Insertional effect following deep brain stimulation electrode implants

KEYWORDS:

• Electrode implant
• insertional effect
• microlesion
• deep brain stimulation
• neuroinflammation
• microthalamotomy

1. Introduction

Deep brain stimulation (DBS) is a neuromodulation technique currently approved for the treatment of movement disorders, epilepsy, and obsessive-compulsive disorder (OCD). In addition, this therapy is being investigated for the treatment of numerous other neuropsychiatry conditions [1,2]. The mechanisms of DBS seem to be intimately dependent on the frequency of stimulation and involve a series of local excitatory and inhibitory effects on neurons, fibers, and glia, which ultimately modulate circuits and structures at a distance from the target [3]. DBS as a therapy involves a series of steps, including the implantation of electrodes into the target and the administration of electrical current into the brain. Numerous studies suggest that the implantation of the electrode by itself, before the delivery of stimulation, induces molecular, neurochemical, and electrophysiological changes that may culminate with behavioral and clinical responses. This effect is often called ‘microlesion’ or ‘insertional’ effect, a phenomenon that is frequently considered to be transient. Disregarding the clinical responses to electrode implantation, especially soon after surgery, may lead to an overestimated interpretation of the effects of DBS.

2. Clinical effects of electrode implantation

The clinical effects induced by the ‘microlesion’ phenomena have been consistently reported [4,5]. In movement disorders, such as tremor, dystonia, and Parkinson’s disease (PD), this has been characterized as an improvement in motor symptoms before active stimulation is delivered. In these conditions, the clinical benefits of electrode insertion can be easily appreciated, as they can be objectively detected and quantified. Surgical targets associated with symptomatic improvement in movement disorders include the ventral intermediate nucleus of the thalamus (Vim), the zona incerta, the subthalamic nucleus (STN), and the globus pallidus internus (GPi). Interestingly, the presence of a microlesion effect seems to indicate the accuracy of targeting and predict postoperative outcome after DBS in patients with tremor [6]. Detecting an insertional effect is also important during programming sessions. Because the duration and magnitude of the insertional effect varies from patient to patient, changes in stimulation parameters need to be carefully and closely monitored to prevent hyper- or hypo-stimulation that may lead to undesirable side effects. Corroborating the physiological nature of the insertional effect, electrode implantation in DBS-treated patients induces brain changes in electrophysiological tests and neuroimaging studies [4].

In addition to movement disorders, a clinical improvement after electrode implantation in the anterior thalamic nucleus, centromedian nucleus, subthalamic nucleus, and hippocampus has been demonstrated in patients with epilepsy. In fact, some of the trials in the field have shown a substantial seizure reduction in the postoperative period, with no subsequent differences being recorded when patients received active vs. sham stimulation [7].

The effects of electrode insertion have also been documented in patients with pain and psychiatric disorders. In these conditions, however, a reduction in clinical symptoms is largely subjective – that is – based on the patients’ report. Although tests to measure nociceptive experiences and psychophysiological functions exist, they have not been systematically employed to measure the effects of electrode insertion. In patients with pain and cluster headache, clinical improvement after the insertion of electrodes into the thalamus and hypothalamus has been demonstrated. In the former condition, the presence of an insertion effect following thalamic electrode implantation seems to correlate with postoperative outcome [8]. Corroborating the biological effect of the phenomenon, side effects, such as stuttering, have been reported following electrode insertion in patients with pain [9]. In psychiatry, while an insertional effect has been clearly observed in OCD [10], it’s occurrence in patients with other psychiatric disorders is still questionable. Early trials investigating the role of DBS in major depressive disorder have shown that patients receiving active and sham stimulation improved considerably after surgery [11,12]. In a recent case series, a patient diagnosed with post-traumatic stress disorder showed an important clinical improvement following electrode insertion prior to stimulation [13].

3. Molecular and biochemistry effects of electrode implantation

The introduction of a foreign body that may at least partially disrupt the brain parenchyma leads to local damage to cells and capillaries, a transient disruption of the blood–brain barrier (BBB) and the activation of immune resident cells. Some of the major players are glia cells, particularly astrocytes and microglia. These cells participate in the development and maintenance of the microenvironment around the electrodes, even after the regulation of blood flow and the integrity of the BBB are regained. Microglia/macrophages, leukocytes, NG2-expressing glial precursors, and astrocytes in particular, are all present in the sheath of brain tissue that surrounds the electrode. Although some of these elements are involved in neuroinflammation, one of the main roles of the encasement of the electrodes, a phenomenon that is also known as glial scar or gliosis, is to limit focal inflammatory responses [14]. At first, astrocytes and microglia are classically activated, secreting pro-inflammatory mediators. The contribution of this initial phase of response to electrode insertion was studied by Perez-Caballero and coworkers, who demonstrated that the administration of non-steroidal anti-inflammatory drugs attenuated the acute antidepressant effects of DBS in a rodent model [15]. Beyond neuro-immune and neuroinflammation roles, astrocytes also play a role in glutamatergic clearance, neuronal, and synaptic pruning. In addition, the insertion of electrodes into the target induces the release of gliotransmitters, including glutamate and adenosine [16]. This suggests that the interaction of neuron-astrocyte-neuron in the tripartite synapsis may also be modulated by electrode implantation. In rodents, the use of astrocytic gliotoxins has not only been shown to attenuate the antidepressant effects of DBS but also inhibited electrode implant-induced neurogenesis [17]. Finally, the above-described changes can directly or indirectly modulate activity in afferent and efferent pathways in the target region, an effect that may contribute to the effects of electrode insertion at a distance from the surgical site. Altogether, the mechanistic aspects and substrates described above suggest that the insertion of electrodes by themselves may increase and subsequently attenuate neuroinflammation, modulate neurotransmitter release, and induce changes in neurons and fibers that may contribute to the behavioral and clinical effects of the microlesion phenomenon [4].

4. Conclusions

The microlesion or insertional effect is a phenomenon induced by DBS electrode insertion prior to the delivery of electrical current. It leads to a cascade of molecular events both locally and at a distance from the target, including the activation of glia cells, the release of neurotransmitters and gliotransmitters. Even though the insertional effect is an important phenomenon that requires attention and careful evaluation, it is largely a transient effect. Patients with expired batteries after long-term DBS treatment often experience a recurrence of their symptoms [18,19], which suggests that the insertional effect is not capable of mitigating disease pathology and/or clinical symptoms for prolonged periods of time. That said, the insertional effect is constantly observed in the acute phase of DBS treatment and should be taken into account both in the clinical and research scenarios.

Studies that investigated the development of an insertional effect reported a great variability in the incidence and duration of this phenomenon. At present, reasons for such variability and why only a certain percentage of patients develops an insertional effect remain elusive. It is possible that the formation of the gliotic sheath may not be uniform across patients and those with more prominent neuropathological underpinnings develop a stronger clinical response. This, however, remains to be demonstrated.

To date, most DBS studies failed to record details about the incidence, duration or the degree of clinical improvement following electrode implantation. More concrete figures will only be acquired when studies addressing these issues are conducted.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.