Approaches to neuromodulation for schizophrenia

Abstract

Based on the success of deep brain stimulation (DBS) for treating movement disorders, there is growing interest in using DBS to treat schizophrenia (SZ). we review the unmet needs of patients with SZ and the scientific rationale behind the DBS targets proposed in the literature in order to guide future development of DBS to treat this vulnerable patient population. SZ remains a devastating disorder despite treatment. Relapse, untreated psychosis, intolerable side effects and the lack of effective treatment for negative and cognitive symptoms contribute to poor outcome. Novel therapeutic interventions are needed to treat SZ and DBS is emerging as a potential intervention. Convergent genetic, pharmacological and neuroimaging evidence implicating neuropathology associated with psychosis is consistent with SZ being a circuit disorder amenable to striatal modulation with DBS. Many of the DBS targets proposed in the literature may modulate striatal dysregulation. Additional targets are considered for treating tardive dyskinesia and negative and cognitive symptoms. A need is identified for the concurrent development of neurophysiological biomarkers relevant to SZ pathology in order to inform DBS targeting. Finally, we discuss the current clinical trials of DBS for SZ, and their ethical considerations. we conclude that patients with severe symptoms despite treatment must have the capacity to consent for a DBS clinical trial in which risks can be estimated, but benefit is not known. in addition, psychiatric populations should have access to the potential benefits of neurosurgical advances. CurreNT sTATe of TreATmeNT for sChizophreNiA► Schizophrenia (SZ) remains a devastating disorder despite antipsychotic, psychological and social treatments.

Neurosurgery for Refractory Schizophrenia: A Systematic Literature Review

“…12 Studies have also reported its benefit in reducing recurrence rates, decreasing the intensity of residual psychosis, and improving cognitive impairment by reducing the negative symptoms. 3 Results from the Corripio et al 25 case report revealed the great potential of this procedure, with a significant improvement in symptoms and only one side effect, which was reversible. 25 However, one disadvantage is the fact that it is still an invasive procedure that has the risk of causing edema, hemorrhages, and seizures.…”

“…Studies have shown that its hyperactivation would be the cause of the hyperdopaminergic state, since its activation stimulates GABAergic neurons in the NAcc, which, in turn, inhibits the GABAergic neurons of the globus pallidus (GP), which are responsible for the inhibition of the dopaminergic neurons in the VTA. 3,[11][12][13] In contrast, a hypodopaminergic state in the mesocortical circuit, linking the VTA to the PFC, would be related to negative symptoms. 1,2 According to the GABAergic and glutamatergic hypotheses, an imbalance in the dopaminergic pathways is related to changes in regulation caused by gamma-aminobutyric acid (GABA) and glutamate.…”

“…In this system, the ventral tegmental area (VTA) makes connections with the nucleus accumbens (NAcc), the septal nuclei, and the amygdala via the medial prosencephalic bundle, and with the prefrontal cortex (PFC) via the cingulate gyrus. [1][2][3]10,11 It is proposed that in psychosis the deregulation of the release of dopamine initially results in an incorrect reward stimulus that would be ignored in another situation, leading to an aberrant overhang in the upper cortical levels, and this would translate clinically as positive symptoms. 11 Activation of the hippocampus leads to the release of dopamine in the mesolimbic pathway.…”

“…1 It is estimated to reach 1% of the world's population, 2 and only 10% to 20% of schizophrenics are able to get a competitive job, leading to hardships in terms of self-sufficiency. 3 In addition, it is among the costliest medical conditions to have in the world. 4 The symptoms of schizophrenia are divided into three components: positive symptoms, which include hallucinations, confused thoughts, and abnormal or grossly disorganized motor behavior; negative symptoms, which are characterized by diminished emotional expression, alogia, dysfunction in socialization, avolition, and anhedonia; and cognitive impairments, which are expressed by attention deficit, impairment in working memory, and executive dysfunction.…”

Multidimensional Connectomics and Treatment-Resistant Schizophrenia: Linking Phenotypic Circuits to Targeted Therapeutics

“…There is current interest in targeting several important network hubs using DBS in ultra-resistant schizophrenia involved in basal ganglia-thalamocortical and DLPFC brain circuits. Hubs identified include the hippocampus, ventral and associated striatum, medial and DLPFC, substantia nigra, nucleus accumbens and the mediodorsal nucleus of the thalamus ( 203 – 205 ). These hubs have been chosen primarily based on known pathological findings in schizophrenia and/or their interconnectedness to other brain hubs that are circuit-specific and related to the excessive and mistimed dopamine release in the striatum.…”