Trends in Neurosciences
ReviewDeep brain stimulation: from neurology to psychiatry?
Introduction
Human stereotaxy was initially developed to treat psychiatric disease by targeting subcortical structures using circumscribed lesion or focal chronic electrical stimulation 1, 2, 3, 4, 5, 6. Owing to the demise of psychosurgery following the lobotomy era and abuses of early attempts at deep brain stimulation (DBS) techniques in psychiatric patients 7, 8, and following the introduction of neuroleptic drugs, functional stereotaxy became limited to the treatment of Parkinson's disease (PD) and other movement disorders (torsion dystonia, action tremor). Such treatment mainly involved lesioning and occasionally DBS 9, 10, 11, 12 of various thalamic subnuclei and basal ganglia structures (globus pallidus, subthalamic region).
Neuromodulation using DBS is a reversible method that re-emerged in the 1990s as a more lenient alternative to lesional surgery in advanced PD, especially in bilateral procedures and when targeting the subthalamic nucleus (STN). Choice of the STN as a target for PD arose from studies on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of PD, which showed increased neuronal activity in the STN [13] and marked amelioration of parkinsonian features following its lesion [14]. This antiparkinsonian effect could be reproduced with DBS of the STN in this model [15] and later in PD patients 16, 17. More recently, DBS has been introduced in the field of psychiatry to modulate neuronal activity in the same areas that were targeted for lesioning in the past 18, 19. Progress in functional neuroimaging and a better understanding of the pathophysiology of psychiatric disorders have contributed to renewed interest in surgical approaches to drug-resistant psychiatric diseases. In this regard, DBS offers several advantages. First, efficacy can be tested in randomized, double-blind, controlled clinical trials 20, 21. Second, DBS can be switched on and off, so that acute effects can be studied in humans 22, 23. Third, it can be coupled to functional neuroimaging studies 24, 25. Finally, implanted electrodes can be used to record neuronal activity within the brain while the patient performs cognitive, emotional or motor tasks [26]. Thus, DBS is not only a therapeutic technique, but also constitutes a powerful tool for the study of brain functions. In this review, we discuss how the observation of non-motor effects of DBS of the STN in both intact animals and parkinsonian patients contributed to the transfer of this technique to the treatment of psychiatric disorders. We propose that focal neuromodulation of corticobasal ganglia (BG)–thalamocortical loops involved in the control of behaviour and emotions might represent a new treatment option in psychiatry paralleling the effect of motor circuit modulation for the treatment of movement disorders.
Section snippets
Surgery for PD: lessons for psychiatry?
PD is both a motor and a neuropsychiatric illness [27]. Dopaminergic treatment reverses akinesia and apathy, but excessive and uncontrolled dopaminergic stimulation, as typically occurs in PD patients treated chronically with levodopa, can lead to motor, cognitive and emotional manifestations that are essentially the opposite of the parkinsonian state (Table 1). Thus, the untreated and treated states of PD represent a model of opposite pathophysiological states linked to dysfunction in
Mechanisms of action of DBS
Experience with DBS in PD patients indicates that the stimulation frequency is a key factor in determining clinical efficacy [65]. Stimulation starts to reduce tremor at a frequency of approximately 50 Hz and reaches a plateau at ∼200 Hz. It is thought that low-frequency stimulation (LFS) activates neurons 66, 67, whereas high-frequency stimulation (HFS) of the STN resulted in neuronal inhibition in experiments in the rat [68] and monkey [69], in agreement with observations in PD patients [70].
Gilles de la Tourette syndrome
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder consisting of multiple motor and one or more vocal or phonic tics, with onset typically in early childhood. Comorbid neuropsychiatric symptoms occur in approximately 90% of patients; the most common of which are attention deficit hyperactivity disorder (ADHD) and OCD [80]. The ventral oral internus (Voi) and centromedial parafascicular (CMpf) thalamic nuclei 18, 81 were the first surgical target sites for stereotactic lesions
Conclusions
The main notion put forward here is that, just as in PD, in which dopamine depletion results in abnormal dysfunction of the motor circuit, psychiatric disorders such as GTS, OCD, depression and addiction are associated with dysfunction of non-motor cortical–BG loops. Thus, in the same manner as for movement disorders, surgery that targets the BG–thalamocortical loop can restore normal cortical activity associated with behavioural and mood disorders 24, 114, 138. DBS for the treatment of
Disclosure statement
Paul Krack has received a research grant and reimbursement of travel costs for attending scientific meetings from Medtronic, a manufacturer of DBS devices, and from the following manufacturers of antiparkinsonian drugs: Euthérapie, Novartis, Glaxo Smith Kline, Boehringer Ingelheim, Lundbeck. He has served on the Advisory Board of Novartis. Jose Obeso has served on the Advisory Board of Glaxo Smith Kline and received an honorarium for lecturing at meetings organized by Glaxo Smith Kline,
Acknowledgments
This article arose as a result of a meeting held in December 2008 (From movement to behaviour and emotions: role of the basal ganglia) jointly organized by Drs Jose Obeso and Julian Alvarez (Centro Internacional de Restauracion Neurologica, Havana, Cuba), with the support of Mr Damian Frontera and family (Valencia, Spain). We gratefully acknowledge Dr. Michael Paterson (CIBERNED, Seville, Spain) for editorial assistance in the preparation of this manuscript.
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