AANS Neurosurgeon | Volume 28, Number 1, 2019


To Infinity and Beyond: The Future of Stereotactic and Functional Neurosurgery

Print Friendly, PDF & Email

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.

Movement disorders

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).

Neuropsychiatric indications

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.


Click to View

1. Bond AE, Shah BB, Huss DS, Dallapiazza RF, Warren A, Harrison MB, Sperling SA, Wang XQ, Gwinn R, Witt J, Ro S, Elias WJ. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: a randomized controlled trial. JAMA Neurol 2017, 74(12):1412-8.

2. Burrows AM, Ravin PD, Novak P, Peters ML, Dessureau B, Swearer J, Pilitsis JG. Limbic and motor function comparison of deep brain stimulation of the zona incerta and subthalamic nucleus. Neurosurgery 2012, 70:125-30.

3. Chudy D, Deletis V, Rogic M, Paradzik V, Grahovac G. Deep brain stimulation for the early treatment of the minimal consciousness state and vegetative state. Stereotact Funct Neurosurg 2017, 90: 1-10.

4. Clair AH, Haynes W, Mallet L. Recent advances in deep brain stimulation in psychiatric disorders. F1000 Research 2018, 7: 699.

5. Cukiert A, Cukiert CM, Burattini JA, Mariani PP, Bezerra DF. Seizure outcome after hippocampal deep brain stimulation in patients with refractory temporal lobe epilepsy: a prospective, controlled, randomized, double-blind study. Epilepsia 2017, 58(10):1728-33.

6. Cukiert A, Lehtimaki K. Deep brain stimulation targeting in refractory epilepsy. Epilepsia 2017. 58:80-84.  

7. Delbeke J, Hoffman L, Mols K, Braeken D, Prodanov D. And then there was light: perspectives of optogenetics for deep brain stimulation and neuromodulation. Front Neurosci 2017, 11: 663.

8. Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O’Readon JP, Eskander EN, Baltuch GH, Machado AD, Kondziolka D, Cusin C, Evans KC, Price LH, Jacobs K, Pandya M, Denko T, Tyrka AR, Brelje T, Deckersbach T, Kubu C, Malone DA. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry 2015, 78(4): 240-8.

9. Dwivedi R, Ramanujam B, Chandra PS, Sapra S, Gulati S, Kalaivani M, Garg A, Bal CS, Tripathi M, Dwivedi SN, Sagar R, Sarkar C, Tripathi M. Surgery for drug-resistant epilepsy in children. N Engl J Med 2017, 377(17): 1639-47.

10. Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, Schwartz M, Hynynen K, Lozano AM, Shah BB, Huss D, Dallapiazza RF, Gwinn R, Witt J, Ro S, Eisenberg HM, Fishman PS, Gandhi D, Halpern CH, Chuang R, Butts Pauly K, Tierney TS, Hayes MT, Cosgrove GR, Yamaguchi T, Abe K, Taira T, Chang JW. A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med 2016, 375(8): 730-9.

11. Food and Drug Administration. “FDA approves first MRI-guided focused ultrasound device to treat essential tremor.” 2016. Accessed: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm510595.htm.

12. Gault JM, Davis R, Cascella NG, Saks ER, Corripio-Collado I, Anderson WS, Olincy A, Thompson JA, Pomarol-Clotet E, Sawa A, Daskalakis ZJ, Lipsman N, Abosch A. Approaches to neuromodulation for schizophrenia. J Neurol Neurosurg Psychiatry 2018, 89: 777-787.

13. Giacino J, Fins JJ, Machado A, Schiff ND. Central thalamic deep brain stimulation to promote recovery from chronic posttraumatic minimally conscious state: challenges and opportunities. Neuromodulation 2012, 15(4):339-49.

14. Gondard E, Teves L, Wang L, McKinnon C, Hamani C, Kalia SK, Carlen PL, Tymianski M, Lozano AM. Deep brain stimulation rescues memory and synaptic activity in a rat model of global ischemia. J Neurosci 2019, pii:1222-18. doi: 10.1523/JNEUROSCI.

15. Ho AL, Ali R, Connolly ID, Henderson JM, Dhall R, Stein SC, Halpern CH. Awake versus asleep deep brain stimulation for Parkinson’s disease: a critical comparison and meta-analysis. J Neurol Neurosurg Psychiatry 2018, 89(7): 687-691.

16. Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, Slavin KV, Berman J, McKhann GM, Patil PG, Rittberg BR, Abosch A, Pandurangi AK, Holloway KL, Lam RW, Honey CR, Neimat JS, Henderson JM, DeBattista C, Rothschild AJ, Pilitsis JG, Espinoza RT, Petrides G, Mogilner AY, Matthews K, Peichel D, Gross RE, Hamani C, Lozano AM, Mayberg HS. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lance Psychiatry 2017, 4: 839-49.

17. Huys D, Kohl S, Baldermann JC, Timmermann L, Sturm V, Visser-Vandewalle V, Kuhn J. Open-label trial of anterior limb of internal capsule-nucleus accumbens deep brain stimulation for obsessive compulsive disorder: insights gained. J Neurol Neurosurg Psychiatry 2019, 0 (1-3): doi:10.1136/jnnp-2018-318996.

18. Jamebozorgi K, Taghizadeh E, Rostami D, Pormasoumi H, Barreto GE, Hayat SMG, Sahebkar A. Cellular and molecular aspects of Parkinson treatment: future therapeutic perspectives. Mol Neurobiol 2018, doi: 10.1007/s12035-018-1419-8. 

19. Jobst BC, Kapur R, Barkley GL, Bazil CW, Berg MJ, Bergey GK, Boggs JG, Cash SS, Cole AJ, Duchowny MS, Duckrow RB, Edwards JC, Eisenschenk S, Fessler AJ, Fountain NB. Geller EB, Goldman AM, Goodman RR, Gross RE, Gwinn RP, Heck C, Herekar AA, Hirsch LJ, King-Stephens D, Labar DR, Marsh WR, Meador KJ, Miller I, Mizrahi EM, Murro AM, Nair DR, Noe KH, Olejniczak PW, Park YD, Rutecki P, Salanova V, Sheth RD, Skidmore C, Smith MC, Spencer DC, Srinivasan S, Tatum W, Van Ness P, Vossler DG, Wharen RE Jr, Worrell GA, Yoshor D, Zimmerman RS, Skarpaas TL, Morrell MJ. Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia 2017, 58(6):1005-14.

20. Kundu B, Brock AA, Englot DJ, Butson CR, Rolston JD. Deep brain stimulation for the treatment of disorders of consciousness and cognition in traumatic brain injury patients: a review. Neurosurg Focus 2018, 45(2): E14.

21. Li MCH, Cook MJ. Deep brain stimulation for drug-resistant epilepsy. Epilepsia 2018, 59(2): 273-90.

22. Lozano AM, Fosdick L, Chakravarty MM, Leoutsakos JM, Munro C, Oh E, Drake KE, Lyman CH, Rosenberg PB, Anderson WS, Tang-Wai DF, Pendergrass JC, Salloway S, Asaad WF, Ponce FA, Burke A, Sabbagh M, Wolk DA, Baltuch G, Okun MS, Foote KD, McAndrews MP, Glacobbe P, Targum SD, Lyketsos CG, Smith GS. A phase II study of fornix deep brain stimulation in mild Alzheimer’s disease. J Alzheimers Dis 2016, 54(2): 777-87.

23. Lozano AM, Hutchison WD, Kalia SK. What have we learned about movement disorders from functional neurosurgery? Ann Rev Neurosci 2017, 40: 453-477.

24. Lozano AM, Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 2013, 77: 406-24.

25. Lozano AM, Lipsman N, Bergman H, Brown P, Chabardes S, Chang JW, Matthews K, McIntyre CC, Schlaepfer TE, Schulder M, Temel Y, Volkmann J, Krauss JK. Deep brain stimulation: current challenges and future directions. Nat Rev Neurol 2019, doi: 10.1038/s41582-018-0128-2.

26. Luigjes J, Segrave R, de Joode N, Figee M, Denys D. Efficacy of invasive and non-invasive brain modulation interventions for addiction. Neuropsychol Rev 2018, doi: 10.1007/s11065-018-9393-5.

27. Merola A, Romagnolo A, Rizzi L, Rizzone MG, Zibetti M, Lanotte M, Mandybur G, Duker AP, Espay AJ, Lopiano L. Impulse control behaviors and subthalamic deep brain stimulation in Parkinson disease. J Neurol 2017, 264: 40-48.

28. Neumann WJ, Turner RS, Blankertz B, Mitchell T, Kuhn AA, Richardson RM. Toward electrophysiology-based intelligent adapative deep brain stimulation for movement disorders. Neurotherapeutics 2019, 16: 105-118.

29. Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, McIntyre CC, Gross RE, Mayberg HS. A connectoic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry 2018, 23(4): 843-49.

30. Pepper J, Hariz M, Zrinzo L. Deep brain stimulation versus anterior capsulotomy for obsessive-compulsive disorder: a review of the literature. J Neurosurg 2015, 122(5): 1028-37.

31. Pleger B. Invasive and non-invasive stimulation of the obese human brain. Front Neurosci 2018, 12: 884.

32. Sajonz BE, Amtage F, Reinacher PC, Jenkner C, Piroth T, Katzler J, Urbach H, Coenen VA. Deep brain stimulation for tremor tractographic versus traditional (DISTINCT): study protocol of a randomized controlled feasibility trial. JMIR Res Protoc 2016, 5(4): e244.

33. Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM, Labar D, Sperling MR, Sharan A, Sandok E, Handforth A, Stern JM, Chung S, Henderson JM, French J, Baltuch G, Rosenfeld WE, Garcia P, Barbaro NM, Fountain NB, Elias WJ, Goodman RR, Pollard JR, Troster AI, Irwin CP, Lambrecht K, Graves N, Fisher R, SANTE Study Group. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology 2015, 84(10):1017-25.

34. Schachter SC, Wheless JW. The evolving place of vagus nerve stimulation therapy. Neurology 2002, 59: S1-2.

35. Shikora SA, Wolfe BM, Apovian CM, Anvari M, Sarwer DB, Gibbons RD, Ikramuddin S, Miller CJ, Knudson MB, Tweden KS, Sarr MG, Billington CJ. Sustained weight loss with vagal nerve blockade but not with sham: 18-month results of the ReCharge trial. J Obes 2015, 365604. doi: 10.1155/2015/365604

36. Tinkhauser G, Pogosyan A, Debove I, Nowacki A, Shah SA, Seidel K, Tan H, Brittain JS, Petermann K, di Biase L, Oertel M, Pollo C, Brown P, Schuepbach M. Directional local field potentials: a tool to optimize deep brain stimulation. Mov Disord 2018, 33(1):159-64.

37. van Dijk KJ, Verhagen R, Bour LJ, Heida C, Veltink PH. Avoiding internal capsule stimulation with new eight-channel steering deep brain stimulation lead. Neuromodulation 2018, 21: 553-561.

38. Welch WP, Sitwat B, Sogawa Y. Use of vagus nerve stimulator on children with primary generalized epilepsy. J Child Neurol 2018, 33(7): 449-52.

39. Wicks RT, Jermakowicz WJ, Jagid JR, Couture DE, Willie JT, Laxton AW, Gross RE. Laser interstitial thermal therapy for mesial temporal lobe epilepsy. Neurosurgery 2016, 79: S83-91.

40. Zhou C, Zhang H, Qin Y, Tian T, Xu B, Chen J, Zhou X, Zeng L, Fang L, Qi X, Lian B, Wang H, Hu Z, Xie P. A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry 2018, 82:224-232.

Leave a Reply

Be the first to reply using the above form.