Neurotherapeutics

Overview

Therapeutic options for patients with affective, behavioral, or cognitive disorders include psychotherapy, pharmacotherapy, and somatic therapies. This chapter will focus on the latter.

Somatic therapies are also commonly known under the labels of brain stimulation or neuromodulation . They are a group of device-based techniques that target specific structures of the nervous systems via surgical ablation or electrical modulation with the goal of therapeutically modifying pathological patterns of brain activity and circuit connectivity. These therapies grow from a systems neuroscience paradigm that emphasizes the role of neural circuits and their processing strategies in healthy brain function, pathophysiology, and therapeutics.

Somatic therapies can be divided into two general groups: invasive and non-invasive modalities. Invasive treatments require the surgical implantation of stimulating electrodes (or surgical ablative disconnection of aberrant pathways) and include ablative limbic system surgeries, deep brain stimulation (DBS), and vagus nerve stimulation (VNS). Non-invasive techniques are able to modulate brain activity transcranially without surgical intervention, and include transcranial magnetic stimulation (TMS) as its most paradigmatic modality. Electroconvulsive therapy (ECT), the oldest of all somatic therapies, occupies a space in between the two categories, as it does not require surgical intervention but it does require general anesthesia; it is generally considered minimally invasive.

Many patients with psychiatric illness can be successfully treated with pharmacotherapy, psychotherapy, or both. However, a significant number of patients do not respond to these interventions. Studies have demonstrated that about 30% to 40% of patients with major depressive disorder (MDD) treated with pharmacotherapy achieve full remission, and 10% to 15% experience no symptom improvement. In addition, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study found that with each failed medication trial the remission rate decreased. Clearly, alternative therapeutic interventions for patients with no response to these treatments are necessary. Nevertheless, while invasive neuromodulation should be reserved for the most refractory patients, non-invasive techniques (including ECT) are being considered in earlier phases of the therapeutic process and are not exclusively for severe treatment-resistant individuals, given their efficacy and relatively benign safety profile (which can be significantly better than certain pharmacological options).

Ablative Limbic System Surgery

Concerns regarding ablative neurosurgery for psychiatric indications are understandable given the indiscriminate use of crude procedures, such as frontal lobotomy, in the middle of the twentieth century. These procedures were associated with severe adverse events, including frontal lobe symptoms (e.g., apathy) or even death. In the latter half of the twentieth century, neurosurgeons began to use much smaller lesions in well-targeted and specific brain regions. As a result, the incidence of adverse events dropped precipitously. Currently used procedures include anterior cingulotomy, sub-caudate tractotomy, limbic leucotomy (which is a combination of an anterior cingulotomy and a sub-caudate tractotomy), and anterior capsulotomy ( Figure 18-1 ). All of these procedures use craniotomy techniques. However, because of the small lesion volume required for an anterior capsulotomy, a gamma knife (a technique that uses focused gamma rays to create ablative lesions) can be used to perform this procedure. These procedures have been used in patients who suffer from intractable mood and anxiety disorders; modest response rates range from 30% to 70%. Because patients eligible for these procedures have failed all other available treatments, a significant positive response to these interventions can be life-saving. While post-operative side effects may occur, they are almost always temporary. Inconvenient side effects include headache, nausea, and edema; more serious adverse events include infection, urinary difficulties, weight gain, seizures, cerebral hemorrhage or infarct, and cognitive deficits. Fortunately, these side effects are uncommon and typically transient.

Deep Brain Stimulation

Deep brain stimulation (DBS) grew from the therapeutic tradition of ablative stereotaxic surgery and the technical developments that led to cardiac pacemakers. It requires the surgical placement of stimulating electrodes in disease-specific deep brain structures via craniotomy and stereotaxic surgery. The intra-cranial electrodes are connected to an internal pulse generator (IPG), which consists of a battery and mini-processor able to generate electrical currents according to clinician-determined parameters. The IPG is surgically implanted in the pectoral region (although other sites are also possible) and connects to the intra-cranial electrodes via a wire that travels through the head and neck's subcutaneous tissue. Clinicians who employ DBS use control devices that communicate wirelessly with the IPG and are able to control and interrogate the system. Patients usually have a simpler version of this control device that allows them to turn the system on or off, and also to make limited changes when treaters allow it. Clinicians can change the voltage, frequency, and pulse width of the electrical pulses according to safety and efficacy criteria, and can also check the impedance of the system, battery status, and patterns of patient use. Most commercially available DBS systems have four contact positions in each stimulating electrode, which can be independently activated to provide positive or negative electrical charges. For example, patient A may have electrode 1 as an anode (positive) and electrode 2 as a cathode (negative), while patient B may have electrode 1 as a cathode (negative) and electrode 4 as an anode (positive), creating a wider electric field (i.e., able to recruit a larger number of fibers) with opposite current direction. This flexibility allows clinicians a significant range of electrode combinations that increase the anatomical precision of stimulation, which can be individualized according to clinical response or biomarkers, such as MRI diffusion tractography.

DBS is a surgical procedure and therefore invasive. Iatrogenic adverse events can be categorized in two primary groups: those related to the surgical procedures and those related to the stimulation of brain regions. Surgical adverse events have an incidence rate of 1% to 4% and include seizures, infection, and hemorrhage. Effects related to stimulation vary depending on the anatomical location of the electrodes and include worsening depression, (hypo)mania, acute anxiety, and gustatory or olfactory sensations. Unlike ablative interventions, permanent cognitive deficits have not been reported in DBS patients. Nevertheless, reversible cognitive effects (such as diminished concentration) have been described, though these are stimulation-dependent and remit with re-adjustment of DBS parameters.

The first US Food and Drug Administration (FDA)-approved indication for DBS was pain, although its approval was later withdrawn given doubts about its efficacy. Today, the primary indication for this treatment modality is Parkinson's disease, and other movements disorders, such as dystonia and essential tremor. The therapeutic approach for these condition requires the surgical modulation of key nodes in the motor circuitry: sub-thalamic nucleus for Parkinson's disease, globus pallidus pars interna for Parkinson's disease and dystonia, and ventral intermediate nucleus of the thalamus for essential tremor. Over 80,000 patients with Parkinson's disease have had DBS electrodes implanted in these brain regions associated with the pathophysiology of the illness.

Basic and clinical research studies investigated the use of DBS for refractory OCD using various brain targets that included the anterior limb of the internal capsule, the ventral capsule/ventral striatum (VC/VS), the nucleus accumbens (NAcc), the sub-thalamic nucleus (STN) and the inferior thalamic peduncle. It should be noted that the first three anatomical targets are very similar, if not practically the same. In 2009, the FDA approved the use of DBS to the VC/VS for the treatment of treatment-resistant OCD (under the humanitarian device exemption mechanism), thus approving the first psychiatric indication and allowing DBS to enter clinical practice in psychiatry.

Several open-label clinical trials have been published using DBS for the treatment of MDD stimulating three main regions: the VC/VS (the same as for OCD), the sub-genual cingulate gyrus (SCG) or Brodmann area 25 (BA25/Cg25) and the NAcc. Response rates (from 50% to 60%) were similar for all regions. Other brain regions, such as the medial forebrain bundle (MFB), lateral habenula (LHb), and inferior thalamic peduncle (ITP), have also been used as DBS targets, but data are still limited to a small number of cases. While these initial results are encouraging, they stem primarily from prospective open-label trials (or case reports and series), and DBS for MDD remains an experimental procedure. Nevertheless, double-blind, placebo-controlled trials are currently underway seeking the necessary safety and efficacy evidence to expand the therapeutic options for patients with treatment refractory MDD.

In addition to OCD and MDD, DBS is also being investigated as a treatment for other conditions that result from physiological changes in brain circuit and lead to pathological processing of affect, behavior, and cognition. A few examples under current active research include addiction, obesity, eating disorders, Tourette's syndrome (TS), Alzheimer's disease, and schizophrenia. Structures such as the ventral tegmental area (VTA) and the nucleus accumbens are targeted for addiction and schizophrenia and the hippocampal fornix is targeted for Alzheimer's disease. As we improve our understanding of the mechanism of action of DBS and its effects on key targets, and we will be able to develop new technologies that increase its specificity, efficacy, and safety, DBS is likely to become a more commonly used treatment for the most refractory patients.