To Infinity and Beyond: The Future of Stereotactic and Functional Neurosurgery
Since the first stereotactic human neurosurgical procedure in 1946, the field of stereotactic and functional neurosurgery has expanded to target various indications, including movement disorders, neuropsychiatric disorders and epilepsy. Clearly, science has driven practice while practice has driven science in this rapidly evolving and growing field. Reflection on this is worthwhile.
Alim-Louis Benabid used deep brain stimulation (DBS) of the ventral intermediate (VIM) thalamus to treat tremor in 1987, and DBS of the subthalamic nucleus (STN) for Parkinson disease (PD) in 1993 (Benabid, 2005). Now standard of care, DBS for the treatment of PD has expanded to other targets including the globus pallidus interna (GPi). Practice also revealed that GPi DBS is effective in treating primary and secondary dystonia. Asleep implantation of DBS electrodes into targets visualized at 1.5 or 3T MRI has become possible through:
- Leveraging decades of human deep brain electrophysiological recordings;
- Advances in MR-compatible navigational platforms;
- Better targeting devices, and
- Dramatically improved software..
The clinical outcomes reported are similar to those of traditional awake, microelectrode-guided procedures (Ho, 2018). The use of diffusion tensor imaging may be further refined targeting over time (Sajonz, 2016). Recent work on novel targets and indications include investigations into substantia nigra pars reticulata (SNr) stimulation for PD patients with postural instability and gait freezing (Lozano, 2017), and zona incerta stimulation for PD accompanied by prominent anxiety and depression (Burrows, 2012).
Recent advances in device design include:
- Commercial release of directional leads, which have enabled current steering (van Dijk, 2018) minimizing stimulation side effects.
- Considerable interest in developing closed-loop stimulation paradigms (Neumann, 2019) to enable delivery of more patient-specific therapy.
- Features of deep brain-recorded local field potentials (LFP) are under investigation as potentially relevant biomarkers that might be used to inform closed-loop devices as sensing-stimulating implanted pulse generators become commercially available in the near future.
- MR-guided high-frequency focused ultrasound has been approved by the FDA for unilateral thalamotomy in the treatment of both essential tremor (Elias, 2016; FDA, 2016) and tremor-dominant PD (Bond, 2017).
Predicated on earlier experience with anterior capsulotomy (Pepper, 2015), DBS has been used to treat obsessive compulsive disorder (OCD) since 1999 and has been approved for use under a humanitarian device exemption since 2009 achieving good efficacy (Huys, 2019) with targets including:
- Ventral capsule/ventral striatum (VC/VS),
- Anterior limb of internal capsule (ALIC), and
- Nucleus accumbens (NAc).
Similarly, DBS has been used for the treatment of Tourette syndrome since 1999 by targeting GPi or thalamus—including centromedian-parafasicular, dorsomedial nucleus and ventral anterior and lateral nuclei (Clair, 2018). DBS for treatment-resistant severe depression has also been under investigation for more than a decade, with targets including VC/VS, NAc, subcallosal cingulate (SCC) and median forebrain bundle (Zhou, 2018). A blinded, sham-controlled study of VC/VS stimulation failed to show benefit during the blinded phase but was effective during the open portion of the study (Dougherty, 2015), and a randomized, sham-controlled trial of SCC stimulation was halted early due to the lack of a significant difference between treatment and sham arms (Holtzheimer, 2017). Interest remains high in revisiting the treatment of refractory depression with updated trial design, as informed by ongoing work in the field (Riva-Posse, 2018).
Previous experience with NAc or STN stimulation for other indications suggested an amelioration in co-morbid alcohol and tobacco use and, in some instances, a decrease in gambling, leading to interest in these targets for treating substance use disorders (Merola, 2017; Luigjes, 2018). NAc and lateral hypothalamic stimulation have been investigated for the treatment of obesity with resulting maintenance in body weight improvement (Pleger, 2018). Vagal nerve stimulation (VNS), FDA-approved for treating epilepsy and depression, has also been applied to obesity with a 23 percent excess weight loss in an experimental group versus 10 percent in control group at 18 months (Shikora 2015). Anorexia has been addressed by targeting subgenual cingulate cortex and NAc (Lozano 2019). While clinical trials for DBS for schizophrenia have been constructed, patient enrollment has been challenging due to unique factors associated with this patient population; however, a number of targets that may influence the striatum, including the ventral tegmental area, hippocampus, NAc, SNr and medial prefrontal cortex, are under consideration (Gault, 2018).
DBS of the anterior nucleus of thalamus was recently approved by the FDA as a treatment for epilepsy (Salanova, 2015), adding to the existing armamentarium of neuromodulatory therapies, including VNS and responsive neurostimulation (RNS), for patients with epilepsy who are not candidates for resection or ablation. While temporal lobectomy remains the gold standard for patients with mesial temporal lobe (MTS) epilepsy (Dwivedi, 2017), and the comparative efficacy of laser ablation amygdalohippocampectomy is currently under investigation (Wicks, 2016) in clinical trials, neuromodulation therapies offer an alternative to anticonvulsant medication alone for patients without MTS or with MTS combined with Wada testing that suggests a decline in memory would accompany resection or ablation. DBS and VNS are indicated for drug-resistant partial epilepsy that cannot be localized (Schachter 2002; Li, 2018). Stimulation of the hippocampus (Cukiert et al., 2017) and of the centromedian nucleus (Cukiert & Lehtimaki, 2017) are under investigation as future targets for DBS, and VNS continues to be used for the treatment of generalized epilepsy (Welch, 2018). RNS is a device that, in its current iteration, allows for sensing and stimulation from one or two strip and/or depth electrodes. Since the practice of stereo-electroencephalography (sEEG) depth electrode placement for seizure localization has gained acceptance, RNS has become a viable option for patients whose seizures arise from eloquent cortex (Jobst, 2017). However, a randomized, controlled trial comparing the efficacy of the various neuromodulation techniques mentioned above for the treatment of refractory non-resectable epilepsy, has not yet been performed.
Memory and Consciousness
A recent study in rats demonstrated that DBS might improve memory function following stroke by increasing synaptophysin expression and improving synaptic function (Gondard, 2019). DBS has been applied to treat memory decline in dementia by targeting the nucleus basalis of Meynert. Unfortunately, a recent phase II trial of forniceal DBS did not yield meaningful improvement in primary cognitive outcomes (Lozano, 2016; Lozano, 2019). DBS has also been implicated in improving consciousness after traumatic brain injury by targeting nuclei involved in consciousness and executive function, including the reticular formation, central and intralaminar nuclei of the thalamus and the centromedian parafascicular complex (Giacino, 2012; Chudy, 2017; Kundu, 2018).
Though Horsley and Clarke quarreled over the application of their famous frame to the first human patient, there has been a continued and spectacular impact on patient care from the field that they launched. Among other stereotactic techniques, DBS affords exciting potential treatment options for movement disorders, neuropsychiatric disease, and epilepsy. Optogenetics involves the focal application of light to achieve spatiotemporal change in neuronal function via cell-membrane-inserted opsins or G-protein-coupled receptors. This technique holds potential for application to STN function for ameliorating symptoms of PD (Jamebozorgi 2018) and is currently under investigation for disrupting epilepsy circuits in animal models (Delbeke, 2017). Looking forward, advances in allied fields such as optogenetics and brain-computer interface may further expand the potential applications of neurosurgery. We anticipate continued innovation and development in the field of functional neurosurgery and better therapies for our patients in the near term.
ReferencesClick to View
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