction TMS if they demonstrated worsening of symptoms. Of the 120 patients who met response or remission criteria at the end of their acute TMS treatment course, 75 (62.5%) continued to meet response criteria throughout the 1-year period. The authors concluded that TMS demonstrated both a statistical and clinically meaningful durability of acute benefit over 12 months.
Patient selection for TMS
Based on the results of the aforementioned clinical trials as well as existing clinical experience, the optimal patient for TMS appears to be someone whose depressive episode has lasted 3 years or less; has failed between one and four adequate antidepressant trials (both medication and psychotherapy); and does not have psychotic features.
TMS safety and tolerability
The overall effectiveness of any treatment must consider both its efficacy as well as any safety and tolerability issues. In this context, TMS appears to be a relatively safe and reasonably well tolerated treatment.9,18 Adverse effects associated with this therapeutic approach involve a number of localized problems at the site of the coil placement. The most common problem includes application site discomfort or pain. This occurs as a result of the intense magnetic pulses applied over the DLPFC. While approximately 50% of patients will experience this problem, most acclimate in a relatively short time period. To help patients manage this discomfort, various parameters can be adjusted, usually temporarily. This includes lowering the stimulation intensity, altering the coil rotation or angle, or slightly changing its location. Because of the rich innervation in this area, stimulation of certain nerve branches (eg, trigeminal nerve) can cause contraction of the muscles around the eye, sensations in the nose and the teeth, or tearing. These occur while the stimulations are being delivered and rarely persist afterwards. Due to muscle contractions, tension-like headaches also occur in about half of patients. Typically these are mild-to-moderate in severity and gradually subside over the first several treatment sessions. The use of analgesics (eg, aspirin, acetaminophen, ibuprofen) as a pretreatment may preclude the headaches or be used to manage them when they occur.
The most serious potential adverse effect is an inadvertent seizure. The incidence appears to be approximately 0.1% over an entire course of TMS treatments. This compares favorably to the incidence of seizures with many medications used to manage depression. Reported seizures have always occurred while the patient was receiving a treatment, resolved spontaneously with supportive therapy, and did not result in any long-term neurological or medical complications. In the two largest studies to date, which used aggressive treatment parameters, no seizures occurred.9,31,32 In the deep TMS study, one seizure incident was reported.33 As a result, a prior history of seizures is a relative contraindication to the use of TMS. Further, care must be taken to avoid situations where multiple medications which can lower the seizure threshold are combined with TMS treatments to assure that the coil is placed sufficiently anterior to the motor cortex, to avoid periods of sleep deprivation, to minimize the use of alcohol or other substances, and to minimize any significant changes in diet and fluid intake which could alter the MT.
In addition to investigating biological markers of TMS response as mentioned earlier, there are several ongoing projects to further refine the application of TMS to achieve therapeutic enhancement. Below we summarize some of these developments.
Multiple magnets (Cervel Neurotech)
This investigational device has multiple coils that utilize a spatial summation technology to directly stimulate deeper structures and achieve higher circuit-level specificity in the brain. Although unpublished, the company reports that the pilot clinical trials to date have produced positive statistical and clinically relevant results.48,49
Theta burst stimulation
Rather than a different magnet design or configuration, this is a modification of pulse parameters utilizing high and low frequencies in the same stimulus train by applying a very high (50 Hz) frequency magnetic field in a very brief burst, which has its own frequency of 4–7 Hz (hence, theta) (ie, three 50 Hz bursts delivered five times a second). This is modeled after animal studies, exploring the firing patterns of hippocampal neurons and long-term depression and long-term potentiation mechanisms. When administered continuously (ie, cTBS), this stimulus pattern is similar to slow TMS (1 Hz), and when delivered intermittently (ie, 8 second pauses between bursts), it is similar to rapid TMS (10–20 Hz). Pilot clinical studies in humans for the treatment of depression have generated initial positive results.50,51Although there are no direct comparison studies yet, TBS may provide the same clinical benefits as TMS but with shorter treatment sessions and lower magnetic intensities.52
TMS phase and frequency coupled to EEG (Neosync)
This device utilizes low magnetic fields produced by rotating spherical, rare earth magnets that synchronize with the patient’s frontal alpha EEG frequency as measured by the device.53 Hypothetically, this can entrain the oscillatory rhythm of the mood-related brain circuitry.
Improved consistency and precision of coil placement with structural MRI
Current TMS treatment protocols determine the coil placement over the DLPFC based on approximate measurements, which rely on the primary motor cortex homunculus or 10–20 EEG coordinate standards. There are TMS devices, however, which incorporate sophisticated MRI-based navigation within their designs and are used in preneurosurgical mapping of the cortex (motor and speech centers).54 The role of individualized and enhanced precision of coil placement is as yet unknown and may not be critical for treatment efficacy with the current protocols. This approach, however, may gain importance in the treatment of much younger individuals and when more focal coil designs are accomplished in the future.
Direct comparison of TMS modalities and devices
While different coil designs, devices, and treatment parameters continue to evolve, clinicians will be challenged in making risk–cost–benefit analyses to decide which treatment modality is optimal. While difficult to perform, direct comparisons of these modalities will be critical to understand the differences and similarities of these devices in clinical practice. This type of research may also improve our understanding of the mechanisms of action and subtypes of depression.
In this context, there are several small studies comparing high frequency, left-sided TMS with low frequency, right-sided TMS.55 They suggest these two modalities are beneficial without a dramatic difference in efficacy. To date, however, the largest sham-controlled studies involve the use of high frequency left-sided treatment. Based on the existing data, low frequency right-sided treatment may be preferred in patients at higher risk for seizures. These studies also suggest that the session duration could be shortened with low frequency right-sided treatment.
Direct inhibition of anterior cingulate cortex
Several imaging studies suggest that overactivity of the anterior cingulate is highly correlated with major depression. Current devices barely reach this region and likely affect it indirectly through synaptic connections. This brings up the testable hypothesis that directly inhibiting the activity of the anterior cingulate cortex with TMS coils which can reach and focus on this region may improve clinical outcomes.
Simultaneous combination with active (psychotherapy, task performance) and/or other passive treatments (bright light therapy, ketamine)
TMS is a passive treatment from the point of view of the patients. Vedeniapin et al56 published a case report indicating that CBT during TMS for depression is feasible and may produce an additive effect. In addition, in a sham-controlled single-blind trial, Hoy et al57 exposed ten healthy study participants to affective stimuli while they were being administered a single session TMS, which suggested that short duration TMS did not alter the mood of healthy subjects. In addition to active tasks, other passive treatments such as light therapy and ketamine infusions could be combined with and potentially enhance the antidepressant effects of TMS.
A multisite study is also currently under way for the treatment of Alzheimer disease.58 This trial combines domain-specific task performance with TMS over different regions of the cortex.
Serial combination with other neuromodulation treatments (ECT, tDCS)
Another combination strategy may be to sequentially perform other brain stimulation treatments such as ECT38 or transcranial direct cortical stimulation (tDCS) with TMS.
In summary, TMS is a promising, novel antidepressant treatment still relatively early in its development. Its efficacy and safety have improved significantly with continued research and clinical experience. The effect size for TMS antidepressant efficacy is at least comparable to those of antidepressant medications even though studies included only treatment-resistant or treatment-intolerant depressed patients. To date, this evidence base satisfies the critical thresholds for FDA clearance and approval of coverage by most third-party payers in health care. Further, there is a signal that TMS may benefit certain subgroups of patients who previously would be referred for ECT. Finally, the durability of TMS’ antidepressant benefit and safety and tolerability profile make it an attractive treatment option for selected patients. Although TMS is labor intensive compared with medications, its efficacy, safety, and tolerability for depression and possibly other disorders are driving additional research to refine and improve its therapeutic potential.
Dr Janicak has served as a consultant and received research grant support from Neuronetics, Inc in the past 12 months. The authors report no other conflicts of interest in this work.
Wednesday, January 13th, 2016 at 5:44 pm
The not-so funny side of the disorder you’ve seen portrayed on screen
Written by: Anissa Anderson Orr | Updated: July 02, 2015
Originally published: https://www.uthealthleader.org/story/the-reality-of-hypochondria
We love to laugh at the geeky, constantly sniffling, hand-wringing hypochondriac portrayed on TV and in movies.
Admit it: It’s fun to watch The Big Bang Theory’s Sheldon manically overreact when he’s convinced he has an untraceable disease, or Woody Allen, the undisputed king of hypochondriacs, going berserk over a buzzing noise in his ear (“I got the classic symptoms of a brain tumor!”).
But absent laugh tracks and one-liners, the disorder isn’t as amusing in real life. Hypochondria causes intense mental and physical distress, and leads to unnecessary doctor visits and tests and missed school and work. It seriously limits life.
Making matters worse, family and friends often misunderstand what’s going on, believing that their loved one is exaggerating for attention’s sake or simply faking sick.
Inside the mind
So why do some people believe they are sick, even when they’re not? People with true hypochondria are absolutely convinced that they have a serious or life-threatening health condition that hasn’t been diagnosed yet, even when there’s no clear medical evidence of a serious health problem.
Convinced of their ill health, they devote an excessive amount of time to looking for symptoms and researching health conditions. And when they’re not checking their pulses or surfing the Web, they’re seeing their doctors — again. These visits ease their minds for a time, but they are not reassured for long and frequently believe their medical care has been inadequate.
What causes this behavior is unknown, but a combination of genetics, environment and a history of trauma may all play roles in hypochondria, says Stefan Ursu, M.D., Ph.D., an assistant professor of psychiatry and behavioral sciences at The University of Texas Health Science Center at Houston (UTHealth) Medical School. He adds that hypochondria shares qualities with anxiety and obsessive compulsive disorder (OCD).
“The course of the disorder is pretty similar to OCD, waxing and waning over time depending on the levels of stress in a person’s life at the moment,” he says. “The focus of the health concern also can change over time.” Patients may fixate on a rare skin condition for a while, and then shift their attention to heart problems weeks or months later.
Treating the worried well
Q&A with Jeffrey Spike, Ph.D., professor at the McGovern Center for Humanities and Ethics and Director of the Campus-Wide Ethics Program at UTHealth
Spike is co-author of The Brewsters, a critically acclaimed book on professional health ethics that’s required reading for all UTHealth students. The book is written in a choose-your-own-adventure novel style, in which the reader plays the roles of health care provider, scientific researcher, patient and their family. Many of the book’s storylines center around Wayne Brewster, a 50-year-old man convinced he has osteoporosis. Spike spoke to HealthLEADER about the challenges and ethical considerations involved in treating patients with hypochondria.
HealthLEADER: What makes treating these patients so challenging?
Spike: As a physician, it is very easy to be impatient with someone who has hypochondria. These patients can be “frequent fliers,” meaning that they come in for visits more often than necessary. You may feel that they have trivial complaints. The big challenge is not to become frustrated and angry and take it out on the patient.
The patient has real issues and concerns. The fact that they are turning to you for help could be a good thing. What you can do is help give them accurate information about their health. Don’t ignore the fact that they could be very anxious, and that anxiety is a medical condition in itself.
What can doctors do to decrease their feelings of irritation?
You can schedule a regular appointment for patients with hypochondria every six months, to help reduce the frequency of their visits. That doesn’t upset your schedule, and give the patients the psychological reassurance they need. And as a physician, you have some good news to give them every time they visit, when you can report that they don’t have the terrible disease they are worried about.
The Brewsters asks readers to consider whether Wayne Brewster should undergo an expensive scan even though it wasn’t medically warranted. How should doctors approach this kind of situation?
It happens quite often that a patient may worry that they have something, but a physician finds no reason for concern. The physician can then choose between having an attitude that their patient is wasting their time, or being empathic to their patient’s concerns and taking the time to explain why it is very unlikely they have that condition. If there is a test that can reassure the patient they don’t have it, and it is not dangerous, not too expensive, and it poses no risk to the patient, then there are times when ordering that test may be justified.
What else would you emphasize?
Good physicians need to be empathic; it really helps you understand your patient and what your patient needs. We probably don’t emphasize that enough in training physicians. We need to have more time to ask patients follow-up questions and address their stress. Our focus should be on treating the whole patient — patients are persons and not just diagnoses.
In some cases anxiety produces real, physical symptoms like muscle and joint pain, headaches, heartburn, other digestive problems and even chest pain and heart palpitations.
“Many times patients are told that what they are experiencing is ‘all in their head,’ and in some ways that’s true,” says Erica Bruce, L.C.S.W., a licensed clinical social worker for UT Physicians who treats many patients referred by cardiologists and gastrointestinal specialists. “But that doesn’t mean the physiological symptoms they may be feeling aren’t real. Our mental and physical health are inextricably linked.”
Change in diagnosis
In an attempt to better address the complex mind-body relationship that defines hypochondria, the most recent edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-V) splits the disorder (also called hypochondriasis)into two diagnoses: Illness Anxiety Disorder and Somatic Symptom Disorder.
Illness Anxiety Disorder describes patients who have exaggerated health concerns and heightened bodily sensations without any significant bodily symptoms — for example, they may think they have the latest headline-making disease after reading about it.
Somatic symptom disorder describes patients who have exaggerated concerns about chronic physical symptoms they have, like Allen’s movie character believing the buzzing in his ear meant he had a brain tumor.
The change in diagnosis also dropped the former requirement that a patient’s exaggerated concerns had to persist “despite appropriate medical evaluation and reassurance.” Now, patients can be diagnosed with either disorder, even if they have not seen a physician for treatment.
Some mental health professionals laud the change for it inclusiveness and for covering people missed by the earlier criteria. Others, Ursu says, are concerned that it will end up diagnosing too many medically ill patients with mental health disorders.
Tools for treatment
Despite the change in diagnosis, many mental health professionals continue to recommend a holistic approach to treat both of the disorders formerly known as hypochondria — employing a variety of tools including medication, cognitive behavioral therapy and lifestyle interventions for the best effect.
In particular, selective serotonin reuptake inhibitors (SSRIs), which are often used for treatment of anxiety and OCD symptoms, have been found to provide relief in some cases.
Mental health professionals also work to help patients identify irrational or distorted thoughts, and stressors that trigger their health obsessions. Exercise and relaxation are key coping strategies. Yoga and meditation help relax muscle tension, which in turn prevents pain, injury and anxiety that fuel the cycle of hypochondria.
“If we don’t take those 15 to 20 minutes a day to decompress, it definitely affects us,” Bruce says. “Our daily stress level is like a balloon. Throughout the day, it fills with our experiences. If our stress balloon is full at the end of the day and we start the next day with a full balloon, it can explode or implode in the form of depression, intense anxiety or panic attacks, or manifest into hypochondria.”
Too much information 24/7
Constantly surfing the Web for health information pumps up that stress balloon, Bruce adds. Web searches instantly yield thousands (or millions) of hits and graphic images of worst case health scenarios:
- A bug bite — deadly MRSA
- Stuffy nose — bird flu
- Stomach pain — the big C: Cancer
“I tell my patients that when you are looking all this information up, it’s like you are trying to be your own medical doctor,” Bruce says. “Leave the diagnosis to your doctor. They have training we don’t have. The Internet gives us a lot of information, but it doesn’t have the ability to assess that information.”
Our 24/7 news cycle only fuels hypochondria further, constantly alerting us to new diseases with pandemic potential. People with hypochondria respond with hyper vigilance in an effort to control the unknown. Bruce says she works with patients to help them focus on what they can control and let go of what they can’t.
Think your behavior borders on hypochondria, and that the disorder is negatively affecting your life? Then take a step back and try to achieve some balance, Bruce advises. If that’s not working, seek mental health treatment that emphasizes a holistic approach to therapy. If a family member suffers from hypochondria, make an effort to encourage coping skills by doing healthy activities together. Broach the issue of treatment with sensitivity and empathy if your loved one needs extra help. Many people with hypochondria may feel defensive, because family and friends have dismissed their feelings and symptoms for years.
“It’s important when you’re talking to family and friends with hypochondria to be supportive and to listen without judgment,” Bruce says.
This site is intended to provide general information only and is not intended to substitute for or be used as medical advice regarding any individual or treatment for any specific disease or condition. If you have questions regarding your or anyone else’s health, medical care, or the diagnosis or treatment of a specific disease or condition, please consult with your personal health care provider.
Monday, December 7th, 2015 at 9:14 pm
Depression connects to every part of our life and our body. Unlike other chronic diseases and disorders that may be isolated to one area of the body, depressions, and other mental illnesses, have a way of touching everything from our central nervous system and organ function to our relationships with others. In order to manage depression, our bodies, mind, and soul play different but equally important roles. Here are a few ways to check-in and learn more about areas you might need to spend a bit more time studying.
- Social Studies – It is common for those suffering from depression to isolate from social engagements, conversations, and activities, choosing instead to be alone, which unfortunately fuels depression and ruins relationships. Do you find yourself canceling on friends at the last minute? Avoiding co-workers in the hallway or sitting silently and aloof in meetings? Do you look for ways to avoid interaction with your family members or closest friends? These actions reflect a need for improvement. If you’re making efforts to make it out of the house to attend at least one social event a week, you’re doing your best to engage in conversations with co-workers, or initiating connections with family and friends, give yourself an A. Depression makes these things difficult, but give yourself credit for even the smallest improvements in engaging in social activities.
- Human Nutrition – This is a topic that is often ignored or undetected in those with depression. Have your eating habits changed drastically – either eating more than usual or not enough? Any sudden weight gain or loss? Is your alcohol consumption more than usual? Be sure to take this subject seriously. Good nutrition is important to keep your body’s immune system, brain function, and muscles healthy and strong in order to avoid any illness that might exacerbate symptoms of depression. A balanced diet of fruits and vegetables, lean meats, and sources of fiber are important. For those with depression, alcohol should be avoided.
- Physical Education (PE) – It’s amazing what a brisk 15 minute walk can do for your mood. Studies from the National Institutes of Mental Health (NIMH) and numerous other sources have shown the positive effects exercise has on mental illness. This doesn’t mean you have to sign up for a marathon or swim 45 laps every day. Start small. A walk around the block, parking further away from the store than usual, or meeting a buddy for a walk at the park are all activities that earn an A in managing depression.
- Philosophy/Advisor – Meditation, church, yoga, or even a break from electronics all add up to giving your brain an opportunity to refocus, reflect, and bring you back to a place of calm. Also, think of your appointments with your therapist as a time when you can let things go and wash away the negativity depression brings. Fresh starts and positive reflections are great ways to keep depression from hindering your abilities to succeed and live a happy and healthy life.
Wednesday, December 2nd, 2015 at 10:44 pm
Anxiety in children is quite common and goes in phases naturally due to the new emotions, settings, and relational dynamics they are constantly experiencing. These phases that come and go are a normal part of childhood. However, when children consistently have feelings of fear, nervousness, and shyness, and they start to avoid places and activities, it is important to take these signs seriously.
According to the Child Mind Institute, 80 percent of children in this country who have a diagnosable anxiety disorder are not being treated. Left to progress, anxiety disorders can lead to depression and create severe barriers to the normal progression of life with regards to relationships, educational progress, experiences, and overall health. Research tells us that untreated children with anxiety disorders are at higher risk to perform poorly in school, miss out on important social experiences, and often become engaged in substance abuse.
What are Parents to Do?
- First, it’s important to be attentive to your child’s feelings. Notice patterns, refusals to participate, or specific stressors that may trigger fear in your child.
- Don’t be afraid to talk to your child about their anxiety, and seek to understand what they’re feeling. It’s important that your child feel that it is safe to talk to you about their feelings without judgement or feelings that they should “just snap out of it.”
- Seek the assistance of a psychologist or social worker. This is paramount in order to assist both your child and you in creating a plan to break through the barriers that anxiety is causing in your child’s life and for your family. In some cases, a therapist may feel that a psychiatrist’s opinion should be sought for pharmaceutical treatment as well.
- Stay calm when your child becomes anxious about a situation or event. Be the reflection of how your child hopes to be able to handle stressful situations in the future. Even small steps in the right direction are important and should be praised and recognized.
- Maintaining a regular routine is important for children with anxiety disorders. Sudden changes can trigger extreme anxiety and fear of the unknown. This is especially important in situations like getting to school on time and going to social outings. Allow extra time for these activities and help them set a plan that you will follow together in order to avoid stressful situations.
- Your child’s anxiety disorder does not mean that you are a bad parent. Acknowledge the stress and feelings that your child’s disorder brings to the family and take measures to build a network of support and well-being for yourself and others in your family.
Children are resilient, and with the right treatment and family plan, children with anxiety disorders can overcome the barriers that keep them from experiencing all there is to enjoy about youth and growing. It doesn’t have to be a lifelong battle. Call the The Solace Center at (281) 778-9530 today to learn more about how we can help.
Tuesday, December 1st, 2015 at 3:18 pm
It’s that time of year again: time for holiday gatherings, gift-giving, family visits, and an abundance of requests for your time, generosity, and talents. For many people, it is difficult to balance the added stress and stay focused on what the season is really about: happiness. An important way to maintain balance and avoid added stressors is to establish healthy boundaries with loved ones, employers, friends, and volunteer groups.
It’s ok to say no.
Our social circles, families, and employers all play a role in creating expectations. During the holidays, expectations often become distorted: your kids expect to receive the latest tech device, your spouse wants you to plan the company party, your in-laws plan to stay for a few more days than usual, and the church has asked you to volunteer extra time. The requests just keep coming. Meanwhile, you’re feeling a pile-up of obligations that leave you little time for the things you need to feel fulfilled and healthy. This is where personal boundaries are important, and remember: it’s ok to say no.
Here are a few tips about boundaries to help you maintain a happy and emotionally healthy holiday season.
- Your time is valuable. Set limits on the amount of your talents and time you’re willing to give to others. For instance, you might let your church group know that you have yoga each week during the time that they’ve requested you to volunteer and it’s important that you maintain your practice. Therefore, you’ll need to pass on their request.
- Set limits on the amount of emotion you give to a relationship. Family members can often trigger certain emotions in us that have the potential to take us down a dark path. Instead of feeding the flame, make a conscious decision to not become emotionally involved. Perhaps a sister in-law tries to pry into your family’s personal business at every family gathering. It’s ok to let her know that there are topics you do not wish to discuss and that you’d like for her to not ask you those questions in the future.
- You’re not super-mom or super-dad. Children need to be taught boundaries. In fact, children who witness their parents practice healthy boundaries often maintain better limits in their own lives. It’s ok to sit down with your children and discuss the realistic expectations for the upcoming holidays. Emphasize what the season is really all about, and discuss everyone’s role in making it a happy and healthy holiday.
We hope you find these tips helpful in maintaining your emotional health this holiday season. For more information, please contact us at www.thesolacecenter.com or by phone at (281) 778-9530
Monday, November 30th, 2015 at 3:23 pm
Anxiety and depression are two of the most common disorders diagnosed among Americans today. According to a 2013 report from The National Institute of Mental Health (NIMH), 40 million Americans are affected by an anxiety disorder, and depression touches 14.8 million people annually. Unfortunately, it is not uncommon for individuals to experience the comorbidity of anxiety and depression.
Given the prevalence of anxiety and depression, it is likely that someone close to you will struggle with one or both of these disorders at some point in their life: a spouse, parent, sibling, or even a child. One of the most important elements of treatment and symptom remission for those who have anxiety or depression is a strong network of understanding and caring loved ones and friends.
In order to support your loved one through the difficulties brought on by anxiety and depression, we’ve highlighted a few key ways you can be a healthy partner and a positive influence in their recovery and ongoing wellness.
- Build your knowledge of what anxiety and depression are. It’s important for supportive partners to understand that neither anxiety nor depression are conditions that a person can will himself or herself to not have; they can’t just “snap out of it.” Unfortunately, these are common misconceptions that can be quite harmful to those who are suffering and cause them to feel shame, guilt, and frustration. Find a reputable book (perhaps one suggested by a therapist) to learn more about anxiety and depression. Read it together with your loved one to show your interest in understanding what they struggle with and that it’s not their fault.
- Be a partner in health. The benefits of regular exercise, hobbies, and healthy social outlets have been shown to be powerful tools to keep symptoms of depression and anxiety at bay. The buddy system works well for everything from going to the gym, to showing up at social outings. Encourage your loved one to participate in things you know he or she enjoys doing, even when they seem to have lost interest. Losing interest in activities one normally enjoys is a common symptom of depression and anxiety, and when left unchecked can cause further isolation.
- Acknowledge when your loved one is going through a tough time. It is important that he or she feels they can talk to you about their feelings, and what they’re going through. Also, be conscious of any statements or actions that may point to a heightened need for treatment, such as mentions of suicide or loss of hope. Sentiments like these should be taken seriously and help should be sought immediately.
- Attend a therapy session with your loved one. If it is appropriate, it might be beneficial for you, as the individual’s primary partner, to go to therapy with your loved one to learn about any new changes or goals the therapist has established. In these sessions, it’s important to be open, honest, and realistic with your loved one and their treatment provider.
As a friend, parent, or spouse of someone with anxiety or depression, your love, understanding, and kindness can be some of the most powerful and successful treatments available. You play an important role in your loved one’s health, but it is important to keep your own health and wellness top of mind, too.