90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

Table of Contents

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

How to Receive Credit

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. OVERVIEW OF BRAIN MODULATION APPROACHES

ELECTROCONVULSIVE THERAPY

NON-INVASIVE TRANSCRANIAL STIMULATION

OTHER MAGNETIC STIMULATION THERAPIES

OTHER ELECTRICAL STIMULATION THERAPIES

3. NEUROMODULATION IN SPECIFIC PSYCHIATRIC DISORDERS

MAJOR DEPRESSIVE DISORDER (MDD)

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

POST-TRAUMATIC STRESS DISORDER

OBSESSIVE-COMPULSIVE DISORDER

SCHIZOPHRENIA

SUBSTANCE USE DISORDERS

EATING DISORDERS

DEPERSONALIZATION/DEREALIZATION DISORDER

4. ELECTROCONVULSIVE THERAPY

CANDIDATES FOR ECT

TREATMENT PARAMETERS IN ECT

EFFICACY

PREDICTORS OF ECT RESPONSE AND RELAPSE

POST-ECT MAINTENANCE

ADVERSE EFFECTS OF ECT

5. TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION IN PSYCHIATRIC DISORDERS

TRANSCRANIAL MAGNETIC STIMULATION (rTMS) IN PSYCHIATRY

TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) IN PSYCHIATRY

6. NEUROMODULATION FOR MAJOR DEPRESSIVE DISORDER (MDD) AND AFFECTIVE DISORDERS

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (rTMS)

TRANSCRANIAL DIRECT CURRENT STIMULATION IN MDD

7. NEUROMODULATION FOR OTHER MENTAL HEALTH DISORDERS

NEUROMODULATION FOR BIPOLAR II DEPRESSION AND BIPOLAR DISORDER

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

POST-TRAUMATIC STRESS DISORDER

OBSESSIVE-COMPULSIVE DISORDER (OCD)

TOURETTE SYNDROME

SCHIZOPHRENIA WITH AUDITORY VERBAL HALLUCINATIONS

SCHIZOPHRENIA, NEGATIVE SYMPTOMS

SUBSTANCE USE DISORDERS

EATING DISORDERS

DEPERSONALIZATION/DEREALIZATION DISORDER

EXTERNAL TRIGEMINAL NERVE STIMULATION (eTNS)

MAJOR DEPRESSIVE DISORDER

PTSD AND COMORBID MDD

PANIC DISORDER

8. INVASIVE NEUROSTIMULATION

VAGUS NERVE STIMULATION

DEEP BRAIN STIMULATION

9. NEUROMODULATION IN CHRONIC PAIN

OVERVIEW OF NONINVASIVE BRAIN STIMULATION IN PAIN

CHARACTERISTICS OF CHRONIC PAIN CONDITIONS

TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION

TRANSCRANIAL DIRECT CURRENT STIMULATION

COMPARISONS OF rTMS AND tDCS IN PAIN TREATMENT

10. INVASIVE NEUROSTIMULATION IN CHRONIC PAIN

MOTOR CORTEX STIMULATION

DEEP BRAIN STIMULATION

THALAMIC DEEP BRAIN STIMULATION

NEUROMODULATION SAFETY IN PAIN TREATMENT

11. SOCIAL ISSUES WITH NEUROSTIMULATORS

RISING CONSUMER USE

REGULATORY CHALLENGES AND SAFETY CONCERNS

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

This course will provide an overview of neuromodulation therapy for neuropsychiatric diseases and conditions and will examine the potential short- and long-term benefits and risks; clinical indications; patient selection; and potential ethical issues associated with neuromodulation therapies, including their non-therapeutic use for cognitive and performance enhancement. Refractory psychiatric disorders are emphasized, as several psychiatric disorders are poorly responsive to standard therapies, leaving patients distressed and functionally impaired. Neuromodulation therapies (aside from ECT for refractory major depressive disorder) are a more recent option for psychiatric disorders, a rapidly growing indication for use. Refractory chronic pain is another therapeutic area discussed in this course.

90350 • Neuromodulation for Refractory Neuropsychiatric and Pain Disorders

Education Category. Medical / Surgical

Release Date. 08/01/2025

Expiration Date. 07/31/2028

How to Receive Credit

To complete this course for continuing education credit please go to http://www.netce.com/course/3161 in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

Course Overview

This course will provide an overview of neuromodulation therapy for neuropsychiatric diseases and conditions and will examine the potential short- and long-term benefits and risks; clinical indications; patient selection; and potential ethical issues associated with neuromodulation therapies, including their non-therapeutic use for cognitive and performance enhancement. Refractory psychiatric disorders are emphasized, as several psychiatric disorders are poorly responsive to standard therapies, leaving patients distressed and functionally impaired. Neuromodulation therapies (aside from ECT for refractory major depressive disorder) are a more recent option for psychiatric disorders, a rapidly growing indication for use. Refractory chronic pain is another therapeutic area discussed in this course.

Audience

This course is designed for physicians, PAs, and nurses involved in the care of patients with refractory pain or neuropsychiatric disorders.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 10 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 10 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 10 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 1 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

As the therapeutic landscape evolves beyond traditional pharmacologic and surgical approaches, neuromodulation offers a promising option for patients with refractory conditions who have not responded adequately to standard treatments. The purpose of this continuing education course is to enhance physician and nurse understanding of neuromodulation therapies for the treatment of neuropsychiatric and chronic pain disorders.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline the background and underlying concepts supporting neuromodulation therapy.

2. Describe the mechanisms, benefits, and risks of electroconvulsive therapy (ECT).

3. Review the implementation of transcranial magnetic and electric stimulation in psychiatric disorders.

4. Evaluate the use of neuromodulation approaches to the management of treatment-refractory major depression disorder (MDD).

5. Compare the efficacy of neuromodulation techniques for the treatment of other psychiatric disorders.

6. Analyze the efficacy and safety of invasive neurostimulation for the management of psychiatric disorders.

7. Formulate strategies for integrating neuromodulation therapies into comprehensive treatment plans for refractory pain conditions.

8. Discuss the potential role of invasive neurostimulation in patients with chronic pain.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Margo A. Halm, RN, PhD, NEA-BC, FAAN

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Neuromodulation, neurostimulation, brain modulation, and brain stimulation are synonymous and describe noninvasive, minimally invasive or invasive techniques that deliver electrical or magnetic stimulation to specific brain region targets for the treatment of psychiatric and pain conditions.

Electroconvulsive therapy (ECT) is the oldest and most established brain stimulation mode in current use. Over the past decade, the most-studied brain stimulation modality in the treatment of psychiatric and pain conditions has been transcranial magnetic stimulation (TMS), followed by transcranial direct current stimulation (tDCS). Several recent modifications of TMS and tDCS are under development to improve efficacy or accelerate treatment response. External trigeminal nerve stimulation (eTNS) is a recent but highly promising approach. Minimally invasive vagus nerve stimulation (VNS) is modestly effective in refractory depression, and invasive stimulation requiring surgical implantation into brain targets has a limited yet highly valuable role in treatment of severe, refractory conditions.

In the context of this course, ECT is given its own section because the indicated use for ECT involves one condition (depression). The non-invasive modalities TMS and tDCS are the most extensively researched brain stimulation approaches and are combined in discussions of specific psychiatric disorders and pain conditions. Invasive brain stimulation is discussed in the last sections of psychiatric disorders and pain conditions.

2. OVERVIEW OF BRAIN MODULATION APPROACHES

Numerous brain stimulation modalities are in varying stages of research development or clinical use in the treatment of psychiatric and pain conditions. Their general characteristics are described in this section. Characteristics specific to treatment of psychiatric or pain disorders are discussed in later sections.

Therapeutic brain stimulation intends to induce durable treatment effects by exploiting brain capacity for plasticity. Neuroplasticity is the process where alterations in brain structure promote functional changes, and represents the process of normal brain functions during learning, adaptation to change, and recovery from brain injury. It is thought that early changes with brain stimulation involve alteration in synaptic strength, with longer exposures trigger longer-lasting anatomical changes such as neuronal sprouting and alterations of dendritic spines. Brain stimulation is best viewed as an intervention that targets specific brain circuits, rather than brain transmitter chemicals (neurotransmitters) [1,2]. Two processes that occur during brain stimulation-induced neuroplasticity [1]:

- Long-term potentiation: Reinforcement of synaptic strength

- Long-term depression: Weakening of synaptic strength

Parameters refers to the range of settings with stimulation devices, adjusted to manipulate energy output and desired treatment effects. Parameters include the location of electrode, magnet or lead placement; and the intensity, duration and pattern of delivered energy. Montage refers to configurations of externally placed or implanted electrode.

Brain stimulation therapy is not new to the 20th century. In the Roman era, electric torpedo fish were placed on the scalp to treat headache or epilepsy, and gouty arthritis was treated by placing painful extremities in pools with torpedo fish. In the mid-1700s, advances in electrophysiology inspired the use of transcranial electrical stimulation with direct currents to treat mental disorders [3,4]. Transcranial electrical stimulation machines for private use became widely available, and study of transcranial electrical stimulation intensified in the 1800s. Transcranial electrical stimulation was claimed to generate euphoria and improve mental performance by some patients and physicians, who advised that currents to the head not exceed 10 mA from risks of burning and shock. Common side effects were headaches, dizziness and nausea; Benjamin Franklin suffered retrograde amnesia after accidentally administering an electric shock to his head [3].

Erratic results and the advent of ECT led to waning interest in direct current brain stimulation [4]. ECT was introduced in 1938 to replace drug-induced convulsive therapy of severe psychosis; epilepsy was mistakenly believed antagonistic to schizophrenia. Depression was later known as a more suitable indication [5]. Psychosurgery using stereotactic lesioning in specific deep brain structures was introduced in 1947 to avoid the side effects of the widely used frontal lobotomy. Deep brain stimulation followed in the early 1950s as treatment for psychiatric illness, Parkinson disease, and pain [5,6]. Primitive forms of magnetic stimulation were first investigated in the 1890s, first shown to stimulate isolated nerves in 1959, and the first modern device was introduced in 1976, the precursor for the first TMS technique in 1985 [3].

These crude, earlier forms of brain stimulation were abandoned or curtailed with replacement by drug therapies, or stigma and rejection over unethical practices and side effects. All have been reintroduced in substantially safer and more effective forms with ethical safeguards; ECT is prohibited without full patient consent [5,6].

ELECTROCONVULSIVE THERAPY

Although not often considered non-invasive due to seizure induction, ECT remains established as a potent and rapidly acting treatment for severe or refractory major depressive disorder (MDD). ECT is considered unrivaled among all therapeutic options for rapidly inducing antidepressant effects, although multiple ECT treatments are usually required [7].

ECT generates electrical stimuli through electrodes applied to the scalp for seizure induction, with the patient in general anesthesia and pre-medicated with a muscle relaxant. Clinical outcomes are highly influenced by electrode placements, electrical intensity and pulse width, and these are described in a later section [8].

ECT is thought to work by generating seizure-induced changes in neurotransmitter activity, neuroplasticity, and functional connectivity. ECT increases levels of brain-derived neurotrophic factor (BDNF), which may promote neuroplasticity and contribute to the antidepressant effect [8,9].

Stigma surrounds this treatment mode and may interfere with patient acceptance of initiating ECT therapy.

NON-INVASIVE TRANSCRANIAL STIMULATION

The preponderance of research on non-invasive neuromodulation involves magnetic or electric stimulation using repetitive transcranial magnetic stimulation (rTMS) or tDCS. Both modalities allow external manipulation of the brain, performed safely without requiring neurosurgical procedures or general anesthesia [10].

Repetitive Transcranial Magnetic Stimulation

First demonstrated in 1985, TMS projects a fluctuating magnetic field (magnetic pulses) through the skull into the brain via an inductor coil placed against the scalp. This generates electrical currents in brain tissue (via electromagnetic induction) of sufficient strength to modulate neuronal firing. Multiple TMS pulses given consecutively are termed repetitive TMS. rTMS is noninvasive, and unlike ECT does not require anesthesia [2,8].

Frequency

Frequency is the intensity of stimulation energy [2]. High-frequency (5–20 Hz) rTMS (HF-rTMS) increases neuronal activity and cortical excitability and increases relative regional cerebral blood flow (with exceptions). Low-frequency (≤1 Hz) rTMS (LF-rTMS) reduces neuronal activity and cortical excitability. HF-rTMS and LF-rTMS, applied to the same brain site, can induce dissimilar effects on brain circuits.

Stimulation strength is tailored to the motor threshold of each patient that is determined by the amount of current, with single-pulse TMS applied to the primary motor cortex (M1), that produces a twitch in a peripheral muscle (a motor-evoked potential) [11,12]. rTMS is usually applied in "trains" of pulses interspersed with rest periods, because prolonged high-frequency stimulation increases seizure risk [13].

Coil Type

Most rTMS studies use a standard figure-8 coil, which has the drawback of poor brain penetration that limits the depth of stimulation delivery, although superficial areas of the prefrontal cortex (PFC) such as the dorsolateral PFC represent important targets fully amenable to rTMS stimulation. This partially explains the preponderance of rTMS studies in MDD, as the dorsolateral PFC is highly relevant in depression [12].

The deep (H) coil delivers pulses deeper than the figure-8 coil to stimulate broader and deeper frontal cortex regions such as the insula and ventrolateral prefrontal cortex, as well as the dorsolateral PFC. This may come at the expense of specificity, where deeper penetration expands the magnetic field to stimulate regions and circuits that interfere with therapeutic response or contribute to adverse effects [2,12].

Mechanism

Trains of magnetic pulses with rTMS temporarily summate to alter neural activity that can modulate cortical excitability. LF-rTMS mostly stimulates low-threshold inhibitory interneurons, and HF-rTMS excite projection neurons [13]. The effects of rTMS are not limited to the brain areas under the stimulation coil, and remote brain areas connected to the stimulated site are affected [14]. Because of synaptic connections, distal effects (cortical and subcortical, ipsilateral and contralateral) on neural activity, regional cerebral blood flow, and neurotransmitter activity may differ from proximal effects. rTMS can be viewed as targeting brain circuits instead of neurotransmitters, although behavioral effects depend on neurotransmitter systems within the manipulated brain circuit [2]. Long-lasting therapeutic effects with rTMS are related to long-term potentiation and long-term depression mediated through N-methyl-D-aspartate (NMDA) synaptic plasticity [15].

Transcranial Direct Current Stimulation (tDCS)

tDCS is a non-invasive, painless brain stimulation treatment in numerous psychiatric and chronic pain conditions. tDCS is delivered through a device that transfers low-intensity (0.5–3 mA) electrical current to the scalp surface with 2 large (20–35 cm^2) saline-soaked sponge-electrodes, an anode and a cathode. The anode and cathode are attached to distinct areas of the scalp with a rubber headband. The current penetrates the skull and enters the brain from the anode, travels through the tissue, and exits via the cathode [16].

In contrast to other non-invasive brain stimulation modes, tDCS does not induce neuron action potentials but instead modulates neuron membrane excitability [15]. Parameters that influence patient response and functional outcomes with tDCS are current polarity, delivered dose, and electrode positions.

Stimulation Types and Effects

The tDCS current is too weak to induce neuron firing, but alters neuron excitability by shifting the resting membrane potentials of neurons in a depolarizing or hyperpolarizing direction, making them more or less likely to re-fire. Changes in spontaneous neuron firing induced by stimulation type [4,10]:

- Anodal stimulation: Depolarizes (raises) neuron membrane potentials, which excites neuronal function and increases cortical excitability.

- Cathodal stimulation: Hyperpolarizes (lowers) neuron membrane potentials, which decreases neuronal function and cortical excitability.

Thus, effects of tDCS on cortical excitability are polarity-dependent (anodal or cathodal), and both cause changes in spontaneous firing.

Mechanisms

With repeated use, tDCS modulates synaptic connectivity by inducing long-term potentiation and depression, mediated in part by NMDA receptor-dependent mechanisms; neuroplastic changes regulated by neurotransmitters systems such as dopamine, acetylcholine, gamma-aminobutryic acid (GABA), serotonin and BDNF; and changes in neuronal membrane channels including sodium and calcium pumps [8,17,18]. tDCS can also upregulate and downregulate functional connectivity within brain networks, including those important for cognitive, motor, and pain processing [18].

OTHER MAGNETIC STIMULATION THERAPIES

While rTMS and tDCS are the dominant techniques, other novel or modified forms of non-invasive magnetic and electric current neuromodulation have been developed and are actively under investigation.

Theta-Burst Stimulation

Theta-burst stimulation is a form of rTMS that delivers a 50-Hz burst of three pulses every 200 ms [19]. Intermittent theta-burst stimulation delivers 600 pulses of stimulation for 2 seconds, followed by an 8-second rest, over two to three minutes. Intermittent theta-burst stimulation is considered excitatory. In contrast, continuous theta-burst stimulation is applied in 40 second trains to result in long-term depression-like decreases in motor cortex excitability. Continuous theta-burst stimulation is considered inhibitory [8].

Magnetic Seizure Therapy

Magnetic seizure therapy is a noninvasive convulsive neurostimulation therapy currently investigated as an alternative to ECT. A neurostimulator and coil are placed directly on the skull. Electrical current passing through the coil generates a strong focal magnetic field (2 Tesla). This passes unimpeded through the skull and soft tissue to reach brain tissue, where an electrical current is induced that causes neuronal depolarization triggering a generalized tonic-clonic seizure. Magnetic seizure therapy and ECT both induce seizures in patients under general anesthesia with assisted ventilation and EEG monitoring, but magnetic seizure therapy may have fewer side effects, particularly cognitive impairment [8,20].

OTHER ELECTRICAL STIMULATION THERAPIES

Transcranial Electrical Stimulation

An early approach to brain stimulation, transcranial electrical stimulation applied high-voltage electric stimuli through electrodes on the scalp. Most of the current travelled along the scalp between the electrodes, but a small portion penetrated the brain to activate neurons. This method was refined in 1980 and termed transcranial electrical stimulation. Transcranial electrical stimulation is credited as the pioneering neurophysiological approach for noninvasive brain stimulation, but interest in transcranial electrical stimulation declined rapidly with the introduction of TMS in 1985 [19].

Transcranial Alternating Current Stimulation (tACS)

Most published research on transcranial electrical stimulation efficacy has involved tDCS. Only recently has tACS attracted attention as a promising alternative approach to directly interact with ongoing oscillatory cortical activity. To date, evaluation of tACS has been primarily limited to possible cognitive enhancing effects in healthy adults, and in the elderly with normal, age-related cognitive declines [21].

Transcranial Random Noise Stimulation (tRNS)

tRNS is a variant of tACS that uses a constantly changing current. While tACS stimulates at a set frequency to entrain oscillatory activity, tRNS stimulates at a randomly changing frequency between 0.1–640 Hz. tRNS at higher frequencies (>100 Hz) may induce larger excitability changes than stimulation with a direct current such as tDCS, because the sodium channels of underlying neurons are repeatedly opened by stimulation. Neuronal homeostatic mechanisms are prevented because the underlying neurons cannot adjust to the constantly randomly changing electrical field. As a relatively new technique, the number of published reports on tRNS treatment in psychiatric and pain disorders is sparse [22].

External Trigeminal Nerve Stimulation (eTNS)

eTNS is an external neuromodulatory device originally developed for use in refractory seizures. The theoretical basis for eTNS is that bilateral electrical stimulation over the trigeminal cranial nerve may neuromodulate cortical and subcortical areas related to neuropsychiatric disorders, such as the amygdala, insular cortex, prefrontal cortex, hippocampus, thalamus, locus coeruleus, nucleus of the solitary tract, and the anterior cingulate cortex. eTNS involves a bottom-up mechanism where stimuli propagate from the cranial nerve in the direction of the brainstem and central brain regions. As such, this represents a novel approach that differs from transcranial stimulation involving top-down mechanisms [23,24].

Two eTNS protocols are described for psychiatric disorder treatment. Both protocols use stimulation frequencies of 120 Hz, asymmetrical alternate current, pulse duration of 0.25 ms and intensity based on patient sensitivity and pain threshold. Protocol I delivers eTNS in 8-hour sessions during sleep for 8 weeks, with a 30 seconds on/30 seconds off cycle, while Protocol II uses 30-minute sessions in 10 weekdays for 2 weeks, with continuous stimulation [24].

Low-Intensity Focused Ultrasound

The concept of using focused ultrasound beams deep in the brain to treat movement disorders was conceived in the 1950s, but the need to make a cranial window in the skull led to its development abandoned. Low-intensity focused ultrasound can be delivered through the intact skull, making ultrasound neuromodulation the focus of considerable interest [7]. An advantage is its ability for deep brain delivery without causing permanent damage or effects [25]. Potential indications include acute symptoms such as seizures, and chronic conditions such as depression where plasticity may be important. Ultrasound neuromodulation is at a much earlier stage of development than TMS or tDCS [7].

Vagus Nerve Stimulation (VNS)

VNS is a minimally invasive therapy, first approved in 1997 for refractory seizure disorders and in 2005 for treatment-refractory MDD. Vagus nerves are cranial nerve with fibers that transmit nerve impulses from the periphery to the brain. Electrical stimulation of the vagus nerve stimulates the nucleus tractus solitaries, enhancing its capacity to modulate brain areas through its neuronal connections distributed to subcortical and cortical brain regions [8].

With VNS, an implantable pulse generator is surgically inserted in the chest region. The lead from the device is attached to the left vagus nerve in the neck, where a small electrical current is delivered. Stimulation is around-the-clock, with typical stimulation periods or "trains" lasting 30 seconds, with 5 minutes of rest between trains. The device parameters (pulse width, frequency, duration of stimulation, and duty cycle) can be modified transcutaneously (as with cardiac pacemakers) using a wand attached to a small handheld programming computer [26].

Motor Cortex Stimulation

Motor cortex stimulation is an invasive procedure, with use in chronic refractory pain first documented in the early 1990s. With motor cortex stimulation, the skull is surgically opened and an electrode array is inserted [13]. In epidural motor cortex stimulation, the electrodes are attached to the dura directly above the motor cortex. In subdural motor cortex stimulation, the dural layer is penetrated for electrode placement.

Motor cortex stimulation affects structures involved in affective, cognitive, and emotional aspects of pain. The analgesic mechanisms of motor cortex stimulation involve extensive changes at various CNS levels, with a likely entry point at the thalamic level that triggers distant effects on limbic, cingulate and orbitofrontal cortices, and descending modulation that reaches the spinal horn. Activation of the endogenous opioid system or gamma-aminobutyric acid transmission in these areas is thought to underlie long-term pain relief with motor cortex stimulation [13,27].

Deep Brain Stimulation

Deep brain stimulation is an invasive neurosurgical procedure performed under MRI guidance, where electrodes are implanted through the skull and dura into discrete brain targets for stimulation. The electrodes are internalized and connected to an implantable pulse generator implanted into the chest below the right clavicle. The implantable pulse generator is accessible with a handheld device, which allows remote monitoring and/or programming of stimulation parameters. The deep brain stimulation parameters of pulse width, frequency, and amplitude (voltage or current) are programmed by the treating physician and titrated to clinical effect. Deep brain stimulation has been extensively developed and refined for use in later-stage Parkinson disease, where it is a standard of care. Deep brain stimulation is also used in other movement disorders, but severe refractory psychiatric and pain disorders represent a growing research field [8].

3. NEUROMODULATION IN SPECIFIC PSYCHIATRIC DISORDERS

Among psychiatric disorders, depression has been the most extensively researched condition, followed by schizophrenia and substance use disorders. The most extensively studied brain stimulation modality is rTMS, followed by tDCS. While non-invasive brain stimulation approaches were developed to provide the efficacy of ECT without the adverse effects, ECT remains established in treating severe or refractory depression. Aside from ECT, deep brain stimulation is its current form has been in clinical use longer than other brain stimulation modes, but its invasive nature and restricted use to severe, refractory patients partially accounts for fewer published deep brain stimulation studies compared to rTMS and tDCS.

With noninvasive neurostimulation in psychiatric disorders and especially rTMS and tDCS, the speed at which the knowledge base is expanding cannot be overstated. Important factors that influence patient response to rTMS or tDCS are absent from earlier studies. Among these factors, perhaps the greatest efficacy-disrupting effect is found with smoking or benzodiazepine user on tDCS response.

In neurostimulation studies of psychiatric disorders, the Clinical Global Impression-Severity (CGI-S) scale may be used to measure patient response and clinical outcomes. This is a clinician rating scale of general improvement. More specific scales may be used to measure response for specific conditions.

MAJOR DEPRESSIVE DISORDER (MDD)

MDD is a disorder of mood involving disturbances in emotional, cognitive, behavioral, and somatic regulation which manifest in depressed mood and feelings of worthlessness or guilt; social withdrawal and agitation; impairments in concentration or decision-making; and insomnia or fatigue [28]. MDD is highly prevalent and associated with serious personal suffering, societal costs, severe symptoms and functional impairment. An estimated 30% of MDD patients do not adequately respond to pharmacotherapy and psychotherapy. Treatment-resistant depression is loosely defined as failure to achieve remission despite therapeutic interventions [29].

The dorsolateral PFC functions to regulate affective states through cognitive control over stress and emotion responsive, and is hypoactive during depressive episodes [30]. The dorsolateral PFC and rostral anterior cingulate cortex areas are closely inter-connected; decreased neuronal activity in these frontal areas underlies apathy, psychomotor slowness, and impaired executive functioning common in MDD [31,32].

Two different scales may be used to assess patient response. The first is the Hamilton Depression Rating Scale (HDRS or HAM-D), a 21-item measure of depression symptoms. In clinical trials, remission is defined as HDRS score <8. The other is the Montgomery-Åsberg Depression Rating Scale (MADRS), a depression scale that measures affective, cognitive, and vegetative symptoms.

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

Generalized Anxiety Disorder (GAD)

Generalized anxiety disorder (GAD) is a chronic psychiatric condition defined by excessive and uncontrollable worry, with at least three of six hyperarousal symptoms (restlessness, muscle tension, fatigue, irritability, difficulty in sleeping, concentration problems). Lifetime prevalence is 5.7%, with higher rates in primary care and psychiatric outpatient samples. GAD is frequently comorbid with depression, complicating presentation, treatment and prognosis. At the individual level, GAD is associated with significant quality-of-life impairments and diminished physical health. At the systems level, GAD is associated with high use of health care services and high costs [33].

Pharmacotherapy (antidepressants, anxiolytics) and cognitive-behavioral therapy are standard treatments for GAD, but fail to achieve symptom remission in 33% to 50% of patients. The best existing treatments leave many patients with GAD without relief, and alternative treatments are needed [33].

GAD is characterized by abnormalities in frontal and limbic structures primarily involving the prefrontal cortex, anterior cingulate cortex, and amygdala; decreased structural and functional connectivity between frontal and limbic regions; and impairments in emotion regulation associated with abnormal functioning in neural circuits that encompass frontolimbic regions including the dorsolateral PFC [34].

Panic Disorder

Panic disorder is characterized by sudden unexpected panic attacks and apprehension about the possible causes and consequences of the attacks. Comorbid agoraphobia is characterized by behavioral avoidance of situations from which escape might be difficult if a panic attack occurred [35].

Patients with panic disorder with and without agoraphobia have shown PFC hypoactivity paired with fear-relevant brain structure (amygdala) hyperactivity, suggesting inadequate PFC inhibition of responses to anxiety-related stimuli [36]. Hypofrontality is shown in patients with panic disorder during cognitive tasks without emotional content, and in responses to emotional stimuli. Altered activation patterns in the left inferior PFC are associated with panic attacks, and altered right anterior PFC associated with severity of agoraphobic avoidance [35,36,37].

A variety of scales are available to assess response of patients with anxiety disorders to neuromodulation therapies, including:

- Generalized Anxiety Disorder 7-item (GAD-7) scale

- Hamilton Anxiety Rating Scale (HARS or HAM-A)

- Panic and Agoraphobia Scale (PAS)

- Panic Disorder Severity Scale (PDSS)

- Clinician-Administered PTSD Scale

- Yale-Brown obsessive-compulsive scale (Y-BOCS) (the standard obsessive-compulsive disorder [OCD] measure)

- Yale Global Tic Severity Scale (YGTSS) (the standard Tourette syndrome measure)

POST-TRAUMATIC STRESS DISORDER

Formerly classed as anxiety disorders, post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder are now separately classed in the fifth revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) [28]. PTSD is a severe, potentially chronic and disabling disorder that can develop following exposure to a traumatic event involving actual or threatened death, serious injury, or sexual assault. Common symptoms include intrusive thoughts, nightmares and flashbacks of the traumatic event, avoidance of trauma reminders, hypervigilance, and sleep disturbance. These symptoms can be highly distressing and substantially impair social, occupational, and interpersonal functioning [28].

PTSD becomes chronic in as many as 40% of cases [38]. An estimated 8% of Americans currently meet PTSD diagnostic criteria, but less than half receive minimally adequate treatment [39]. PTSD is often comorbid with depression, substance misuse, and suicidality, and often responds poorly to conventional treatments [40]. Few therapies target the trauma memories, considered the root cause of clinical expression, symptom chronicity and impairment in PTSD. The potential of neurostimulation to modulate dysfunctional brain regions led to clinical trials in PTSD [40].

OBSESSIVE-COMPULSIVE DISORDER

OCD has a lifetime prevalence of 2% to 3% and an early onset in adolescence or young adulthood. The core OCD symptoms are:

- Obsessions, which are unwanted, disturbing, and intrusive thoughts, images, or impulses generally perceived by the patient as excessive or irrational

- Compulsions, defined as repetitive behaviors and mental acts that serve to ameliorate obsessions and reduce emotional distress

The obsessions and compulsions are often highly distressing to the patient. OCD is a frequently debilitating and often severe [28].

Even with the currently available treatment options, OCD has a tendency to chronicity and can have a devastating effect on occupational functioning, relationships and social life. With standard therapies involving selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy plus exposure and response prevention, around half of patients achieve 40% to 60% symptom reduction. Roughly 10% of patients are refractory to standard therapies and may become profoundly disabled. OCD pathology is thought to involve dysfunction of the cortico-striato-pallido-thalamo-cortical pathway, failure of ventral striatum inhibition, and pathological hyper-connectivity between cortical and striatal structures [41].

SCHIZOPHRENIA

Schizophrenia is a chronic psychotic disorder characterized by disordered cognition, emotion and perception of reality, Patients may experience positive symptoms (hallucinations, delusions) and exhibit behaviors perceived as odd and bizarre. Negative symptoms may be present at any disease stage, and persistent symptoms can include affective flattening, attentional/motor impairment, alogia, avolition, asociality and anhedonia. These are grouped into the subdomains of diminished expression (affective flattening) and amotivation (avolition/apathy) [17].

Traditionally viewed as an illness defined by psychosis, successful schizophrenia treatment was defined as resolution of delusions and hallucinations. Recently recognized is the substantial impact of negative symptoms on functional impairment. Resolution of positive symptoms, even in early-stage schizophrenia, may not translate into functional recovery. Full functional/social recovery occurs in less than 15% of schizophrenics, largely due to negative symptoms [42].

Efforts have expanded the definition of successful treatment outcome beyond clinical recovery to incorporate functional recovery. This recent focus on the relevance of negative and cognitive symptom in functional recovery prompted research efforts into more broadly effective treatments, including brain stimulation. Neurostimulation targets were suggested by the results of modafinil treatment studies. Modafinil increases dorsolateral PFC activity, and in schizophrenic patients, improved working memory, emotion recognition, cognitive flexibility, motor activity, and quality of life [42].

To assess patient response to therapy, clinicians may use the Auditory Hallucinations Rating Scale (AHRS), a seven-item scale that assesses the number of voices experienced and voice frequency, loudness, vividness, attentional salience, length, and distress caused [22]. For schizophrenia with negative symptoms, the Positive and Negative Syndrome Scale (PANSS) may be useful. Using this measure, moderate-to-severe negative symptoms score ≥15 on the Negative Subscale [43].

SUBSTANCE USE DISORDERS

Substance use disorder is a chronic relapsing disorder even following optimal detoxification and treatment, and substance craving is an important contributor to relapse. The reward effects of alcohol and abused drugs are mediated by the mesocorticolimbic system, comprised of the ventral tegmental area (VTA), nucleus accumbens, amygdala, and prefrontal cortex [44]. Also involved in substance use disorder is abnormal reinforcement in brain reward circuitry, and inhibitory control mechanisms exerted by the dorsolateral PFC and other prefrontal cortical networks [17].

Nicotine dependence imposes significant morbidity, mortality, and socio-economic burdens. It remains among the leading causes of mortality worldwide, and of preventable deaths in developed countries. Despite availability of approved medications for nicotine dependence, only 6% of smokers who report wanting to quit each year are successful in doing so for longer than one month. This mostly results from poor abstinence rates, and therapeutic alternatives are urgently needed. Emerging positive evidence suggests that non-invasive brain stimulation with TMS or tDCS can reduce smoking-related behaviors [45].

EATING DISORDERS

Anorexia Nervosa

Anorexia nervosa is a disorder characterized by a pathological fear of food, eating and gaining weight, and sustained (more than three years) duration of significant underweight (body mass index [BMI] <18.5 kg/m^2) [46,47]. Onset is usually peri-pubertal and anorexia nervosa mainly affects girls and women. The lifetime prevalence of anorexia nervosa in women is 2% to 4%, median duration is 5 to 7 years, and illness duration is more than 15 years in 30% [47]. The disorder has a high mortality rate, and only 10% to 30% of adults with anorexia nervosa recover through the best available therapies [46].

Patients with anorexia nervosa have limited treatment options, especially with prior treatment nonresponse [47]. Pharmacotherapy is largely ineffective and poorly accepted [46]. Patients underweight for three to five years have worse treatment response and outcome, possibly from the neurotoxic effects of starvation and stress hormones (cortisol) to the brain. This makes the first years from onset critical for successful intervention [47].

Anorexia nervosa is associated with structural changes such as reduced grey matter in fronto-limbic-striatal areas; functional changes with over-active limbic drives from the insula and amygdala, and diminished prefrontal activity; and hypoactivity of PFC regions during response inhibition and set-shifting tasks, a marker of poor inhibitory control that promotes anorexia nervosa chronicity. Improved, neuroscience-based treatments are needed that target the neural substrates of anorexia nervosa [46].

The Eating Disorder Examination Questionnaire (EDE-Q) measures eating disorder symptoms and general psychopathology. This has been the most common measure of response to therapy in the literature.

Bulimia Nervosa

Bulimia nervosa is an eating disorder with recurrent episodes of binge eating characterized by eating large amounts of food in a discrete amount of time (i.e., within a two-hour period) and feeling of lack of control over eating during episodes; and recurrent inappropriate compensatory behavior to prevent weight gain (purging). The binge eating and compensatory behaviors both occur at least once a week, on average, for three months, and patient self-evaluation is unduly influenced by body shape and weight [28].

Similar to anorexia, reduced PFC activity may contribute to symptoms in bulimic patients through impaired inhibitory control of binge eating and purging; poor cognitive flexibility that perpetuates compulsive body checking and exercise; and obsessive pre-occupation with eating, weight and shape [46].

Binge-Eating Disorder

The lifetime prevalence of binge-eating disorder is roughly 5% of the U.S. adult population, and 1.2% to 4.5% are diagnosed with subthreshold binge-eating disorder and any binge eating. Compared to obese individuals who do not binge-eat, patients with binge-eating disorder are more prone to depression, anxiety, body dissatisfaction, low self-esteem, and social withdrawal [48].

Cognitive-behavioral therapy can reduce binge symptoms, but many patients lack response and treatment-related weight-loss is minimal. Effective and lasting treatments for binge-eating disorder are needed to alleviate symptoms of this psychological disorder and the medical consequences of obesity [48].

DEPERSONALIZATION/DEREALIZATION DISORDER

Depersonalization/derealization disorder is characterized by distressing feelings of unreality and alteration, with persistent or recurrent experiences of feeling detached from, as if an outside observer of, one's mental processes or body. The condition has an estimated prevalence of 1%, commonly begins in early adulthood and tends to become chronic [28]. Depersonalization/derealization disorder can appear as a symptom of other psychiatric disorders, including 12% of cases of panic disorder [49]. Depersonalization is a commonly described symptom in patients with temporal lobe epilepsy, and may occur with use of some illicit substances [50]. Several pharmacotherapies have been trialed but most have not led to sufficient symptom improvement [51,52]. The Cambridge Depersonalization Scale (CDS) may be used with these patients to assess response.

4. ELECTROCONVULSIVE THERAPY

CANDIDATES FOR ECT

During the course of its long history, ECT became stigmatized in the viewpoints of patients, most psychiatrists and the lay public. While not undeserved considering the past misuse and crude technique of this procedure, the persistence of stigma has outlived substantial refinements in method and established efficacy and represents a barrier to treatment.

ECT is reserved for use in complex and acutely severe clinical presentations of MDD; in these patients, ECT is considered unrivaled for rapid induction of antidepressant effects [7]. ECT is recommended as first-line treatment in the following patients: extremely severe melancholic depression; those who refuse to eat or drink; have a very high suicide risk; very high levels of distress; psychotic depression; refractory MDD; catatonia; or previous positive ECT response [53].

With psychotic depression, ECT is a first-line option, and highly effective; a large study of bitemporal ECT efficacy reported remission rates of 95% in study completers [53,54].

TREATMENT PARAMETERS IN ECT

ECT outcomes are highly influenced by electrode placements, electrical intensity, and pulse width. Electrode placements are generally right unilateral, bitemporal, or bifrontal [8].

Electrical intensity is the ECT "dose." The delivered electrical intensity dose is individualized and based on seizure threshold—the minimum intensity to induce a generalized seizure. Doses five to eight times seizure threshold maximize the efficacy of unilateral placement, while doses 50% to 100% above seizure threshold for bilateral placement are usually sufficient [53].

Pulse width in ECT includes brief pulse width and ultra-brief pulse width (≤0.5 ms) [8]. The recommended first-line parameter for ECT in MDD is right unilateral or bifrontal placement; second-line placement is ultra-brief pulse right unilateral or bifrontal, or brief pulse bitemporal placement [8]. If there is no response to right unilateral after four to six sessions, switch to bilateral bitemporal or bifrontal.

Twice/week ECT has similar efficacy to three times/week but requires longer treatment duration; more than three treatments/week are not recommended due to greater cognitive side effects [8].

Dose level above seizure threshold determines the relative efficacy of electrode placements but can increase cognitive side effects. Generally, bitemporal ECT is more effective than unilateral, but cognitive side effects are greater. At six times threshold, unilateral efficacy approaches bitemporal ECT, but cognitive impairment is greater than with lower doses. Bifrontal ECT is less studied, but appears as effective as high-dose unilateral and bitemporal placement. Research evidence is insufficient to conclude a cognitive benefit for bifrontal over bitemporal ECT, but clinical experience suggests bifrontal ECT may induce fewer cognitive side effects than bitemporal. Bifrontal ECT may be associated with lower rates of ECT-induced cardiac arrhythmia, suggesting a safety advantage over unilateral and bitemporal ECT in patients with cardiovascular comorbidity [53,55].

Ultra-brief pulse width unilateral ECT allows effective treatment with markedly fewer cognitive side effects. Ultra-brief pulse efficacy appears comparable to standard brief pulse unilateral ECT but may require more treatments to achieve remission. Ultra-brief pulse bifrontal ECT is effective in cognitive sparing but ultra-brief pulse bitemporal is ineffective and not recommended [53,56,57,58].

Efficacy is balanced against side effects. ECT for most patients should begin with ultra-brief pulse unilateral ECT, as this has fewer cognitive side effects but may require a longer treatment course. When speed and reliability of ECT response is crucial, as with patients who are dehydrated or at extreme risk for suicide, bifrontal or bitemporal ECT should be considered [53].

EFFICACY

ECT is one of the most rapidly effective treatments for MDD. Response rates can reach 70% to 80% and remission rates 40% to 50% or higher, depending on the patient population and electrode placements; remission rates of 55% for right unilateral, 61% for bifrontal, and 64% for bitemporal were reported in a population of patients with unipolar (77%) or bipolar (23%) depression [8,59].

After an acute course of ECT, relapse rates are high, and greatest in the first six months post-ECT (37.7%). Even patients receiving post-ECT maintenance showed high relapse rates at one year (51.1%) and two years (50.4%) [60].

PREDICTORS OF ECT RESPONSE AND RELAPSE

ECT nonresponse is strongly predicted by severity of previous treatment resistance. In highly treatment resistant patients, ECT response rates were roughly 50% versus 65% in patients without previous treatment failure [61,62].

Highest response rates are associated with older age, psychotic features, shorter MDD duration, less previous treatment non-response, and possibly lower depressive severity [8]. Lower relapse rates are found in MDD cohorts with higher proportions of psychotic patients and older patients. Pre-ECT medication resistance is not associated with relapse risk [8].

POST-ECT MAINTENANCE

Initial ECT response can be maintained with medication or ECT. Post-ECT antidepressant use reduces relapse rates by roughly 50% [60]. Strongest evidence supports the post-ECT relapse reduction efficacy of nortriptyline plus lithium or venlafaxine plus lithium, and both show comparable efficacy [63,64].

Patients continuing their antidepressants during ECT show lower relapse rates versus antidepressant initiation after ECT (29.2% vs 41.6%), suggesting concurrent instead of sequential use of ECT and medication improves long-term outcomes [60]. Lithium during ECT may increase risks of cognitive side effects, encephalopathy, and spontaneous seizures; benzodiazepines and anticonvulsants may raise seizure threshold and decrease seizure efficacy, but lamotrigine may be less problematic than other anticonvulsants [8,65].

Continuation/maintenance ECT is safe and effective for reducing relapse, and shows comparable efficacy to nortriptyline plus lithium in relapse rates at six months (37.2% vs 37.7%) [66,67]. The frequency of continuation/maintenance ECT should be tailored to the patient, but is typically weekly for four weeks, then biweekly for eight weeks, and then monthly. More frequent sessions can be added with signs of relapse [8].

There are few psychotherapy studies of post-ECT relapse prevention, but patients randomized to cognitive-behavioral group therapy plus continuation medication have shown lower relapse rates at 6 and 12 months compared to continuation/maintenance ECT plus medication or medication continuation alone [68,69].

ADVERSE EFFECTS OF ECT

The use of general anesthesia, muscle relaxants, oxygenation and monitoring has minimized ECT-related morbidity, and mortality is estimated at less than one death per 73,440 treatments. ECT-related damage to brain structures has not been found. Adverse effects of headaches (45%), muscle soreness (20%) and nausea (1% to 25%) during treatment are transient and treated symptomatically. Roughly 7% of patients with MDD switch into a manic or mixed state [8].

Cognitive impairment is the greatest concern, and includes transient post-ECT disorientation due to postictal confusion and general anesthesia; retrograde amnesia (difficulty recalling information learned pre-ECT), and anterograde amnesia (difficulty retaining information learned post-ECT) (Table 1). Mild, short-term impairment in memory and other cognitive domains often occur during, and just after, ECT [53].

Table 1: ECT-RELATED FACTORS WITH HIGHER VERSUS LOWER RISK OF SHORT-TERM COGNITIVE IMPAIRMENT

ECT-Related Factors

Short-Term Cognitive Impairment

Higher Risk

Lower Risk

Electrode placement

Bitemporal

Bifrontal, unilateral

Pulse width

Brief (1.0–1.5 ms)

Ultrabrief (0.3–0.5 ms)

Stimulation dose

Suprathreshold

Lower electrical dose

Treatment frequency

3 times/week

2 times/week

Concurrent medications

Lithium, agents with known cognitive side effects

Reducing or discontinuing these agents

Anesthesia

High–dose

Lower doses

Source: [8]

Anterograde and retrograde memory are variably affected. Within two to four weeks, impaired anterograde memory usually returns to normal or may improve versus pre-ECT levels [70]. Retrograde impairment can persist for prolonged periods [71]. Perhaps most distressing to some patients is loss of autobiographical memory recall. Patients have reported persistent retrograde amnesia beyond six months; researchers counter by stating these subjective complaints could not be confirmed with objective testing, concluding they reflect persistent depressive symptoms [72,73]. Patients and their immediate family/partner should be informed of the potential effects on memory before undergoing ECT [53].

Absolute contraindications to ECT have not been identified, but several factors are associated with increased safety risk, including [8,9]:

- Space-occupying cerebral lesion

- Increased intracranial pressure

- Recent myocardial infarction

- Recent cerebral hemorrhage

- Vascular malformation or unstable aneurysm

- Pheochromocytoma

- Class 4 or 5 anesthesia risk

5. TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION IN PSYCHIATRIC DISORDERS

Important background information on rTMS and tDCS use that spans the range of psychiatric disorders is presented in this section, including factors that influence patient response, safety, and contraindications. Disorder-specific information is discussed further later in this course.

TRANSCRANIAL MAGNETIC STIMULATION (rTMS) IN PSYCHIATRY

Many psychiatric disorders have been evaluated in rTMS treatment, with the greatest evidence of efficacy in treatment-resistant depression [13]. Nicotine dependence is the most studied substance use disorder [12].

Concurrent Medications and rTMS Safety

Evidence Based Practice Recommendation

The safety guidelines for rTMS were determined in study participants who were largely free of antidepressant medications. While it is possible that psychotropic medication can affect the motor threshold, the National Network of Depression Centers and the American Psychiatric Association indicate there are no known absolute contraindications to psychotropic medication usage during rTMS. All medication use and change should be documented.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5846193

Last Accessed: July 24, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Potentially problematic medications commonly used in psychiatry and pain includes tricyclic antidepressants (nortriptyline, amitriptyline), antipsychotic drugs (chlorpromazine, clozapine), and antiviral medications. Abuse of alcohol or some illicit substances can increase cortical excitability and risk of a TMS-induced seizure. Withdrawal from CNS sedatives, including alcohol and benzodiazepines, increases seizure risk and patients must be asked about recent and current use. Recent substance abuse should be a contraindication to rTMS therapy [13]. The antidepressant bupropion is associated with increased seizure risk in some populations, raising concerns of its use during rTMS therapy. A systematic review found no evidence that supports excluding patients taking bupropion from rTMS [74].

Adverse Effects with rTMS

Seizure induction is the most serious adverse effects with rTMS, but fewer than 25 cases have been reported worldwide to date. The estimated incidence of spontaneous seizures is 0.01% to 0.1% with rTMS, 0.1% to 0.6% with antidepressant drugs, and 0.07% to 0.09% in the general population. HF-rTMS is contraindicated in patients with seizure history. Safety of LF-rTMS has been demonstrated in patients with epilepsy but is not established in patients with depression and seizures. Seizure history is usually considered an absolute contraindication [8].

Contraindications to rTMS

Evidence Based Practice Recommendation

According to the National Network of Depression Centers and the American Psychiatric Association, a comprehensive review of the patient's health status (including historical and current medical, surgical, neurologic, and psychiatric conditions and medications) and physical examination are evaluation components to determine the medical safety and necessity of rTMS.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5846193

Last Accessed: July 24, 2025

Level of Evidence: Expert Opinion/Consensus Statement

Absolute contraindications to rTMS are ferromagnetic metal in the head (e.g., plates or pins, bullets, shrapnel) and metallic hardware anywhere in the head, except the mouth (e.g., Cochlear implants, brain stimulators or electrodes, aneurysm clip) [8,13]. Relative contraindications include [8,13]:

- Presence of a brain lesion (vascular, traumatic, neoplastic, infectious or metabolic) or major head trauma

- Ferromagnetic metal in neck or chest

- Microprocessor implants in the neck, such as vagus nerve stimulator

- History of epilepsy or induced seizures

- Microprocessor implants below the neck: Spinal pumps or stimulators, cardiac pacemaker, implantable defibrillator

- Medications that lower seizure threshold

- Recent withdrawal from CNS sedatives that raise seizure risk (e.g., alcohol, benzo-diazepines)

- Pregnancy

- Hearing loss, tinnitus

TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) IN PSYCHIATRY

Compared with rTMS, tDCS is more recently introduced, with fewer published efficacy and safety studies in psychiatric disorders. Antagonist effects on tDCS treatment response from two drug agents were first identified in a 2016 review of tDCS in psychiatric disorders [16]. Nicotine inhibits schizophrenic patient response to tDCS. This effect is confirmed experimentally, and evident empirically in tDCS studies outcomes of schizophrenia; higher rates of current smokers repeatedly showed direct association with lower tDCS response rates [16]. In patients with MDD, co-use of benzodiazepines blunts therapeutic response to tDCS [16].

The efficacy-disrupting effects of concurrent benzodiazepine use in MDD trials and cigarette smoking in schizophrenia trials was not previously known, and throws reported outcomes of tDCS studies with negative or ambiguous findings into question (unless patient prevalence of benzodiazepine use or smoking was recorded) [16].

Serotonergic neurotransmission is enhanced by SSRI antidepressants, which facilitates neural excitation of anodal tDCS, but switches the inhibited excitability of cathodal tDCS to facilitated excitability. Similar effects are found with amphetamine, and the NMDA receptor agonist D-cycloserine [18].

Mood stabilizer antiepileptic agents interfere with tDCS-elicited excitability changes by blocking voltage-gated sodium and calcium channels [75].

Dopaminergic agents variously interact with tDCS to amplify or block the intended effects. Neuroleptics and other dopamine receptor antagonists suppress tDCS effects, while dopaminergic agonists have a non-linear synergistic effect on tDCS-induced excitability, and a prolonging effect on excitability inhibition. This may be relevant to the reduced tDCS effects in smokers during nicotine withdrawal [76].

Several biological, psychological, and lifestyle factors have been identified that influence tDCS response and contribute to the variable efficacy in tDCS trials [16]. COMT gene polymorphism moderated tDCS effects in patients with schizophrenia [77]. Prefrontal tDCS intensified cravings in patients with substance use disorder with drug-related cues present [78]. tDCS shows greater therapeutic effect in more severe MDD than in mild/moderate MDD [79]. Finally, severity of treatment-resistance in MDD negatively influences tDCS response, although attention should be paid to how treatment-resistance is defined [16].

Safety

Using conventional tDCS protocols (sessions ≤40 min, ≤2 times/day, ≤4 mA, electrodes that minimize skin burns), repeated sessions in more than 1,000 subjects receiving more than 33,200 sessions has not produced any reports of serious adverse events or irreversible injury to date. This includes diverse subject populations and patients from vulnerable populations [16,80]. Reports in the published evidence include patients receiving more than 100 tDCS sessions without adverse events from cumulative exposure; lack of unexpected or serious adverse events in more than 40 studies with more than 600 older adults; lack of decrements in behavior or mood in stroke populations; and no finding of drug agents that increase risk of serious adverse effects [80].

Seizure concerns with TMS have spread to tDCS, but evidence of increased seizure risk with tDCS is absent. tDCS produces static and not pulsed electric fields that are two orders of magnitude below those of rTMS, ECT and transcranial electrical stimulation, and thus, no apparent seizure risk [80].

6. NEUROMODULATION FOR MAJOR DEPRESSIVE DISORDER (MDD) AND AFFECTIVE DISORDERS

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (rTMS)

As a medical intervention with seizure risk, rTMS should only be performed in a medical setting under physician guidance and supervision. The medical team should include a psychiatrist when used as treatment for acute depression, and psychiatrists who use TMS benefit from training in brain stimulation methods [19].

Clinical guidance regarding the recommended approach to administering rTMS and theta-burst stimulation has been established for patients with MDD [8]. The initial session should stimulate at 110% to 120% of resting motor threshold (or 70% to 80% for theta-burst stimulation). The stimulation frequency and site should be selected (Table 2). Stimulations should be performed five times per week. The initial course is usually 20 sessions over a four-week period; this may be extended to 30 sessions (over six weeks) in non-remitting partial responders. Patients may return to this therapy as needed to maintain response.

Table 2: RECOMMENDED rTMS AND TBS PROTOCOLS IN MDD

Approach

Intensity and Site

First-line

HF-rTMS to left DLPFC

LF-rTMS to right DLPFC

Second-line

Bilateral rTMS to DLPFC (left HF and right LF)

LF-rTMS to right DLPFC (if nonresponse to left DLPFC HF-rTMS)

HF-rTMS to left DLPFC (if nonresponse to right DLPFC LF-rTMS)

TBS protocols:

- Intermittent TBS to left DLPFC

- Left intermittent and right continuous TBS to DLPFC

- Intermittent TBS to bilateral DMPFC

Third-line

HF-rTMS to bilateral DMPFC

DLPFC = dorsolateral prefrontal cortex, DMPFC = dorsomedial prefrontal cortex HF-rTMS = high-frequency rTMS, LF-rTMS = low-frequency rTMS, MDD = major depressive disorder, rTMS = repetitive transcranial magnetic stimulation, TBS = theta-burst stimulation.

Source: [8]

Unless otherwise stated, in the studies discussed in this section, HF-rTMS is applied to the left dorsolateral PFC, and LF-rTMS to the right dorsolateral PFC.

Most studies of rTMS in MDD have involved patients with some degree of treatment resistance (at least one to two failed antidepressant trials). Overall, rTMS is considered a first-line treatment for patients with MDD and at least one failed antidepressant trial [8].

Efficacy is established with both HF-rTMS and LF-rTMS of the left and right dorsolateral PFC, respectively. Differences in outcome are few, although LF may require shorter treatment duration. Non-responders of HF may respond to LF, and vice versa. Bilateral stimulation combines HF left and LF right dorsolateral PFC, but requires intensive setup but is not superior to unilateral approaches [8].

Evidence Based Practice Recommendation

A European consortium of experts found definite antidepressant efficacy of deep HF-rTMS over the left DLPFC in major depression.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: A (Definitely effective or ineffective based on at least two Class I studies or one Class I study and at least two Class II studies)

rTMS efficacy is established in treatment-resistant depression using the most stringent criteria. A meta-analysis of HF-rTMS in patients with treatment-resistant depression found significantly greater efficacy and effect size over sham [81]. randomized sham-controlled trials of HF-rTMS using adequate sessions (20 to 30) and treatment durations (≥4 weeks) achieved 40% to 55% response and 25% to 35% remission rates, similar to results of uncontrolled trials showing 58% response and 37% remission rates [82]. A meta-analysis also found superior remission rates with LF-rTMS (35%) versus sham (10%) [83].

HF-rTMS of the dorsomedial PFC (DMPFC) produces antidepressant effects. A randomized controlled trial found slightly better outcomes for DMPFC rTMS, while an uncontrolled trial of DMPFC rTMS reported 50% response and 36% remission rates [84,85,86].

Post-rTMS Maintenance of Efficacy

Relapse is frequent after successful rTMS without maintenance treatment. An uncontrolled study reported a median 120 days until relapse, with 25%, 40%, 57%, and 77% relapsing at 2, 3, 4, and 6 months, respectively [87]. In contrast, rTMS maintenance as needed over 12 months in 257 patients was able to sustain remission in 71% of remitters, and response in 63% of responders [88]. Another study found 38% of rTMS responders relapsed within 24 weeks (mean: 109 days post-treatment). With reinstatement of as-needed rTMS, 73% met response and 60% met remission at 24 weeks [89].

A 20-week gradual taper of maintenance rTMS (from 3 sessions/week to 1 session/month) was compared to no maintenance, and relapse rates were 38% with maintenance versus 82% without maintenance. Five "clustered" maintenance sessions over three days every month extended the mean relapse to 10.8 months [8,90,91].

rTMS versus ECT

The available evidence suggests ECT is generally more rapid and effective in antidepression effects, with greater side effects and lower patient acceptance than rTMS. An open-label study compared efficacy and patient acceptance of ECT versus rTMS in outpatients with treatment-resistant depression. While both therapies significantly improved depression scores, benefits were greater with ECT than rTMS, and anxiety symptoms decreased with ECT but not rTMS. Patients who received ECT reported they would have chosen rTMS if it had been financially available, even when informed rTMS was less effective than ECT for treatment-resistant depression. The authors stated this reflects the level of stigma that surrounds ECT [29].

A meta-analysis compared the efficacy of ECT and rTMS in MDD. ECT was superior to HF-rTMS in response (64.4% vs 48.7%) and remission (52.9% vs 33.6%), and discontinuation was similar (8.3% vs 9.4%). ECT was superior in psychotic depression, but HF-rTMS and ECT were comparable in non-psychotic depression. ECT had a slight advantage over rTMS in overall improvement in HAM-D scores. Data on medium or long-term efficacy was insufficient. The same results were found with ECT versus LF-rTMS. ECT led to greater impairment in cognitive domains such as visual memory and verbal fluency. ECT and rTMS seemed comparably effective in patients with MDD without psychosis, but ECT was more effective with psychotic depression [92].

Other meta-analyses found larger differences favoring ECT for all outcomes, especially in MDD with psychotic features. rTMS response is poor in patients with ECT failure, and rTMS should be considered before pursuing ECT because patients lacking ECT response are unlikely to benefit from rTMS [8].

rTMS and Antidepressants

rTMS has mostly been evaluated as an add-on therapy to stable antidepressant regimens, and no evidence shows outcomes are improved by discontinuing antidepressants before rTMS. However, some evidence suggests that initiating antidepressants during rTMS promotes higher response and remission rates than rTMS alone [8,83].

In patients with treatment-resistant depression receiving LF-rTMS, responders showed lower psychomotor retardation at baseline than non-responders, and ex-smokers showed substantially higher response rates than current smokers [93].

Adverse Effects

The most frequent adverse effects were scalp pain during stimulation (40%) and transient headache after stimulation (30%). Both diminish with repeated treatment, respond to over-the-counter analgesics, and resulted in few study dropouts. The cognitive safety profile of rTMS appears benign; studies that assessed rTMS and cognitive performance found no differences between active and sham rTMS [8,94].

Unresolved Issues

Although published evidence suggests that daily prefrontal rTMS has a significantly greater antidepressant effect than sham, with a magnitude of effect at least as large as antidepressant drugs, some issues remain unresolved [19]. The optimal hemisphere and position of coil placement remains unclear in depression treatment. Whether coil placement using individualized location via neuronavigated methods is superior to general algorithms for probabilistic positioning is not clear. Also, duration of rTMS treatment and patient follow-up are inadequate in many older studies.

Deep rTMS

Personality traits such as extraversion and neuroticism have attracted increasing attention as characteristics in predicting MDD response to pharmacotherapy, psychotherapy, and more recently, neuromodulation. Deep rTMS allows stimulation of deeper cortical regions, and the influence of personality dimensions in antidepressant response to deep rTMS in treatment-resistant depression was evaluated. After four weeks of daily deep rTMS (20 Hz, 3,000 pulses/session) of the left dorsolateral FPC, clinical remission was associated with higher baseline levels of agreeableness and conscientiousness. Levels of agreeableness and extraversion were linearly associated with antidepressant response. Neuroticism was not associated with antidepressant effects. Five-factor personality assessment may have prognostic value in deep rTMS for treatment-resistant depression, as agreeableness, extraversion, and conscientiousness were associated with reductions in depressive symptoms during treatment [95].

Theta-Burst Stimulation

A variation of rTMS is theta-burst stimulation. In MDD, theta-burst stimulation is delivered at lower intensities than rTMS (70% to 80% of active motor threshold) and requires only one to three minutes of stimulation [8]. Studies of both theta-burst stimulation types suggest lasting effects on cortical excitability that exceed standard rTMS. Increased cortical excitability with intermittent theta-burst stimulation has persisted longer than HF-rTMS. With continuous theta-burst stimulation, persistence in reduction of cortical excitability has been less consistent. Enthusiasm over the promising rapid effects on synaptic plasticity with theta-burst stimulation should be tempered by the highly variable patient response [19].

Small randomized controlled trials of dorsolateral PFC theta-burst stimulation showed superiority over sham with left intermittent theta-burst stimulation but not right continuous theta-burst stimulation, with bilateral stimulation (left intermittent/right continuous) showing mixed results. Data on bilateral DMPFC theta-burst stimulation suggest similar outcomes between intermittent theta-burst stimulation and longer conventional 10-Hz rTMS. Randomized controlled trial of conventional rTMS and theta-burst stimulation are in progress [8].

A randomized sham-controlled trial of 20 sessions found intermittent theta-burst stimulation safe, and resulted in immediate statistically significant decreases in depressive symptoms versus sham. After the two-week double-blind protocol, only 28% of patients showed ≥50% reduction in depression scores, but response rates increased to 38% an extra two weeks later to indicate delayed clinical effects. Importantly, 30% of the responders were in clinical remission. The findings suggest that only four days of accelerated intermittent theta-burst stimulation treatment in treatment-resistant depression may lead to meaningful clinical responses within two weeks post-stimulation [96].

Intermittent theta-burst stimulation was examined in a crossover randomized sham-controlled trial of 50 suicidal, antidepressant-free patients with treatment-resistant depression. Patients received 20 intermittent theta-burst stimulation sessions over four days, and the alternate condition (active or sham) at study day 7. This study found a significant decrease in suicide risk, lasting up to one month, unrelated to active or sham stimulation and unrelated to depression response. A high placebo response to sham was noted in those receiving sham intermittent theta-burst stimulation before they crossed over to active intermittent theta-burst stimulation. None of the patients committed suicide until six months after intermittent theta-burst stimulation treatment [97].

Magnetic Seizure Therapy

A randomized controlled trial of magnetic seizure therapy versus unilateral ECT found similar rates of response (60% vs 40%) and remission (30% vs 40%). A large uncontrolled magnetic seizure therapy trial reported a 69% response rate and a 46% remission rate, similar to published ECT outcomes [98,99]. Studies evaluating magnetic seizure therapy versus sham stimulation, relapse following magnetic seizure therapy, or relapse prevention await publication [8].

Magnetic seizure therapy has shown lower rates of headaches and muscle aches than ECT, without noticeable anterograde or retrograde amnesia. Reorientation time (time from seizure and anesthesia emergence to fully oriented by person, place, and time) was briefer with magnetic seizure therapy (2 to 7 minutes) than ECT (7 to 26 minutes). The sole randomized controlled trial in magnetic seizure therapy (versus unilateral ECT) found comparable neuropsychological testing results after 12 treatments [98,100].

TRANSCRANIAL DIRECT CURRENT STIMULATION IN MDD

The first published trial of tDCS in depressive disorders appeared in 2006. Almost all affective disorder studies have evaluated tDCS treatment in unipolar MDD [17,101].

The number of sessions, and anode/cathode polarity are thought to influence tDCS efficacy [16]. Most MDD have trials consist of placement of the anode over the left dorsolateral PFC and cathode over a noncortical region, or left dorsolateral PFC anodal stimulation combined with right dorsolateral PFC cathodal stimulation (bilateral tDCS). Minimum stimulation with 2 mA for ≥30 minutes per day over two weeks is required for an antidepressant effect.

With these parameters, six-week remission rates were higher in tDCS plus sertraline (47%) versus tDCS (40%) or sertraline (30%) alone, suggesting tDCS may potentiate antidepressant effects [102,103]. tDCS may also enhance psychotherapy outcomes [8,9]. Data from randomized sham-controlled trials suggest that multiple session tDCS can induce durable benefit in patients with MDD [16].

Treatment of Acute MDD Episodes

A review of six randomized sham-controlled trials found active tDCS significantly superior to sham in response (34% vs 19%), remission (23.1% vs 12.7%), and improvement in depression. Treatment-resistant depression and higher tDCS "doses" were negative and positive predictors of tDCS efficacy, respectively. The authors concluded the tDCS treatment effect size was comparable to those of rTMS and antidepressant drug treatment in primary care [104].

A meta-analysis of tDCS in MDD evaluated improvement in HAM-D scores, and a moderate-large effect size was found that favored active tDCS over sham. Two additional randomized sham-controlled trials were added, effect sizes were calculated for response and remission, and active tDCS was found not superior to sham in response or remission. Closer examination of the involved studies indicated that tDCS showed negative results in studies with high treatment resistance samples, and positive results in studies where subjects were lower in treatment non-response. Concurrent use of antidepressants, mood stabilizers, or benzodiazepines hampered patient response to tDCS. As such, tDCS seems efficacious for the treatment of depression, but it is not recommended in treatment-resistant depression or as an add-on to medication [75].

Maintenance of Acute Response

Several studies have evaluated persistence of acute effects and relapse following initial tDCS treatment, and strategies to prevent relapse. In one study, three months after completion of acute tDCS treatment, antidepressant effects persisted in almost half (47.8%) of patients without maintenance tDCS, and the need to prolong acute tDCS efficacy was noted [105].

Following clinical response to acute treatment, subjects received continuation tDCS every week for three months, and then every two weeks the final three months. Cumulative relapse-free survival was 83.7% at three months and 51.1% at six months; with decreased continuation tDCS at three months, relapse increased from 16.3% to 48.9%. Medication resistance was the greatest predictor of relapse during continuation tDCS [106].

Another study of tDCS relapse followed subjects 24 weeks. After response to acute treatment, subjects received up to nine tDCS sessions every two weeks for three months, followed by one tDCS session/month for three months. The mean response duration was 11.7 weeks, and relapse-free survival rate at 24 weeks was 47%. Patients with treatment-resistant MDD showed substantially worse 24-week survival versus patients with non-depression (10% vs 77%) [107].

tDCS versus Antidepressants

In a double-blind trial, patients with MDD were randomized to active tDCS, sham tDCS and fluoxetine 20 mg. More rapid improvement in depressive symptoms occurred with active tDCS than with fluoxetine, and after six weeks, active tDCS and fluoxetine showed the same improvement in depression scores and were significantly superior to sham [108].

Another study randomized 120 patients with MDD to active or placebo sertraline 50 mg plus active or sham tDCS in a four-arm trial. The combined active sertraline plus active tDCS was superior to all other groups, both groups with one active agent (sertraline or tDCS) did not differ and were superior to the group with placebo plus sham. Of note is that sertraline and tDCS were started concurrently in non-resistant patients, which could account for the additive effect rather than blocked response seen with tDCS as an add-on to stable but marginally ineffective antidepressants [109].

Side Effects

At present, tDCS trials are reviewed and conducted in accordance with the Non-Significant Risk U.S. Food and Drug Administration (FDA) designation for medical devices [80]. tDCS is generally well-tolerated. Frequent adverse events (>50%) include reddening of the skin, itching, burning, heat, and tingling sensations at the site of electrode placement. Sporadically reported adverse events with similar rates between active tDCS and sham include nausea, euphoria, reduced concentration, and anxiety. Study dropout rates from adverse events are comparable for tDCS and sham (both 3%), but long-term data on safety and tolerability are lacking [8]. No post-acute side effects emerged during follow-up in the longer-term maintenance studies [105].

tDCS is recommended as a third-line treatment for MDD, with more research needed to establish optimal stimulation parameters [8]

7. NEUROMODULATION FOR OTHER MENTAL HEALTH DISORDERS

NEUROMODULATION FOR BIPOLAR II DEPRESSION AND BIPOLAR DISORDER

The depressive phase of bipolar disorder has few published studies, and treatment of manic symptoms in even fewer studies. Brain stimulation in bipolar disorder has used the parameters in unipolar depression treatment, but important differences between the two disorders require tailored stimulation for bipolar disorder [110].

In patients with bipolar II depression, quetiapine plus four weeks of HF-rTMS, LF-rTMS, or sham found quetiapine/active rTMS did not differ from quetiapine/sham on any outcome measure [111]. The few tDCS studies in bipolar depression or mania found some support but used small patient numbers [17,101].

ANXIETY DISORDERS AND ANXIETY-RELATED DISORDERS

Unless stated otherwise in this section, rTMS targets are HF-rTMS of the left dorsolateral PFC, and LF-rTMS of the right dorsolateral PFC. The efficacy of rTMS in anxiety symptom reduction was evaluated in 14 randomized sham-controlled trials, primarily involving patients with PTSD or OCD. Active TMS was not clinically or statistically superior to sham in reducing anxiety symptoms in patients with OCD, PTSD, or panic disorder [112]. It should be noted that while clinically relevant anxiety can be present in patients with PTSD or OCD, these conditions are no longer classified as anxiety disorders by the DSM-5-TR because their core features differ in pathological basis and clinical presentation from anxiety disorders (e.g., GAD, panic disorder) [28].

Few studies have evaluated tDCS in anxiety disorders. However, tDCS modulation of dorsolateral PFC activity led to significant reductions in fear vigilance to threatening stimuli, similar to that observed with anxiolytic treatments. This finding that tDCS acutely altered the processing of threatening information suggests a potential mechanism that could be harnessed for treatment of clinical populations. These results were obtained from healthy volunteers [113].

Generalized Anxiety Disorder

A randomized sham-controlled trial evaluated 30-session (over six weeks) LF-rTMS in 25 patients with GAD. Patients undergoing active rTMS (versus sham) experienced higher response rates (71% vs 25%) and significant reductions in anxiety, worry, and depressive symptoms. At three months post-rTMS, 43% of active rTMS patients showed remission, versus 8% with sham. Response rates with active rTMS were maintained during follow-up, with some additional gains in remission rates. At post-treatment, right dorsolateral PFC activation was increased for active rTMS only, and changes in neuroactivation significantly correlated with changes in worry symptoms. These findings provide preliminary evidence that rTMS may improve GAD symptoms by modifying neural activity in the stimulation site [114].

A secondary analysis study was performed to determine if dorsolateral PFC neuromodulation improved emotion regulation in patients with GAD [114]. Statistically significant improvements in self-reported emotion regulation difficulties were found at post-treatment and three-month follow-up with active rTMS only. Improvements primarily involved the domains of goal-directed behaviors and impulse control, and were significantly associated with global clinician ratings of improvement. These preliminary results support rTMS as a treatment for GAD and suggest improved emotion regulation as a possible mechanism of change [34].

Bilateral LF-rTMS was evaluated in 13 patients with comorbid GAD and MDD, who received 24 to 36 rTMS sessions over five to six weeks. Following the last treatment, 11 of 13 (84.6%) patients achieved remission in anxiety symptoms (<5 on the GAD-7), and 10 of 13 patients (76.9%) achieved remission in depressive symptoms (<8 on the HAM-D). In this small pilot study, most patients with comorbid GAD/MDD achieved significant improvement in anxiety and depressive symptoms after bilateral rTMS [115].

Panic Disorder

In two randomized sham-controlled trials of LF-rTMS, patients with panic disorder were treated for two or four weeks as augmentation therapy. Active rTMS was superior to sham in reducing panic symptoms in one trial, and all patients showed improvement with no differences between active and sham in the other trial. The available data were insufficient to draw conclusions about rTMS efficacy in panic disorder [14].

Deep rTMS and Anxiety Reduction

The anxiolytic effects of deep rTMS in MDD patients were reviewed. Data from six open-label studies found that relative to baseline, large anxiolytic and antidepressant outcomes were obtained after 20 daily sessions of high-frequency deep rTMS. Unlike the antidepressant effect, anxiolytic effects were more heterogeneous across studies, and unrelated to concurrent antidepressant treatment [116].

POST-TRAUMATIC STRESS DISORDER

In 20 veterans, LF-rTMS for 10 sessions led to significant improvement in core symptoms of PTSD and depression versus sham. Improvements persisted for two months post-rTMS, and declined over time [117].

A meta-analysis of five randomized sham-controlled trials found rTMS significantly superior to sham in reducing PTSD core symptom scores. No single stimulation frequency (1 Hz vs 20 Hz) target (left vs right dorsolateral PFC) or mode (rTMS vs deep TMS) differed markedly in effect [118].

In a chart review of 10 patients who received five treatments of 5-Hz rTMS for comorbid PTSD and MDD, significant reductions were observed in 80% patients for PTSD symptoms, and 60% patients for MDD symptoms. The intermediate pulse frequency of 5-Hz may be effective in patients with PTSD and serious comorbidity and was well-tolerated without serious adverse effects [119].

Deep rTMS in PTSD

Following three sessions per week for four weeks of deep rTMS or sham to the medial prefrontal cortex (mPFC) in 30 patients with PTSD, significant improvement in intrusive symptoms was observed (mean reduction: 31%) with active but not sham deep rTMS. This suggested the potential of deep rTMS to treat core PTSD symptoms and suggests a role of mPFC hypoactivity in presentation of the disorder [40,120].

OBSESSIVE-COMPULSIVE DISORDER (OCD)

rTMS and tDCS have been increasingly researched in OCD. In clinical trials, LF-rTMS of the supplementary motor area, orbital frontal cortex, or right dorsolateral PFC shows the most promising efficacy, while older studies targeting the prefrontal dorsal cortex were not as successful. Larger-scale investigations of tDCS have yet to be published in OCD [1].

Patients with OCD were randomized to rTMS frequencies of 1 Hz, 10 Hz, or sham of the right dorsolateral PFC for 10 sessions. Patients were assessed after the last session and three months later. Compared with 10 Hz or sham, 1 Hz led to significantly greater improvements in obsessive-compulsive and anxiety symptoms, greater clinical benefit, and significantly larger percentage change in global improvement. One Hz LF-rTMS of the right dorsolateral PFC is a promising treatment approach in OCD [121].

The efficacy of rTMS in OCD was evaluated by reviewing 15 randomized sham-controlled trials. rTMS was significantly superior to sham for OCD symptom reduction. The risk of publication bias was low, and between-study heterogeneity was low. Meta-regression showed no particular influence of any variable on the results. In all, rTMS was superior to sham for amelioration of OCD symptoms [122].

In two trials, patients with treatment-resistant OCD received rTMS or sham for two and four weeks. Compared with sham, active rTMS led to significantly greater improvements in symptom severity; and cognitive performance in auditory perception, visual perception, short-term memory, and processing speed [123,124].

TOURETTE SYNDROME

Open-label trials suggested LF-rTMS of the supplementary motor area in patients with Tourette syndrome may be effective, but a randomized sham-controlled trial found no benefit [125].

SCHIZOPHRENIA WITH AUDITORY VERBAL HALLUCINATIONS

In rTMS studies of patients with schizophrenia with auditory verbal hallucinations, evaluation of placebo response found a significant effect size of placebo response in parallel studies but not crossover studies. The authors suggest that placebo effect should be considered a source of bias in open-label trials and randomized sham-controlled trials without documented efforts to improve concealment of active rTMS [126].

Studies of rTMS treatment in schizophrenic symptoms such as auditory hallucinations have found contradictory results. A review of 10 randomized sham-controlled trials using LF-rTMS reported a positive effect size favoring rTMS over sham, with the left temporoparietal cortex appearing an effective target [127]. Studies published after 2013 were not available for this review. A study of HF-rTMS to the left temporoparietal cortex over 2 days found no difference between active rTMS or sham [128]. The overall sham-controlled outcomes of rTMS to the left temporoparietal cortex are mixed; even when rTMS was effective following 10 sessions, treatment effect began dissipating one month later [129].

Auditory verbal hallucinations are commonly observed persistent symptoms in schizophrenia, even when patients are stabilized by antipsychotic medication. The primary indication for tDCS in psychotic disorders is reduction of auditory verbal hallucinations. Eliminating or reducing these debilitating residual symptoms requires inhibition of neuronal activity of the left temporoparietal junction (TPJ) that mediates auditory verbal hallucinations [17].

Most tDCS treatment studies in schizophrenia have used anode placement over the l-dorsolateral PFC and the cathode over the left TPJ. After 10 twice-daily sessions, this placement has been consistently shown in sham-controlled randomized controlled trials to ameliorate symptoms of the illness, with robust reductions in auditory verbal hallucinations at acute and three-month follow-up, improvements in other schizophrenic symptoms, and substantive decreases in treatment-resistant auditory verbal hallucination frequency. Further support for this tDCS protocol comes from uncontrolled trials of schizophrenic patients with persistent auditory verbal hallucinations, with significant reductions in psychotic and auditory verbal hallucination symptoms reported. Several case reports described refractory schizophrenic patients who achieved responses ranging from significant reductions in psychotic and auditory verbal hallucinations, to full remission. Greater therapeutic response in nonsmokers was noted [16].

In a randomized sham-controlled trial of tDCS to the left TPJ in patients with schizophrenia with auditory verbal hallucination and negative symptoms, acute beneficial effects in negative symptoms and prolonged (up to three months) reductions in auditory verbal hallucination were observed with active tDCS [130].

Active vs sham frontotemporal tDCS was evaluated by functional MRI for effects on auditory verbal hallucinations and resting-state functional connectivity of the left temporo-parietal junction in schizophrenic patients. Reductions in hallucination severity following active tDCS correlated with decreased functional connectivity between the left TPJ, the left anterior insula and the right inferior frontal gyrus; and with increased functional connectivity between the left TPJ, the left angular gyrus, left dorsolateral PFC and the precuneus, regions that mediate language-related and self-other recognition networks [131].

A series of motor-evoked potential studies in schizophrenic patients found diminished excitability and enhanced neuroplasticity with anodal or cathodal tDCS [17].

SCHIZOPHRENIA, NEGATIVE SYMPTOMS

Earlier meta-analyses found rTMS benefitted negative symptoms, with effect sizes ranging from non-significant and small to very large. This large range reflected differences in study duration, stimulus frequency, outcome measures, and illness duration [42]. A randomized sham-controlled trial found treatment response with active rTMS was sustained over 24-week follow-up, but a large, randomized sham-controlled trial failed to show greater benefit with active versus sham rTMS [132,133]. Many factors known to influence rTMS response make it difficult to reconcile negative findings with those from numerous earlier reports [42].

In patients with schizophrenia with predominant negative symptoms, 15 sessions of 10-Hz rTMS to the left dorsolateral PFC for three weeks was not superior to sham for improving schizophrenic cognitive domains, in contrast to previous preliminary findings [134].

A randomized sham-controlled trial evaluated 2 mA tDCS of the bilateral dorsolateral PFC. After 10 daily sessions, statistically significant reductions in PANSS negative, general, and total scores occurred with active tDCS, but not sham [135].

tDCS-induced neural changes, measured by EEG oscillations, were assessed in patients with schizophrenia following tDCS to the left dorsolateral PFC. A significant increase in gamma synchronization in the dorsolateral PFC was found with 2-mA tDCS but not 1-mA or sham. Increased gamma synchronization correlated with improved working memory performance, suggesting that 2-mA tDCS may modulate neural synchrony, and restore neural and behavioral functioning in schizophrenia [136].

Building on this, 20 patients with schizophrenia with predominant negative symptoms were randomized to 10 sessions of active 2-mA or sham tDCS to the left dorsolateral PFC and received imaging by functional connectivity MRI (fcMRI). Negative symptom scores decreased 36% with tDCS (sham: 0.7%). Analysis of MRI indicated changes in subgenual cortex and dorsolateral PFC connectivity within frontal-thalamic-temporo-parietal networks in the active but not sham group [137].

Smoking Status and tDCS Response

The rate of current tobacco use disorder in clinical samples of patients with schizophrenia is 62%, significantly higher than in the general population and in other psychiatric disorders [138]. This high prevalence is thought to arise from nicotine-induced improvements in working memory, selective attention, and cognitive impairments in patients with schizophrenia. These nicotine effects are linked to stimulation of the alpha7-nicotinic acetlycholine receptor, which enhances thalamo-cortical functional connectivity and dopamine release regulation. Nicotine can modify neuroplasticity, and in contrast to nonsmokers, single-session, excitability-diminishing cathodal tDCS does not induce plasticity in patients with schizophrenia who smoke [139].

Neural plasticity induced by tDCS may differ between patients with schizophrenia who do and do not smoke. This was explicitly investigated in the first-ever study that evaluated the effects of cigarette smoking on tDCS response in patients with schizophrenia. Patients with schizophrenia with treatment-resistant auditory verbal hallucination received 10 sessions of frontotemporal tDCS (2 mA). Auditory verbal hallucinations symptoms decreased 20% in the entire sample, 46% in nonsmokers, and 6% in smokers. When response was defined as ≥25% symptom reduction, 83% of non-smokers vs 20% of smokers were responders. tDCS had no effect on cigarette use. This was the first published report to describe the impairing effect on tDCS response and efficacy in patients with hallucinatory schizophrenia who are actively smoking. Adjustment for age, medication use, and illness duration did not impact this effect [140].

Combined Therapies in Refractory Schizophrenia

Many (40% to 70%) patients with treatment-resistant schizophrenia remain symptomatic despite an adequate clozapine trial [141]. Brain stimulation approaches are promising for these patients, but clozapine co-administration has raised safety concerns. Studies have been reviewed to determine if this safety issue was resolved. While ECT is effective in clozapine-refractory schizophrenia, safety with the combination is not known. Until sufficient data accumulate, vigilance for adverse effects related to lowered seizure threshold, cognitive impairment, and cardiovascular events is required. In patients receiving clozapine, HF-rTMS over the dorsolateral PFC and LF-rTMS over the temporo-parietal cortex are safe, but efficacy is uncertain [141].

SUBSTANCE USE DISORDERS

The dorsolateral PFC plays a key role in self-regulatory control mechanisms and is a common brain stimulation target in disorders of fronto-limbic dysregulation. rTMS of the dorsolateral PFC has demonstrated potential in reducing addictive behaviors and craving for nicotine, alcohol, and cocaine [46].

Placement of right-anodal plus left-cathodal tDCS over the bilateral dorsolateral PFC has reduced a variety of substance cravings in patients with substance use disorders, and bilateral stimulation with both polarities may be equally effective [142]. tDCS can enhance patient ability to inhibit potent responses, a clinical important finding because impaired inhibitory control contributes to relapse in patients with substance use disorder [17].

Smoking Cessation/Tobacco Use Disorder

Relapse is common within days after smoking cessation, and combining the anti-craving effects of rTMS with nicotine replacement therapy (NRT) may attenuate withdrawal symptoms and craving to increase abstinence rates in smokers with severe nicotine dependence attempting to quit [143].

The day after quitting, smokers who failed to quit with standard treatments started NRT (21-mg patch) and received active 1-Hz rTMS or sham of the right dorsolateral PFC (10 sessions) for two weeks. Abstinence rates and craving were measured during combined treatment and up to 12 weeks after quitting. At the end of combined treatment, more participants were abstinent with active rTMS (89%) than sham (47%). Compulsive craving was significantly decreased with active rTMS but not sham, but no lasting effect was found [143].

Similar results were shown by an earlier randomized sham-controlled trial of 10-Hz rTMS to the left dorsolateral PFC for 10 daily sessions. Active rTMS, but not sham, led to significantly reduced cigarette consumption and blocked craving during treatment, but the effects dissipating after the rTMS sessions ended [144].

Deep rTMS was evaluated in 115 smokers randomized to 13 daily sessions of HF, LF, or sham deep rTMS to the lateral PFC and bilateral insula. HF (but not LF or sham) deep rTMS significantly reduced cigarette consumption and nicotine dependence. The combination of high-frequency deep rTMS and exposure to smoking cues enhanced cigarette reduction, with abstinence rates of 44% at the end of the treatment and 33% at six-month follow-up [145].

Results from two studies provided data to encourage larger trials in determining the clinical usefulness of this intervention. A single-session randomized sham-controlled trial of 1-mA anodal stimulation over the left dorsolateral PFC found that active tDCS (versus sham) significantly increased latency to smoking and decreased total number of cigarettes smoked [146].

Cathodal tDCS stimulation is a way to manipulate cortical excitability through inhibition. tDCS inhibition of the frontal-parietal-temporal association area (FPT) was examined for effects on attention bias to smoking-related cues and smoking behavior in a small short-term trial. Bilateral cathodal tDCS stimulation of the FPT area modestly decreased attention to smoking-related cues and significantly decreased daily cigarette use [147].

Alcohol Use Disorder

Most rTMS studies in alcohol use disorder have investigated craving but not drinking reduction. As with studies in nicotine dependence, most used HF-rTMS to target the dorsolateral PFC. The effect of rTMS on craving for alcohol was mixed, with some studies showing an effect while others do not [12].

More promising results came with using H-coil rTMS, but these were preliminary open trials. A small study of bilateral H coil stimulation of the PFC in patients with comorbid alcohol use disorder and dysthymic disorder found improvements in depressive symptoms and reductions in craving for alcohol. Another pilot study using H-coil stimulation of the medial PFC reported decreased alcohol intake by mean drinks per day and mean drinks on days of maximum alcohol use [12].

Four sessions of HF-rTMS was evaluated in a randomized sham-controlled trial of 17 residents of an alcohol detoxification program. At one-month follow-up, active (but not sham) HF-rTMS led to significantly decreased depressive symptoms and fast EEG frequencies, significantly increased inhibitory control and executive function, but no effect was found on craving or drinking reduction [148].

Published randomized controlled trials of tDCS in alcohol use disorder have shown mixed results. In 13 subjects with alcohol use disorder, one session of tDCS to the bilateral dorsolateral PFC significantly decreased alcohol craving (versus sham), which remained suppressed during exposure to alcohol cues [149].

In a relapse reduction study, 33 outpatients with severe alcohol use disorder received twice-daily 2 mA tDCS to the bilateral dorsolateral PFC for five days. At six-month follow-up, tDCS did not diminish craving, but 50% treated with active tDCS versus 11.8% with sham remained alcohol-abstinent. Active tDCS also led to improved perception of quality of life [150].

A disconnect between alcohol craving and alcohol use was also reported in a study of 13 patients with alcohol use disorder who received five weekly sessions of anodal tDCS to the left dorsolateral PFC. Active tDCS suppressed cravings but showed an unexpected trend for more frequent relapse; neither was found with sham [151].

Stimulant Use Disorders

Very promising results came from a pilot study in which 18 subjects with cocaine use disorder received 12 sessions of 10-Hz H-coil rTMS or sham to the bilateral PFC. After four weeks of stimulation, cocaine use in active and sham groups both decreased without difference, but decreases in cocaine use showed a significant difference at three months and six months post-baseline favoring the active rTMS group. Transient mild headaches were reported during stimulation [152].

Patients with addiction to crack cocaine received five sessions of active or sham bilateral dorsolateral PFC stimulation. The active tDCS group showed a higher percentage of abstinence at three-month follow-up versus sham [153]. This study protocol was replicated in a larger group of patients whose crack cocaine cravings were suppressed for at least one week by active versus sham tDCS. Effects on crack cocaine use were not studied [154].

Abstinent methamphetamine users received single-session anodal tDCS or sham to the right dorsolateral PFC. Active tDCS acutely reduced craving at rest, but significantly increased methamphetamine craving during methamphetamine-related cue exposure. Neither effect was found with sham [78].

Mixed Substance Abuse Disorders

The effect of rTMS on craving in substance addiction was evaluated in a review of eight randomized sham-controlled trials. Active TMS was significantly superior to sham, but only in studies targeting the right dorsolateral PFC with HF-rTMS. This finding was consistent throughout the reviewed studies [155].

EATING DISORDERS

Eating behavior and eating disorder treatment is an area of study in noninvasive neurostimulation, and the sole evaluated modalities are rTMS and tDCS. The dorsolateral PFC is a complex brain region involved in executive functions that support cognitive control of food intake. Enhanced dorsolateral PFC activity may alter the reward-cognition balance toward facilitation of cognitive control, and possible suppression of reward-related mechanisms that drive food craving and overeating [10].

Anorexia Nervosa

The dorsolateral PFC is implicated in emotion regulation. HF-rTMS may improve food restriction and other maladaptive emotion regulation strategies in anorexia nervosa by remediating prefrontal region hypoactivity associated with poor impulse control and impaired cognitive flexibility in anorexia nervosa [46].

In a uncontrolled trial, 10 patients with anorexia nervosa received single-session HF-rTMS to the left dorsolateral PFC, and showed short-term improvements in anxiety, feeling full, and feeling fat [156]. In patients with chronic anorexia nervosa receiving HF-rTMS to the left dorsolateral PFC, significant improvements in eating disorder symptoms and mood were found after six months in 60%, with 40% deemed "recovered" based on psychometric scores. However, most participants lost weight, and therapeutic effects on psychopathology waned by 12 months [157].

Bulimia Nervosa

Several single-session rTMS studies in small numbers of patients with bulimia were performed, and reported positive short-term effects of reduced binge-eating episodes and food craving [46]. Sham-controlled single-session studies of HF-rTMS of the left dorsolateral PFC reported inconsistent effects, with positive effects reported in one study of 38 patients and no effects in a study of 10 patients [158,159]. Randomized controlled trial with sham control using 20 rTMS sessions did not find benefit beyond sham [46,160].

Binge-Eating Disorder

A trial of 30 subjects with binge-eating disorder evaluated singles-session 2-mA tDCS or sham to the dorsolateral PFC. Compared with sham, tDCS decreased craving for sweets and savory proteins with greatest reductions in men; decreased total and preferred food intake by 11% and 17.5% regardless of sex; and reduced desire to binge eat in men on the day following active tDCS. Reductions in craving and food intake were predicted by eating less often for reward motives, and greater intent to restrict calories, respectively. The findings of enhanced cognitive control and/or decreased need for reward may reflect tDCS action on functional mechanisms, and should be further researched [48].

DEPERSONALIZATION/DEREALIZATION DISORDER

Patients with chronic refractory depersonalization/derealization disorder received 17 to 20 sessions of LF-rTMS to the right ventrolateral PFC (VLPFC) over 10 weeks. Mean depersonalization symptom scores decreased 44.4%. After one session, 71% of patients showed partial response (symptom reduction ≥25%). After trial completion, 28% of patients showed full response (symptom reduction ≥50%), 57% had partial response, and 14% had no response. Mean anxiety scores decreased 28.4% from baseline. Side effects were transient mild headache [52].

Several subjects showed transient disinhibitory behaviors immediately after rTMS, including wearing the physician's jacket, labile affect, spontaneous laughter without apparent origin, and spontaneous discussion of provocative subjects. None were persistent or clinically concerning. Patients commented the measuring scales that assessed treatment response did not capture the phenomenological changes they experienced [52].

EXTERNAL TRIGEMINAL NERVE STIMULATION (eTNS)

eTNS is an emerging external neuromodulation approach originally developed for refractory seizures. Early evidence of safety and improved mood led to trials in MDD. Brain projections of the trigeminal system suggest eTNS may alter activity in structures regulating mood, anxiety, and sleep [161].

MAJOR DEPRESSIVE DISORDER

Initial open-label trials showed response rates of 54.5%, 75%, and 100%, and remission rates of 63.6% and 90.9%. A randomized sham-controlled trial of 40 patients found high placebo response to sham, but active eTNS still led to a significant mean reduction of 6.36 points in HDRS scores versus sham. An open-label eTNS trial in older patients with MDD (mean age: 73 years) found 80% response and 40% remission rates [163].

PTSD AND COMORBID MDD

Patients with PTSD and comorbid MDD received eTNS eight hours nightly for eight weeks as a pharmacotherapy adjunct. After eight weeks, significant improvement was found in depression, core PTSD symptoms, and quality-of-life measures. eTNS was well-tolerated with few adverse events [161]. Another open-label eTNS trial in comorbid PTSD/MDD reported the same positive outcomes [162].

PANIC DISORDER

Seven patients with panic disorder received ten daily sessions of TNS. At day 10, panic disorder symptom severity showed a significant decrease from baseline, remaining stable at follow-up day 45. Significant global clinical gains were also reported at days 10 and 45. Cognitive function was unchanged. All patients reported mild paresthesia underneath the electrodes during stimulation. One patient dropped out after four sessions from stimulation-related headaches. No other adverse events were observed [164].

eTNS is well-tolerated, without reports of serious adverse events or changes in cognitive performance. These data, while impressive, mostly come from small, short-term uncontrolled trials [23,24,163].

8. INVASIVE NEUROSTIMULATION

Most invasive neurostimulation studies in psychiatric disorders have been performed in treatment-resistant MDD, but this is currently expanding into refractory Tourette syndrome, OCD, and addictive disorders.

VAGUS NERVE STIMULATION

The FDA approved VNS in 2005 as adjunctive therapy in refractory MDD with four or more failed adequate antidepressant trials. Some studies below also enrolled patients with treatment-resistant bipolar depression, and VNS outcomes were similar for both [165].

Worth noting in the VNS studies is the severity of MDD in the patient population, distinguished by chronicity (average duration of illness: >25 years, and current episode: 7 years), treatment-resistance (average of seven drug failures, and ECT failure in >50%), high rates of lifetime hospital admissions and suicide attempts [165]. However, VNS was found ineffective in patients with eating disorders or schizophrenia [10,166].

Dose Response

VNS "dose" is measured by electrical output, in mA of current. A comparison of low (0.25 mA), medium (0.5–1.0 mA) and high (1.25–1.5 mA) dose VNS found greater improvement in depressive symptoms with higher doses, greater sustained antidepressant response and less frequent suicide attempts with medium- and high-dose versus low-dose VNS [167].

Efficacy

Open-label studies found an average 31.8% response rate, but a randomized sham-controlled trial found no difference between VNS and sham at 12 weeks [168]. VNS efficacy may increase over time, and six trials comparing VNS to treatment as usual found at 12, 24, 48, and 96 weeks that VNS/treatment as usual remission rates were 3%, 5%, 10%, and 14% versus 1%, 1%, 2%, and 4% for treatment as usual alone [169]. Median time to VNS response was nine months in one study. In patients with response by 3 months (35%), response was maintained by 61.5% at 12 months, and 50% at 24 months [170,171].

High retention and low dropout rates suggest that patients without measurable response or remission gain therapeutic benefits undetected by depression rating scales [165]. Higher success rates with VNS in treatment-resistant depression were reported with careful patient selection to screen out comorbid personality disorders or active substance use disorders [26].

Adverse Effects

The most common adverse events after one year of VNS were voice alteration (69.3%), dyspnea (30.1%), pain (28.4%), and increased cough (26.4%), mostly from active VNS and resolved by halting stimulation. VNS tolerability improves over time, and adverse effect reports diminish. Compared to treatment as usual, patients with treatment-resistant depression receiving VNS showed lower all-cause mortality rates, including suicide [8].

DEEP BRAIN STIMULATION

Treatment-Resistant Depression

Deep brain stimulation treatment for treatment-resistant depression remains investigational. Deep brain stimulation is mostly used to augment antidepressants, and few patients are free of psychotropic drugs when implanted [8]. The main deep brain stimulation brain targets are [8]:

- Subcallosal cingulate white matter

- Ventral capsule/ventral striatum (VC/VS)

- Nucleus accumbens

- Medial forebrain bundle

The most common target in treatment-resistant depression is the subcallosal cingulate. Patients in deep brain stimulation trials are refractory to antidepressants, psychotherapy, and (often) ECT [8].

Short-term outcomes with deep brain stimulation show 30% to 60% response rates and 20% to 40% remission rates at three or six months, and medial forebrain bundle deep brain stimulation in seven patients reported response and remission rates of 85.7% and 57.1% [172,173].

As with VNS, two randomized sham-controlled trials of deep brain stimulation were halted early from lack of benefit, later seen as premature with recognition that efficacy increases with longer stimulation [8]. Outcomes of four studies showed depression severity was significantly reduced by 12 months. At 3, 6, and 12 months, response rates were 36.6%, 53.9%, and 39.9%, with remission rates 16.7%, 24.1%, and 26.3% [174].

Subcallosal cingulate deep brain stimulation studies of greater than one year duration reported response rates of 36% and 92% at one and two years, and a 58% remission rate at two years. A longer trial reported 62.5%, 46.2%, and 75% response rates at one, two, and three years, with 20% and 40% remission rates at two and three years. Long-term subcallosal cingulate and medial forebrain bundle deep brain stimulation led to improved health-related quality of life [173,175,176].

Maintaining Response

A small trial suggested that maintaining remission requires ongoing deep brain stimulation. Patients were treated to remission with subcallosal cingulate deep brain stimulation, and then randomized to on/off or off/on stimulation for three months. Most patients relapsed with deep brain stimulation turned off, and none with deep brain stimulation on [177].

Adverse Effects

Adverse events during long-term deep brain stimulation have been secondary to implantation (e.g., intracranial hemorrhage), perioperative risks (e.g., wound infection), effects of specific brain region stimulation, or deep brain stimulation parameters. Deep brain stimulation is generally well tolerated despite the risks of invasive neurosurgical procedures, and the pooled one-year dropout rate with subcallosal cingulate deep brain stimulation was 10.8%. Worsening neuropsychological performance has not been observed with any brain target, but improved cognitive performance has been reported [174].

Transient psychosis and hypomania have emerged when changing parameters during nucleus accumbens stimulation, resolved by switching parameters. No hypomania episodes were reported with subcallosal cingulate deep brain stimulation, including patients with bipolar disorder. Oculomotor adverse events of blurred vision and strabismus occurred in all patients receiving higher amplitude medial forebrain bundle deep brain stimulation. Reports of suicidality and completed suicide were deemed not device-related, but risk of suicidality may be increased by a history of pre-deep brain stimulation suicidality or major life stressors [8].

Tourette Syndrome

Deep brain stimulation is an emerging treatment option for patients with severe refractory Tourette syndrome. In 156 published cases, deep brain stimulation led to an overall 52.68% improvement of symptoms. Outcomes of controlled trials significantly favored stimulation versus sham. Significant symptom reductions were found across deep brain stimulation targets, with no differences in outcome indicating modulation of a common network. Despite the small patient numbers, deep brain stimulation for Tourette syndrome is a valid option for medically intractable patients [178].

Treatment-Resistant Obsessive-Compulsive Disorder

Deep brain stimulation efficacy in severe, refractory OCD was reviewed in 25 trials. Outcome was change in Y-BOCS scores; response was ≥35% improvement in Y-BOCS (Table 3) [41]. Reported adverse effects included serious events during surgery (i.e., two seizures, three intracerebral hemorrhages), device-related adverse events, and stimulation-related events. Device-related events included breaks in stimulation leads and battery failure resulting in acute psychiatric symptoms until replacement [41]. Stimulation-related adverse events were acute increases in anxiety and hypomania, induced by changing stimulation parameters or battery depletion. All cases resolved with parameter adjustment. Cognitive problems resolved with time or parameter adjustment. No personality changes during deep brain stimulation were observed.

Table 3: DEEP BRAIN STIMULATION (DBS) TARGET OUTCOMES IN OCD

Trial Characteristics

ALIC

Nucleus Accumbens

Ventral Capsule/Ventral Striatum

Subthalamic Nucleus

Inferior Thalamic Peduncle

Number of trials

5

8

4

5

1

Follow-up, months

23–51

3–24

12–36

3–6

36

Mean DBS response rate

75%

45.5%

50.0%

57.1%

100%

Mean reduction in Y-BOCS

46.5%

37.8%

41.5%

45.3%

82.5%

ALIC = anterior limb of the internal capsule.

Source: [41]

Neural circuits involved in OCD and depression include the VC/VS and anterior cingulate gyrus. VC/VS deep brain stimulation combined with anterior cingulotomy was evaluated in patients with refractory OCD and MDD. Mean baseline Y-BOCS scores were 34.7, decreasing to 23.0 at three months, and stable two years post-surgery at 19.0. These outcomes were comparable, but not superior, to published outcomes for VC/VS deep brain stimulation alone, and deep brain stimulation may be sufficient to control refractory OCD [179].

Substance Addiction

A few small deep brain stimulation studies have been performed in severely addicted patients. Five severely alcohol dependent patients received nucleus accumbens deep brain stimulation. Followed an average 38 months, all five showed significant craving reductions, two remained abstinent for more than four years, and three had truncated relapses [180]. Two patients with heroin dependence received nucleus accumbens deep brain stimulation; depressive and anxiety symptoms improved, with drug use reduced but not ceased [181].

9. NEUROMODULATION IN CHRONIC PAIN

Pain processing in the brain is not limited to one area or sensory system. The cerebral pain processing neural network is complex, and mediates the vegetative, sensory-discriminative, affective, and cognitive aspects of pain. The vegetative and neuroendocrine effects of pain perception are mainly linked to subcortical regions such as the amygdala and hypothalamus. The sensory-discriminative aspects of pain involve the spinothalamic tract, lateral thalamus, somatosensory areas, and the posterior insula with input from the descending corticothalamic pathways originating in the motor cortex. The affective/cognitive processing of pain involves the anterior insula, cingulate cortex, and prefrontal regions [18,182].

Brain stimulation is not usually considered for acute nociceptive/inflammatory pain, because the standard of care involves resolution of the underlying cause [13]. Brain stimulation is solely used in chronic pain, typically in patients for whom standard therapies have failed to relieve pain. In most forms of chronic pain, the mechanisms that generate pain have dissociated from the original peripheral tissue injury source. Instead, pain is perpetuated by alteration in CNS structures involved in transmitting, processing and response to pain signals. Alteration in these regions is termed central sensitization [183].

OVERVIEW OF NONINVASIVE BRAIN STIMULATION IN PAIN

In the early 1990s, epidural motor cortex stimulation (eMCS) showed repeated efficacy in pharmaco-resistant neuropathic pain. These methods were adopted by TMS researchers in chronic pain using stimulation to the primary motor cortex (M1) and precentral gyrus in the hemisphere contralateral to pain [27]. Stimulation parameters were refined over time to maximize efficacy. An early 10-day protocol of 5 Hz rTMS of M1 in patients with diverse chronic neuropathic pain reported minimal benefit, the result of using low frequency (5 Hz) stimulation and small number of pulses (500) per session. A subsequent five-day protocol of 20 Hz HF-rTMS of M1 led to durable pain reduction in patients with post-stroke pain, trigeminal neuropathic pain, and phantom limb pain [19].

Several rTMS targets have been evaluated in neuropathic pain, and M1 is preferable to premotor or primary somatosensory cortical regions. In refractory pain, dorsolateral PFC stimulation is less studied, despite efficacy of this target in depression and the established link between depression and chronic pain [19].

When used in pain treatment, a figure-8 coil delivering biphasic pulses should be placed over the precentral gyrus (M1) contralateral to the painful side with a posteroanterior orientation [13,27]. HF-rTMS (10–20 Hz) is used to activate projecting axons and local interneurons and applied below the motor activation threshold to avoid inducing muscle contractions. Focal neuropathic pain can be relieved by HF-rTMS (but not LF-rTMS) to the contralateral M1 area. Repeated rTMS sessions can induce cumulative pain reductions for at least several weeks following 10 consecutive sessions, but optimal timing for long-term efficacy and safety remain studied.

Investigation of tDCS in pain treatment began more recently than rTMS, and there are fewer published studies on treatment outcomes and parameter settings. However, the positive pain outcomes are found with using current intensities of 1–2 mA delivered for 15 to 20 minutes, and electrode size 25–35 cm^2. Treatment is given daily (consecutive or with breaks) over one or more weeks. Within these dose parameters, tDCS has extensive evidence of safety and tolerability [18,184].

The properties of tDCS make it a promising approach for pain treatment, including the potential to address pathological alterations in neural activity, excitability, and connectivity at multiple levels and sites of cerebral pain processing. Reversal of maladaptive plasticity in cerebral pain processing systems is associated with pain relief. The potential of tDCS to prevent or reverse such maladaptive changes, or enhance adaptive neuroplastic changes in pain processing networks is highly relevant in pain management [18]. Proposed mechanism of action in chronic pain include [27]:

- M1 stimulation reduces thalamic and brainstem nuclei hyperactivity that underlies pain.

- Dorsolateral PFC stimulation is thought to mediate analgesic effects by modulating pain-related affective-emotional networks

Higher stimulation intensity or duration to enhance efficacy has been examined, but prolonged M1 stimulation at higher intensities may reverse the intended effects on neural excitability [185].

CHARACTERISTICS OF CHRONIC PAIN CONDITIONS

Brain stimulation therapies have been evaluated for efficacy, safety, and tolerability in the following pain conditions.

Neuropathic Pain

Neuropathic pain is caused by abnormality, trauma, or disease of the somatosensory nervous system, resulting from various etiologies including traumatic or surgical injuries to peripheral nerves, infectious diseases (e.g., herpes zoster, postherpetic neuralgia), metabolic disorders (e.g., diabetic peripheral neuropathy), and injuries or diseases that affect the CNS such as stroke or spinal cord injury. Nearly 25% of people with chronic diabetes have neuropathic pain [186,187].

Among adults in the general population, an estimated 7% to 8% have chronic pain with neuropathic features, and 5% have moderate-to-severe pain with neuropathic features [188]. Neuropathic pain is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders, and disruption of family and social life [189]. Neuropathic pain is reported to be more severe than non-neuropathic pain and the management of chronic neuropathic pain is challenging; more than 50% of patients experience partial or no pain relief, and the adverse effects of medications used to manage the pain may limit their clinical utility in general and in elderly patients in particular [186,187].

Spinal Cord Injury Pain

In the United States, spinal cord injury occurs in 17,000 persons annually, and an estimated 282,000 patients are living with spinal cord injury. Six months after discharge, 27% of patients with spinal cord injury report pain that is severe enough to interfere with most daily activities. Spinal cord injury pain can develop at or below the level of spinal injury and does not correlate well with the magnitude or location of the lesion. Injury from gunshot is associated with more severe pain. Neuropathic, musculoskeletal, and/or visceral pain can contribute to spinal cord injury pain, and central neuropathic pain can develop weeks to months following injury [190,191].

Central Poststroke Pain

Pain is reported by 11% to 55% of stroke survivors, and can arise from muscles, joints or viscera, or from the peripheral or central nervous system. The most common types of poststroke pain include hemiplegic shoulder pain, pain due to spasticity, and central poststroke pain. Along with spinal cord injury pain, central poststroke pain is a central neuropathic pain condition with pain
arising from a cerebrovascular lesion in the central somatosensory nervous system. Sensory descriptors used in patients with central poststroke pain include burning, aching, pricking, lacerating, shooting, squeezing, throbbing, sharp, stabbing, painful pins and needles, dull, and cramping. Treatment of central poststroke pain is difficult, due to the limited efficacy and dose-limiting side effects of available drugs [192].

Failed Back Surgery Syndrome

In the United States, more than 300,000 spinal surgeries are performed annually, mainly in the lumbar spine, and as many as 100,000 result in failure where the patient experiences new-onset pain in addition to unresolved pain from the original problem. The level of pain is widely variable and may occur with neurologic deficits. Contributors to pain and the clinical features of failed back surgery syndrome include recurrent disk herniation, epidural abscess, scar tissue formation around the nerve root, facet joint syndrome, and muscle spasm. Patients with persistent radicular pain, usually from chronic nerve injury, greatly benefit from treatment that addresses the neuropathic pain [193].

Lumbosacral Radiculopathy Pain

Lumbosacral radiculopathy results from nerve root irritation and compression, resulting in a symptom distribution of the affected lumbar or sacral nerve root such as numbness, weakness, or paresthesia. Sciatica is the most common symptom of lumbar radiculopathy and refers to pain that radiates down the leg below the knee in the distribution of the sciatic nerve to indicate nerve root compromise from mechanical pressure or inflammation [194].

Chronic low back and neck pain are highly prevalent but largely unaddressed in brain stimulation trials because origin is usually multifactorial, psychosocial contribution is often prominent and the torso has less cortical representation [13].

Temporomandibular Disorders

Temporomandibular disorders (TMDs) involve persistent pain in the cheek and jaw area of the face and have an estimated 11% prevalence in community samples. TMD pain considerably impedes quality of life, with nearly 80% of patients with TMD reporting regular discomfort eating and more than 40% reporting difficulty performing their jobs. The importance of CNS factors in TMD etiology is established, and neuroimaging has revealed structural, functional, and neurochemical aberrations in TMD pain [195].

Phantom Limb Pain

Phantom limb pain is painful or unpleasant sensation in the distribution of the lost or deafferentated body part. Phantom limb pain can resemble neuropathic pain with descriptors such as sharp, shooting, or electrical-like; or resemble nociceptive pain with dull, squeezing, or cramping pain. The pain can be widespread throughout the missing limb or confined to a smaller limb area. The prevalence of phantom limb pain following amputation may be as high as 85%. Phantom limb pain remains an extremely difficult pain condition to treat, and most pharmacologic therapies are not successful [196].

Postherpetic Neuralgia

Postherpetic neuralgia is persistent neuropathic pain after the healing of herpes zoster infection. Risk of developing postherpetic neuralgia increases with age, and the duration can be months to years. Pain levels range from mild to excruciating, with pain severity placing the patient at risk for suicide. In the United States, postherpetic neuralgia is the most common cause of suicide in patients with chronic pain older than 70 years of age. In postherpetic neuralgia, peripheral and CNS sensitization generate pain characterized by severe or excruciating pain from light touch (allodynia) or severe spontaneous pain without allodynia. Postherpetic neuralgia pain is highly resistant to conventional pain treatment [197].

Complex Regional Pain Syndrome

Complex regional pain syndrome is thought to result from injury to autonomic, central, and peripheral nervous systems. It presents as pain affecting one or multiple limbs without following a dermatomal distribution. The pain is disproportionate to the inciting injury, and pain severity can be disabling. The affected limb(s) undergo marked changes in skin color, texture, and/or temperature. Absence of nerve injury is termed CRPS-I, with CRPS-II describing complex regional pain syndrome that develops after nerve damage. However, recent studies have shown nerve damage in patients classified as CRPS-I, suggesting a false dichotomy [198]. The pathophysiology of complex regional pain syndrome is multifactorial, and while multimodal conventional treatment is indicated, some patients with complex regional pain syndrome do not respond to standard approaches and develop refractory disease [199].

Migraine Headache Pain

Most patients with chronic refractory headaches have medication overuse headache, alleviated by detoxification from their headache medication. A subset remains with chronic refractory headache pain. Neuromodulation options can be considered in selected cases [200].

Migraine has a lifetime prevalence of 18%, and women experience higher past-year rates (13% to 18%) than men (5% to 10%). The main clinical feature of migraine is a unilateral or bilateral throbbing or pulsating headache of moderate-to-severe pain, often preceded by an aura. Other symptoms include gastrointestinal disturbances (nausea or vomiting) and intense sensitivity to light or sound. Medical treatment is particularly challenging, with non-response to high-dose preventive medications or side effects that complicate treatment course in many cases [200].

Cluster Headache

The main clinical feature of cluster headaches is severe, excruciating pain with unilateral distribution around and above the eye and along the side of the head or face; pain sensation described as sharp, boring, burning, throbbing, or tightening; and restlessness or agitation during the headache. Autonomic features associated with cluster headache include ipsilateral conjunctival injection and lacrimation, rhinorrhea or nasal blockage, and ptosis. The pain is more severe than any other headache type and ranks among the most severe known to humans, which has earned cluster headache the term "suicide headache" from reports of suicidal behavior in patients desperate to stop the pain [201]. Treatments for cluster headache are effective in some patients, but patients may not respond to medication, and ablative or destructive methods can be ineffective [200].

Fibromyalgia

Fibromyalgia afflicts an estimated 5 million adults in the United States, of whom 80% to 90% are women [202]. The cardinal features of fibromyalgia are widespread pain and tenderness in multiple regions of the body, not attributable to another condition. Abnormal reactivity to painful stimuli or discomfort is characteristic of fibromyalgia. Pain with fibromyalgia is described as a persistent, diffuse, deep, aching, throbbing sensation in muscles that is most often continuous. Patients with fibromyalgia suffer from a complex symptom spectrum that includes pain, as well as sleep problems, fatigue, cognition difficulties, and depression [203].

The pathophysiology of fibromyalgia involves CNS dysfunction and neurotransmitter dysregulation that results in central sensitization to pain, where disordered processing in central afferent neurons accounts for the dominant symptoms of pain and tenderness in fibromyalgia [204].

TRANSCRANIAL MAGNETIC AND ELECTRIC STIMULATION

Daily rTMS sessions for at least one week can produce durable cumulative effects, but maintenance of efficacy requires additional rTMS sessions at regular intervals [27]. Two systematic reviews synthesized the results of published rTMS studies in chronic pain. Both found rTMS effective, with strongest evidence in neuropathic pain. A consortium of European experts found definite efficacy for HF-rTMS of the M1 in neuropathic pain [129].

Neuropathic Pain

Evidence Based Practice Recommendation

According to a European consortium of experts, HF-rTMS of M1 contralateral to pain side displays definite analgesic efficacy for neuropathic pain; LF-rTMS is probably ineffective.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: A (Definitely effective or ineffective based on at least two Class I studies or one Class I study and at least two Class II studies)

Of nine randomized controlled trials evaluated, three had major limitations from using less than 1,000 pulses per session and studies used 5-day or 10-day stimulations. HF-rTMS (5–20 Hz) to M1 showed efficacy at short-term (≤1 week from last session) and mid-term (1 to 6 weeks from last session) follow-up. Pain scores were reduced by 20% to 45% following active stimulation, and 35% to 60% of patients were responders (>30% pain relief). These analgesic effects were obtained in neuropathic pain regardless of anatomical origin or whether the pain had central or peripheral nervous system involvement [27].

HF-rTMS to M1 contralateral to the pain side received a Level A recommendation for consistent analgesia in patients with neuropathic pain. This was based on results of 511 patients indicating significant efficacy, with pain relief >30% in 46% to 62% of patients, and >50% pain relief in 29% of patients [129]. There were also modest but significant analgesic long-term effects with repeated sessions.

In contrast, LF-rTMS to M1 contralateral to the pain side received a Level B recommendation (probably ineffective) in patients with neuropathic pain. This was based on results of 138 patients in six randomized sham-controlled trials, which consistently reported the absence of any significant analgesic effect of active rTMS versus sham [129].

Of the few rTMS studies targeting the dorsolateral PFC in neuropathic pain, the results were inconsistent and tended to show lack of efficacy [27].

Evidence Based Practice Recommendation

A European consortium of experts has found probable efficacy of HF-rTMS of the left M1 or the left DLPFC in improving quality of life of patients with fibromyalgia.

https://www.sciencedirect.com/science/article/pii/S1388245719312799

Last Accessed: July 24, 2025

Level of Evidence: B (Probably effective based on at least two Class II studies or the combination of one Class I or II study and at least two Class III studies)

Neuropathic pain syndromes tend to show greatest benefit from rTMS to the M1, but some nonneuropathic chronic pain syndromes, such as CRPS-I or fibromyalgia, may have a neuropathic component. Focal lesions with defined onset, such as pain from shingles or trauma, have advantages of known localization and time of onset, but early cases often improve spontaneously which complicates treatment outcomes in research; thus, established cases with pain duration of at least one year are preferable [13].

rTMS should be applied contralaterally for localized neuropathic pain, or to the left hemisphere for widespread neuropathic pain or fibromyalgia. HF-rTMS (≥5 Hz) stimulation should be used, delivered by a figure-8 coil oriented parallel to the midline over M1 for ≥1 week with ≥1,000 pulses per session. Increasing the total pulses per session and repeating the sessions over several days or weeks may enhance rTMS analgesia [27].

CRPS-I

One randomized controlled trial using 10 daily sessions of 10 Hz rTMS in patients with refractory CRPS-I pain found significantly greater analgesic effects with active than sham rTMS over the three-week treatment period [27,205].

HF-rTMS of M1 in patients with CRPS-I showed significant and rapid reductions in pain intensity, but persistence after stimulation was, on average, short-term. There was high variation in duration of treatment response, with total pain relief for three months post-rTMS reported [129].

Fibromyalgia

HF-rTMS to the left M1 was evaluated in several controlled trials. Significant reductions in global pain on a numerical scale, and improvements in quality of life up to one month following 10 daily sessions were found, as well as extension of these effects for several months with maintenance sessions after completion of the original treatment course [129].

HF-rTMS to M1 was effective in five randomized sham-controlled trials at short term but not at mid-term follow-up. Results of one trial were negative for pain intensity but positive for improvement in quality of life, and another study with 14 sessions of left M1 rTMS over 21 weeks reduced pain for only one month beyond stimulation [27].

HF-rTMS to the left dorsolateral PFC also showed analgesic efficacy, with a mean 29% difference in pain relief between active and sham conditions. This degree of analgesia was also found with LF-rTMS to the left dorsolateral PFC. LF-rTMS to the right dorsolateral PFC showed mixed results, with open-label trials showing positive effect that was not replicated by a sham-controlled trial [129].

Most studies conducted in fibromyalgia using LF-rTMS (1 Hz) to the right dorsolateral PFC or HF-rTMS (10–20 Hz) to the left dorsolateral PFC reported results suggesting that analgesic effects were independent of antidepressant effects. Outcomes with highest-quality evidence show durable and clinically relevant pain reduction preceding improvements in depression [27].

Migraine

HF-rTMS of the motor cortex, in contrast to the left dorsolateral PFC, has shown consistent efficacy in multiple trials that showed significant improvement in headache frequency, pain score and functional disability after active rTMS versus sham. LF-rTMS to M1 showed no benefit beyond placebo effect [129].

HF-rTMS of the left dorsolateral PFC showed mixed results in sham-controlled trials, with significant decreases in migraine attack frequency and intensity, and reductions in oral medication found up to 1 month after 12 sessions in one study, and 23 sessions of active rTMS over 8 weeks less effective than sham in decreasing the number of headache days in another trial [129].

Facial Pain and Cluster Headache

HF-rTMS to the M1 in 19 sessions over six months led to significant relief of refractory facial pain, including cluster headache, with a 40% response rate at six-month follow-up. The analgesic effect remained when session duration was shortened from 20 to 10 minutes while keeping pulses per session (2,000) constant [206].

The effectiveness of maintenance rTMS to prolong analgesia and increase long-term pain reduction was evaluated in 55 patients with chronic refractory facial pain, including cluster headache, trigeminal neuropathic pain, and atypical facial pain. Subjects received 10 HF-rTMS treatments of M1 over two weeks, two sessions in week 3, one session in weeks 4 and 6, and monthly sessions the next 5 months. Pain intensity was measured on a 0–10 scale. Significant decreases from baseline to day 15 were found in permanent pain (5.2 to 3.2) and paroxysmal pain (8.6 to 4.5) intensities, and daily number of pain attacks (5.6 to 2.3). At day 15, 73% had a pain reduction ≥30%, decreasing to 40% at day 180. The analgesic effect was similar for all pain types, but significantly lower when session duration was shortened [206].

Phantom Limb Pain

Land mine victims with phantom limb pain received 10-Hz rTMS or sham of the M1 contralateral to the amputated leg in 10 daily sessions. Follow-up, in days, began after the last session. Active rTMS led to significantly greater reduction in pain intensity scores at 15 days vs sham, but the difference was non-significant at 30 days. At 15 days, 70.3% with rTMS versus 40.7% with sham attained clinically significant pain reduction (≥30%). Traumatic amputees with phantom limb pain were able to experience clinically significant pain reduction following 10-session HF-rTMS without side effects, and further work will identify protocols to extend analgesia [207].

Postherpetic Neuralgia

A randomized controlled trial evaluated high-frequency rTMS in 40 patients with postherpetic neuralgia. After 10 sessions of active or sham rTMS of the M1, active rTMS led to an overall 16.89% greater pain reduction than sham at final stimulation, and one and three months post-stimulation. Analgesic effects were associated with long-term improvement in quality of life [208].

Postoperative Pain Secondary to Gastric Bypass Surgery

HF-rTMS of the left dorsolateral FPC led to immediate, short-term analgesic effects and significant reduction of morphine consumption in small open-label trials [129].

Concomitant Medications and Substances

Potentially problematic prescription medications used by some pain patients include tricyclics (e.g., nortriptyline, amitriptyline), antiviral medications, and antipsychotic medications (e.g., chlorpromazine, clozapine). Consuming or discontinuing commonly abused substances can increase cortical excitability and risk of a TMS-induced seizure. Withdrawal from sedatives (e.g., alcohol, benzodiazepines) increases seizure risk, so patients should be asked about recent and current use, and recent substance abuse should be an exclusion criterion [13].

TRANSCRANIAL DIRECT CURRENT STIMULATION

Pain outcomes with tDCS are highly influenced by the brain state of the chronic disorder, adjunct pharmacological interventions, and the number of tDCS treatment sessions is a critical factor for pain relief effectiveness [18,209]. tDCS has been evaluated in diverse pain conditions, including difficult-to-treat pain syndromes such as fibromyalgia, complex regional pain syndrome, central pain due to spinal cord injury or stroke, headaches, and acute post-operative pain. Published evidence ranges from case reports to randomized controlled trials [18].

A main drawback with tDCS is that it produces diffuse brain current flow. High-definition tDCS was introduced to increase the specificity of targeted brain stimulation. High-definition tDCS uses five electrodes. With the M1 target, the anode is placed over the left M1, with the four return cathodal electrodes placed 5 cm radially from the cathode [209].

Fibromyalgia

The efficacy of 2 mA tDCS over the M1 or dorsolateral PFC (10 sessions over 2 weeks) was evaluated in a randomized sham-controlled trial of patients with chronic medically refractory fibromyalgia. Both M1 and dorsolateral PFC stimulation (but not sham) resulted in significant decreases in pain intensity and a positive benefit on quality-of-life measures immediately following the sessions, but only the M1 stimulation produced longer-lasting pain relief thorough 60-day follow up. The analgesic effects of dorsolateral PFC stimulation dissipated by 30-day follow up [210].

Prefrontal areas are involved in the affective/cognitive processing of pain, and tDCS to the dorsolateral PFC may be more relevant to modulation of the emotional experience of pain than for the somatosensory aspect of pain or pain intensity [18].

An optimized protocol for fibromyalgia pain treatment with tDCS has been published. High-definition 2-mA tDCS of M1 led to clinically significant benefits of ≥50% pain reduction in 50% of patients, with both responders and nonresponders benefiting from a cumulative treatment effect of significant pain reduction and improved quality of life over time. An estimated 15 high-definition tDCS sessions (median) are needed for ≥50% pain reduction [209].

Temporomandibular Disorders

TMD has a high prevalence and in many patients, pain and masticatory dysfunction persist despite a range of treatments. Women with chronic myofascial TMD pain received five sessions of active or sham 2-mA high-definition tDCS to the M1. Compared with sham, active tDCS led to significantly higher number of subjects with ≥50% pain reduction at four weeks, pain-free mouth opening at one-week follow-up, and sectional pain area, intensity and their sum measures contralateral to M1 stimulation during the treatment week. There were no changes on emotional measures. high-definition tDCS M1 stimulation led to clinically meaningful improvement in sensory-discriminative pain and motor measures up to four weeks post-treatment in patients with chronic myofascial TMD pain [211].

Phantom Limb Pain

Eight subjects with unilateral lower or upper limb amputation and chronic phantom limb pain received active or sham 1.5 mA anodal tDCS to M1 daily for five days. Active but not sham tDCS decreased background pain and frequency of phantom limb pain paroxysms through one-week post-tDCS. Also, on each treatment day, active tDCS patients reported immediate pain relief and increased ability to move their phantom limb. Immediate patient response to sham was variable, with increased or decreased pain from baseline [212].

Burn Pain

Burn pain severity and anxiety are highly correlated in burn patients, and a randomized sham-controlled trial assessed the effect of single-session cathodal 1-mA tDCS to the sensory cortex on pain anxiety in 60 patients with severe burn. Following stimulation, pain anxiety scores were significantly reduced with tDCS compared to sham. Post-stimulation assessment was followed by burn dressing; afterwards, pain anxiety scores remained significantly lower with tDCS versus sham. Acute pain anxiety reduction in patients with burns may be attained with cathodal tDCS [213].

Interferon-Induced Pain

Interferon-alpha (IFN) is a standard treatment for chronic hepatitis C infection, and many patients develop painful symptoms during the three- to six-month treatment course. BDNF is a marker of inflammatory-mediated pain, and tDCS was evaluated for effects on pain and plasma BDNF in 28 patients with hepatitis C infection. Following five days of 2-mA anodal stimulation of M1, active tDCS (compared with sham) reduced pain scores with a mean 56% reduction, enhanced BDNF levels with a mean increase of 37.48%, reduced chronic pain scores and analgesic use. Multivariate regression identified a significant interaction between pain reduction and BDNF level increase with active tDCS only [214].

COMPARISONS OF rTMS AND tDCS IN PAIN TREATMENT

Lumbosacral Radiculopathy Pain

Patients with neuropathic pain due to lumbosacral radiculopathy received rTMS (10 Hz) and tDCS (anodal 2-mA) in a sham-controlled crossover trial. Active rTMS was superior to tDCS and sham in pain intensity reduction. tDCS was not superior to sham, but its analgesic effects correlated to rTMS, suggesting common mechanisms of action. Lowered cold pain thresholds with rTMS correlated to its analgesic efficacy, but had no effect on individual neuropathic symptoms. rTMS was more effective than tDCS and sham in patients with neuropathic pain due to lumbosacral radiculopathy, and may modulate sensory and affective dimensions of pain [215].

Fibromyalgia

The treatment efficacy of rTMS and tDCS of fibromyalgia was evaluated by reviewing 16 randomized sham-controlled trials. Significant improvements in fibromyalgia domains were found [204]. Overall treatment effect sizes were large for pain, sleep disturbance, fatigue, and tender points. Effect sizes were medium for depression and general health/function. rTMS showed a significantly greater effect size than tDCS. Primary motor cortex (M1) stimulation produced a subtle but greater effect size in pain reduction versus dorsolateral PFC, and dorsolateral PFC stimulation may be better for depression improvement. Clinically meaningful improvements in anxiety or cognition, or dose-response effect in fibromyalgia pain reduction, were not found for either modality.

Several studies delivered stimulation for two to four weeks, which possibly led to underestimated efficacy because rTMS in treatment-resistant MDD usually requires four to six weeks of daily treatment for durable response/remission.

Adverse events were generally minor, most commonly skin discomfort at the stimulation site, headache, neck pain, and dizziness. Many studies found no significant difference between active and sham stimulation. Some temporary neurobehavioral adverse effects were observed, including insomnia, sleepiness, restlessness, and worsening of depressive symptoms. Detrimental cognition effects or seizures were not observed [204].

10. INVASIVE NEUROSTIMULATION IN CHRONIC PAIN

Deep brain stimulation is more invasive than motor cortex stimulation because electrodes are implanted through the skull, dura, and brain to stimulate deep targets. Morbidity associated with motor cortex stimulation and deep brain stimulation have greatly improved over time since their introduction [13]. For intractable pain, patients selected for motor cortex stimulation/deep brain stimulation should have evidence of exhaustive but failed conservative management, screening for secondary gain, and receive a psychological evaluation. Trial stimulation is mandatory with deep brain stimulation, but is symptom dependent with motor cortex stimulation. Motor cortex stimulation/deep brain stimulation in chronic intractable pain are both proven effective in specific pain indications (>40% pain reduction for ≥12 months) [216].

MOTOR CORTEX STIMULATION

Motor cortex stimulation is based on observations in the 1990s that stimulation
of the precentral gyrus below motor thresholds relieved pain in patients with thalamic pain. Subsequent investigations have shown efficacy in trigeminal neuropathic pain, deafferentation syndromes such as post-stroke pain and spinal cord injury pain, and brachial plexus injuries [187].

Stimulation of central motor systems (e.g., cerebral cortex, pyramidal tracts) can influence descending inhibition of nociceptive spinal and thalamic transmission and induce analgesia. Motor cortex stimulation is increasingly used in chronic, refractory neuropathic pain, with efficacy supported by clinical trials that show response (≥30% pain reduction) in 55% to 64% of patients [27]. Few studies have evaluated long-term outcomes [217].

Refractory Neuropathic Pain

A review of 17 open-label trials reported mixed pain outcomes, but analgesic efficacy may have been underestimated by brief study durations. Motor cortex stimulation has shown delayed, fluctuating analgesic effects, and randomized sham-controlled trials have found substantial pain relief at one year with initial non-responders [27].

Some, but not all studies have strongly correlated preoperative M1 rTMS response with follow-up response to motor cortex stimulation. Other studies found improved motor cortex stimulation outcomes using (versus not using) preoperative rTMS. Positive preoperative rTMS response predicts better motor cortex stimulation outcomes and can improve patient selection [27]. In 20 patients with refractory neuropathic pain followed a mean 6.1 years after motor cortex stimulation, mean pain reduction at any time ranged from 28.9% to 37.2%, and immediate post-rTMS improvement predicted long-term pain reduction. Greatest long-term benefit occurred in physical pain and dependence (autonomy in daily activities); little changed were disability, anxiety, stress and depression [217].

Motor cortex stimulation is safe and effective in central and peripheral neuropathic pain (≥40% to 50% pain reduction in approximately 50% of patients), with best outcomes in central post-stroke pain and neuropathic facial pain [218]. Benefit is established in spinal cord injury pain. Multiple randomized sham-controlled trials with ≥12-month follow-up show sustained response rates in 60% of patients with central and peripheral neuropathic pain. Intracranial motor cortex stimulation is more effective than non-invasive stimulation, and partial rTMS responders should be considered for motor cortex stimulation [13,219,220].

DEEP BRAIN STIMULATION

Deep brain stimulation is effective in relieving diverse intractable pain, including chronic pain refractory to medication, conservative approaches, and TMS. Deep brain stimulation shows efficacy in failed back surgery syndrome, phantom limb pain and peripheral neuropathic pain, and possibly greater efficacy in nociceptive versus neuropathic pain. Deep brain stimulation shows superior outcomes in cluster headaches. Although deemed investigational by the FDA, deep brain stimulation has a clear role in chronic refractory pain [221].

Deep brain stimulation sites in pain treatment differ from those in refractory psychiatric disorders. Effective deep brain stimulation targets in pain control [27]:

- The sensory ventral posterior lateral and medial (VPL/VPM) thalamus

- Periventricular and periaqueductal gray (PVG, PAG) matter

- Internal capsule

- Anterior cingulate cortex

The PVG and VPL/VPM overlap in analgesic mechanisms; some deep brain stimulation studies target both for synergistic effects [8,222]. Greatest long-term deep brain stimulation efficacy is found with PVG/PAG, with/without sensory thalamus or internal capsule stimulation (87% or 79%). Less effective is thalamus stimulation alone (58%) [223]. Deep brain stimulation of the ventral PVG/PAG is thought to trigger non-opioid analgesia and acts through autonomic mechanisms, with dorsal PVG deep brain stimulation triggering endogenous opioid release [27].

The early excitement over deep brain stimulation for pain was dampened when two open-label studies sponsored by Medtronic failed to reach their defined efficacy targets. The first trial enrolled 196 chronic pain patients from 1989–1993 but did not achieve ≥50% pain reduction in ≥50% of patients. The second trial began in 1992 but failed from lack of accrual by 1998 [224].

Without this large-scale prospective data, the FDA has not approved deep brain stimulation for pain and only permits off label use [225]. Due to its off-label status for pain treatment in the United States, only a few surgeons publish their deep brain stimulation pain outcomes [222].

Subsequent large deep brain stimulation trials showed beneficial outcomes. Patients with diverse neuropathic pain syndromes were followed for one to eight years. The best long-term pain outcomes were found in failed back surgery syndrome, and CRPS-II (66% with ≥50% pain reduction). Central pain from spinal cord injury or post-stroke pain showed poor response [225,226].

Following deep brain stimulation of the PVG/PAG grey area or VPL/VPM/internal capsule, patients were followed a mean 78 months and ≥50% pain reduction was attained in patients with failed back surgery syndrome (74%), peripheral neuropathy (60%), thalamic pain (20%), and in patients with trigeminal neuropathy or phantom limb pain but not spinal cord injury or postherpetic neuralgia [227].

Consistent findings of earlier trials were deep brain stimulation efficacy in failed back surgery syndrome and neuropathic pain of peripheral origin; poor response in spinal cord injury or post-stroke pain; and initial benefit may be lost after several years [225].

Intractable Neuropathic Pain

Deep brain stimulation study reviews found long-term pain relief in more than 80% of patients with intractable failed back surgery syndrome, 58% with post-stroke pain, and higher rates in peripheral neuropathic pain (phantom limb pain, polyneuropathies) [13].

In 59 patients with long-term follow-up after deep brain stimulation of the PVG (53.8%), VPL/VPM (12.8%), or both (33.3%), ≥50% pain reduction was attained in patients with phantom limb pain (89%), brachial plexus injury (50%), post-stroke (69%) and spinal cord injury (57%) pain, and chronic headache (54%) [228]. Complications included implantable pulse generator changes (42%), lead revisions (18%), lead erosion requiring removal, and infection, with two treated by antibiotics and five requiring device removal [222].

In seven open-label studies in peripheral or central neuropathic pain, mean pain reduction approached 50%, although pain relief varied largely across studies. The best outcomes occurred with somatosensory thalamus deep brain stimulation in peripheral neuropathic pain [27]. The dorsal anterior cingulate cortex is a potential deep brain stimulation target in chronic neuropathic pain that warrants further study, given its central role in cognitive and affective processing [189].

Intractable Cluster Headache

The American Headache Society practice recommendation for unilateral hypothalamic deep brain stimulation was downgraded to Negative B, based on a study showing active deep brain stimulation no different from sham in pain reduction and serious adverse effects during deep brain stimulation treatment [201].

THALAMIC DEEP BRAIN STIMULATION

Thalamic deep brain stimulation of refractory pain was largely abandoned from inadequate efficacy. Diffusion tensor imaging-based segmentation is a new method to improve thalamic lead positioning and clinical outcome, and was evaluated in five intractable pain patients receiving sensory thalamus deep brain stimulation. Diffusion tensor imaging identified the narrowly specific lead placement shared by four patients with significant post-deep brain stimulation pain relief, and ineffective lead placement in one patient lacking deep brain stimulation response. Diffusion tensor imaging confirmed thalamic lead placement and may be useful for guiding the procedure in the future [229].

Deep brain stimulation is generally safe, with an overall frequency of adverse events of 8% to 9%. These include lead fractures, wound infections, intraoperative seizure and postoperative burr-hole site erosion. Contraindications to pain treatment include psychiatric disorders, coagulopathy, and ventriculomegaly that preclude direct electrode passage to the surgical target [27].

NEUROMODULATION SAFETY IN PAIN TREATMENT

A systematic review concluded all neurostimulation techniques, including invasive procedures, were found safe to very safe. Reports of deaths or serious adverse events after invasive procedures in thousands of patients are conspicuously few. By far the most common side effects of invasive neurostimulation involved stimulation device malfunction or electrode movement. However, due to the invasive nature, implanted neurostimulation should be reserved for patients in whom conventional pain management is ineffective, intolerable or contraindicated; with clearly defined pain conditions; and after an optimal selection process [27].

11. SOCIAL ISSUES WITH NEUROSTIMULATORS

Consumer use of neurostimulators is rapidly expanding, far outpacing regulatory oversight and known safety implications. While patients can obtain devices through purchase, assembly of parts, or clinician prescribing, direct-to-consumer tDCS devices with non-medical product use claims are increasingly available. tDCS is the dominant modality in product availability and consumer demand [7]. Fueling this tDCS 'home use' movement is perception of safety, low device cost, published benefit in some neuropsychiatric disorders, and popularized media accounts of enhancement in normal neuropsychological function.

RISING CONSUMER USE

tDCS may reduce the symptoms of several neuropsychiatric disorders. Patients with these conditions can be highly motivated to seek tDCS therapy, but access is limited to clinical trial enrollment because tDCS remains investigational. Access to clinical trials of tDCS is not pragmatic or possible for many. Even after completing a study, patients have few options for therapy continuity, and unable to access tDCS under medical care, are seeking alternative routes of access [230,231]. This increasingly involves the Internet-mediated "do-it-yourself" tDCS movement of individuals who stimulate their own brains with tDCS outside of research or medical settings for self-improvement goals [231,232].

Some tDCS trials suggest improved cognition, attention, memory, language, and learning ability in healthy subjects [4]. These interesting results began attracting media attention, such as a New York Times article titled "Jump-Starter Kits for the Mind" [233]. The popularized positive effects of neuromodulation have spurred a growth industry in tDCS devices for non-therapeutic enhancement [7].

REGULATORY CHALLENGES AND SAFETY CONCERNS

The FDA designates medical devices by risk level for illness or injury as Class I (low-risk; bandages, dental floss); Class II (medium-risk; breast pump kits, over-the-counter TENS devices for pain); or Class III (high-risk; heart replacement valves, deep-brain stimulating electrodes) devices [232]. The definition of "medical device" is based on intended use and not mechanism of action. A product is a medical device if it is intended for use in diagnosis or treatment, or intended to affect the structure or function of the body [232].

The FDA classifies a product as a medical device according to its representation by the manufacturer, and the level of product regulation is greatly impacted by the intended use claims. This is relevant to how consumer tDCS devices makers represent their product. The websites of most direct-to-consumer tDCS devices tend to imply that intended use was for enhancing or optimizing brain function. Other makers have used the term "kit" to distance their product from possible FDA device classing. "Wellness," but not therapeutic, claims generally place a product outside the definition of a medical device, avoiding FDA regulation. The FDA states this solely applies to low-risk consumer "wellness" devices, but risk level only defines the regulatory process once a device is deemed within FDA jurisdiction [232].

A strong contributor to consumer demand is perceived safety. Safety reviews of tDCS trials treating more than 1,000 subjects with more than 33,200 sessions found no reports of serious adverse effects, irreversible injury or cognitive impairment with standard tDCS protocols (sessions ≤40 min, ≤2 times/day, ≤4 mA, electrodes that minimize skin burns) [16,231]. Another review noted that adverse effects were mentioned in only 56% of 172 published trials, indicating that systematic assessment and reporting of adverse effects was absent from a large portion of the evidence base [235].

A case report described respiratory and motor paralysis, muscle cramping, and nausea in a patient who, during electrical stimulation therapy, was accidentally delivered a current 10 times higher than intended. This report was shown to underscore the risk of applying electrical stimulation outside of established parameters, with clinically unsupervised home use of tDCS increasing the risk of permanent injury [234,235]. The efficacy and high overall safety reported in tDCS trials is specific to the device and clinical protocol. Changing any aspect of the device, electrode placement, or delivered dose is likely to obviate the desired effect. Direct-to-consumer tDCS products cannot claim the benefits of illness treatment or enhancement of normal function found by tDCS trials because they deviate in these aspects [235].

Other concerns with home use of tDCS include data that suggest cognitive enhancement mediated by tDCS may occur at the expense of other cognitive functions; the lack of long-term safety data; and the innumerable scenarios of inept home use and potential harm that may arise. An ethical concern is the media "neuro-hype" surrounding tDCS can shape public risk-benefit perception, promote therapeutic misconceptions, and impact the uptake of this technology. This increases the potential for desperate and vulnerable patients to overestimate tDCS benefits and under-estimate the risks [16,234].

12. CONCLUSION

A diverse array of brain stimulation modalities are available or being evaluated for the treatment of chronic psychiatric and pain conditions. Noninvasive approaches include ECT, which remains established as the most reliable means for rapid antidepressant induction; the more recent rTMS and tDCS, introduced to rival ECT efficacy without cognitive adverse effects or need for general anesthesia; several very recent variants of rTMS and tDCS; and trigeminal nerve stimulation (eTNS). The most-studied non-invasive brain stimulation is rTMS, followed by tDCS.

Unlike ECT, use of rTMS and tDCS have expanded beyond MDD. Efficacy in MDD is established with rTMS and more modest with tDCS. rTMS shows greater efficacy in anxiety-related disorders, substance use and eating disorders, while tDCS shows greater efficacy in alleviating residual audio verbal hallucinations and negative symptoms in schizophrenia. In diverse chronic pain conditions, rTMS is somewhat more effective than tDCS. VNS may have a role in severely treatment-resistant MDD, and motor cortex stimulation is effective in central refractory neuropathic pain. Deep brain stimulation is the most invasive modality, and may provide long-term, clinically meaningful symptom reduction and improved quality of life in patients with a range of intractable psychiatric or chronic pain conditions.

The current rate of knowledge expansion and publication output involving rTMS and tDCS cannot be overstated. The continuous refinement and improvements in specificity of stimulation and duration of response is rapidly making non-recent publications obsolete.

Many brain stimulation devices show consistent and significant treatment responses in various psychiatric and pain conditions. From a rigid, evidence-based perspective, the strength of evidence for efficacy is considered weak in many stimulation-responsive conditions. This does not imply the therapy is ineffective, but instead reflects the small numbers of treated patients in many clinical conditions [187]. Compared to long-term efficacy, safety and adverse effects are much more established in rTMS and tDCS; with ECT and deep brain stimulation, all three dimensions of treatment outcome are established. However, in real world clinical care, decision-making weighs potential benefits against known risks across the range of options. Most patients evaluated for response to brain stimulation have multiple prior failed treatments. Brain stimulation offers the potential to offset patient non-response or intolerance to standard therapies.

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Evidence-Based Practice Recommendations Citations

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