Letter to the Editor: Deep brain stimulation for schizophrenia

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TO THE EDITOR: We read with great interest the review by Mikell et al.3 (Mikell CB, Sinha S, Sheth SA: Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target. J Neurosurg 124:917–928, April 2016). These authors summarize current understanding of the pathophysiology of schizophrenia based on dysfunction in dopaminergic and glutamatergic signaling. They suggest several nodes of the basal ganglia–thalamocortical circuit as therapeutic targets for deep brain stimulation (DBS): the hippocampus, the ventral striatum, and the associative striatum.3 Regarding this dopamine dysregulation–based hypothesis, we believe that there are other targets that

TO THE EDITOR: We read with great interest the review by Mikell et al.3 (Mikell CB, Sinha S, Sheth SA: Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target. J Neurosurg 124:917–928, April 2016). These authors summarize current understanding of the pathophysiology of schizophrenia based on dysfunction in dopaminergic and glutamatergic signaling. They suggest several nodes of the basal ganglia–thalamocortical circuit as therapeutic targets for deep brain stimulation (DBS): the hippocampus, the ventral striatum, and the associative striatum.3 Regarding this dopamine dysregulation–based hypothesis, we believe that there are other targets that could be useful for DBS: the mediodorsal thalamus and the internal globus pallidus.1,4,5,9 Moreover, in the last few years, findings from voxel-based morphometry, diffusion tensor imaging, and functional MRI suggest structure and functional alterations of the medial prefrontal cortex, specifically the area correlated to the anterior midline node of the default mode network.6,8 This area corresponds to the subcallosal cingulate gyrus, which includes Brodmann area 25. The failure of task-related deactivation in this medial frontal cortex is related to the symptoms of schizophrenia. Actually, a meta-analysis of the whole-brain voxel-based approach revealed that abnormalities in white matter areas in schizophrenia were consistently identified across the studies in only 2 locations, one of them corresponding to this anterior cingulate subgenual area.2 This region has been stimulated with DBS in other neuropsychiatric disorders, and in our experience in treatment-resistant depression, no associated complications have been observed.7 We suggest that this could be another possible target for the treatment of resistant schizophrenia.

Schizophrenia remains one of the leading causes of disability worldwide, with 30% of patients refractory to treatment. We agree that given the severity of this disease and its high consumption of resources, new treatment strategies are needed. We are conducting a prospective, randomized, double-blind clinical trial (clinical trial no.: NCT02377505, clinicaltrials.gov) aimed at assessing the tolerability and efficacy of DBS in refractory schizophrenia (founding Grant Nos. PI12/00042 [E.A.] and PI12/00686 [S.S.] from the Instituto de Salud Carlos III). We randomized the therapeutic target (nucleus accumbens vs subgenual area), and after the start of stimulation and a period of clinical stability, we made a crossover phase of generator on or off. We are studying treatment response in terms of neuroimaging (MRI, PET) and clinical variables. Completion of this ongoing study and an exhaustive analysis of the data are needed for definitive answers.

References

  • 1

    Buchmann ADentico DPeterson MJRiedner BASarasso SMassimini M: Reduced mediodorsal thalamic volume and prefrontal cortical spindle activity in schizophrenia. Neuroimage 102:5405472014

  • 2

    Ellison-Wright IBullmore E: Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 108:3102009

  • 3

    Mikell CBSinha SSheth SA: Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target. J Neurosurg 124:9179282016

  • 4

    Mwansisya TEWang ZTao HZhang HHu AGuo S: The diminished interhemispheric connectivity correlates with negative symptoms and cognitive impairment in first-episode schizophrenia. Schizophr Res 150:1441502013

  • 5

    Oertel-Knöchel VKnöchel CMatura SRotarska-Jagiela AMagerkurth JPrvulovic D: Cortical-basal ganglia imbalance in schizophrenia patients and unaffected first-degree relatives. Schizophr Res 138:1201272012

  • 6

    Pomarol-Clotet ESalvador RSarró SGomar JVila FMartínez A: Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?. Psychol Med 38:118511932008

  • 7

    Puigdemont DPortella MPérez-Egea RMolet JGironell Ade Diego-Adeliño J: A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention. J Psychiatry Neurosci 40:2242312015

  • 8

    Salgado-Pineda PFakra EDelaveau PMcKenna PJPomarol-Clotet EBlin O: Correlated structural and functional brain abnormalities in the default mode network in schizophrenia patients. Schizophr Res 125:1011092011

  • 9

    Young KAManaye KFLiang CHicks PBGerman DC: Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia. Biol Psychiatry 47:9449532000

Disclosures

The authors report no conflict of interest.

Response

We thank the authors for their interest in our article. We are intrigued by the suggestion of the subgenual anterior cingulate cortex (Cg25) as a potential therapeutic target. Evidence from the original trial of DBS for depression1 indicating that Cg25 stimulation boosted dorsolateral prefrontal cortex and dorsal anterior cingulate cortex blood flow seems consistent with the idea that stimulation of this area could treat the frontal dysfunction observed in schizophrenia. We eagerly await the results of the authors' trial and agree that further work is needed to understand this difficult disease.

References

1

Mayberg HSLozano AMVoon VMcNeely HESeminowicz DHamani C: Deep brain stimulation for treatment-resistant depression. Neuron 45:6516602005

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Article Information

INCLUDE WHEN CITING Published online April 22, 2016; DOI: 10.3171/2015.12.JNS152874.

© AANS, except where prohibited by US copyright law.

Headings

References

1

Buchmann ADentico DPeterson MJRiedner BASarasso SMassimini M: Reduced mediodorsal thalamic volume and prefrontal cortical spindle activity in schizophrenia. Neuroimage 102:5405472014

2

Ellison-Wright IBullmore E: Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 108:3102009

3

Mikell CBSinha SSheth SA: Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target. J Neurosurg 124:9179282016

4

Mwansisya TEWang ZTao HZhang HHu AGuo S: The diminished interhemispheric connectivity correlates with negative symptoms and cognitive impairment in first-episode schizophrenia. Schizophr Res 150:1441502013

5

Oertel-Knöchel VKnöchel CMatura SRotarska-Jagiela AMagerkurth JPrvulovic D: Cortical-basal ganglia imbalance in schizophrenia patients and unaffected first-degree relatives. Schizophr Res 138:1201272012

6

Pomarol-Clotet ESalvador RSarró SGomar JVila FMartínez A: Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?. Psychol Med 38:118511932008

7

Puigdemont DPortella MPérez-Egea RMolet JGironell Ade Diego-Adeliño J: A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention. J Psychiatry Neurosci 40:2242312015

8

Salgado-Pineda PFakra EDelaveau PMcKenna PJPomarol-Clotet EBlin O: Correlated structural and functional brain abnormalities in the default mode network in schizophrenia patients. Schizophr Res 125:1011092011

9

Young KAManaye KFLiang CHicks PBGerman DC: Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia. Biol Psychiatry 47:9449532000

1

Mayberg HSLozano AMVoon VMcNeely HESeminowicz DHamani C: Deep brain stimulation for treatment-resistant depression. Neuron 45:6516602005

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