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| A) | Neuroplasticity | ||
| B) | Induction of seizures | ||
| C) | Neurotransmitter inhibition | ||
| D) | Neurotransmitter activation |
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
| A) | magnets. | ||
| B) | bee sting. | ||
| C) | electric fish. | ||
| D) | electric current. |
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].
| A) | treating hysteria with seizures. | ||
| B) | treating depression with seizures. | ||
| C) | treating Parkinson disease with seizures. | ||
| D) | replacing drug-induced seizures in treating psychosis. |
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].
| A) | Theta-burst stimulation (TBS) | ||
| B) | Magnetic seizure therapy (MST) | ||
| C) | Transcranial direct current stimulation (tDCS) | ||
| D) | Repetitive transcranial magnetic stimulation (rTMS) |
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.
| A) | BP bifrontal placement | ||
| B) | UBP right unilateral placement | ||
| C) | Brief pulse (BP) right unilateral placement | ||
| D) | Ultra-brief pulse (UBP) bitemporal placement |
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].
| A) | lithium during ECT. | ||
| B) | antidepressants after ECT. | ||
| C) | benzodiazepines before ECT. | ||
| D) | lithium plus nortriptyline before ECT and continuing both. |
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].
| A) | seizure. | ||
| B) | manic switch. | ||
| C) | cognitive decline. | ||
| D) | psychotic reaction. |
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].
| A) | ECT | ||
| B) | rTMS | ||
| C) | tDCS | ||
| D) | DBS |
RECOMMENDED rTMS AND TBS PROTOCOLS IN MDD
| Approach | Intensity and Site | |||
|---|---|---|---|---|
| First-line |
| |||
| Second-line |
TBS protocols:
| |||
| 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. | ||||
| A) | Thalamus | ||
| B) | Cingulate gyrus | ||
| C) | Primary motor cortex (M1) | ||
| D) | Dorsolateral prefrontal cortex (DLFPC) |
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.
| A) | High-frequency rTMS is superior to low-frequency rTMS. | ||
| B) | Some benefit is possible but is obscured by inconsistent findings. | ||
| C) | Superior outcomes found in open-label trials were not replicated by sham-controlled studies. | ||
| D) | Newer trials with improved brain target selection consistently show superior outcomes in OCD symptom reduction. |
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].
| A) | Nonsmoking patients did not show added benefit from tDCS. | ||
| B) | tDCS and rTMS show comparable efficacy in reducing AVHs. | ||
| C) | rTMS consistently and significantly reduced AVHs, linked to normalizing aberrant functional connectivity in key brain regions. | ||
| D) | tDCS consistently and significantly reduced AVHs, linked to normalizing aberrant functional connectivity in key brain regions. |
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].
| A) | refractory OCD. | ||
| B) | refractory MDD. | ||
| C) | post-stroke pain. | ||
| D) | refractory bipolar disorder. |
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].
| A) | diagnostic heterogeneity in studied patients. | ||
| B) | the extent of comorbidity in studied patients. | ||
| C) | disease severity and extent of treatment resistance in studied patients. | ||
| D) | None of the above |
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].
| A) | limited to patients with bipolar disorder. | ||
| B) | when the DBS device is discontinued after long-term therapy. | ||
| C) | during stable DBS with potential to become treatment-resistant. | ||
| D) | during parameter adjustment that resolve by switching parameters. |
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].
| A) | DBS. | ||
| B) | VNS. | ||
| C) | eMCS. | ||
| D) | ECT. |
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].
| A) | Low-frequency stimulation of DLPFC | ||
| B) | High-frequency stimulation of DLPFC | ||
| C) | Low-frequency stimulation of motor cortex (M1) | ||
| D) | High-frequency stimulation of motor cortex (M1) |
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.
| A) | has no effect. | ||
| B) | enhances efficacy. | ||
| C) | poses increased safety risks. | ||
| D) | can reverse the intended effects on neural excitability. |
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].
| A) | 30,000 | ||
| B) | 50,000 | ||
| C) | 75,000 | ||
| D) | 100,000 |
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].
| A) | DBS. | ||
| B) | VNS. | ||
| C) | rTMS to the M1. | ||
| D) | rTMS to the DLFPC |
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].
| A) | FBSS. | ||
| B) | cluster headache. | ||
| C) | phantom limb pain. | ||
| D) | peripheral neuropathy. |
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].