Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target

Mikell, Charles B.; Sinha, Saurabh; Sheth, Sameer A.

doi:10.3171/2015.4.jns15120

Cited by 44 publications

(23 citation statements)

References 126 publications

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“…It is thus suggested that the striatum can be a therapeutic target for promoting SVZ neurogenesis. Clinically, this is achievable using deep brain stimulation (DBS) and brain-implanted devices of closed-loop technology (Krook-Magnuson et al, 2015; Mikell et al, 2016; Velasques et al, 2014). Other novel methods including optogenetics and pharmacogenetic may also have clinical potential of specific stimulation (Little and Brown, 2014; Peled, 2011).…”

Section: Discussionmentioning

confidence: 99%

Optogenetic stimulation of glutamatergic neuronal activity in the striatum enhances neurogenesis in the subventricular zone of normal and stroke mice

Song

Mohamad

et al. 2017

Neurobiology of Disease

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Neurogenesis in the subventricular zone (SVZ) of the adult brain may contribute to tissue repair after brain injuries. Whether SVZ neurogenesis can be upregulated by specific neuronal activity in vivo and promote functional recovery after stroke is largely unknown. Using the spatial and cell type specific optogenetic technique combined with multiple approaches of in vitro, ex vivo and in vivo examinations, we tested the hypothesis that glutamatergic activation in the striatum could upregulate SVZ neurogenesis in the normal and ischemic brain. In transgenic mice expressing the light-gated channelrhodopsin-2 (ChR2) channel in glutamatergic neurons, optogenetic stimulation of the glutamatergic activity in the striatum triggered glutamate release into SVZ region, evoked membrane currents, Ca2+ influx and increased proliferation of SVZ neuroblasts, mediated by AMPA receptor activation. In ChR2 transgenic mice subjected to focal ischemic stroke, optogenetic stimuli to the striatum started 5 days after stroke for 8 days not only promoted cell proliferation but also the migration of SVZ neuroblasts into the peri-infarct cortex with increased neuronal differentiation and improved long-term functional recovery. These data provide the first morphological and functional evidence showing a unique striatum-SVZ neuronal regulation via a semi-phasic synaptic mechanism that can boost neurogenic cascades and stroke recovery. The benefits from stimulating endogenous glutamatergic activity suggest a novel regenerative strategy after ischemic stroke and other brain injuries.

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Section: Discussionmentioning

confidence: 99%

Optogenetic stimulation of glutamatergic neuronal activity in the striatum enhances neurogenesis in the subventricular zone of normal and stroke mice

Song

Mohamad

et al. 2017

Neurobiology of Disease

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“…Based on these findings, we hypothesize that in this clearly defined subgroup, the pathophysiology involves deep brain structures that are not in reach of rTMS or transcranial direct current stimulation. In theory, deep brain stimulation would be the proper method for reaching these deep-seated targets [135], and our studies indicate the specific patient population for this method. However, we have little hope that this could ever become standard treatment for this patient group, which, by definition, is pathologically suspicious and often lacks a feeling of illness and confidence in any medical treatment.…”

Section: Clinical Implications Of Synopsismentioning

confidence: 99%

Systems Neuroscience of Psychosis: Mapping Schizophrenia Symptoms onto Brain Systems

et al. 2017

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Schizophrenia research has been in a deadlock for many decades. Despite important advances in clinical treatment, there are still major concerns regarding long-term psychosocial reintegration and disease management, biological heterogeneity, unsatisfactory predictors of individual course and treatment strategies, and a confusing variety of controversial theories about its etiology and pathophysiological mechanisms. In the present perspective on schizophrenia research, we first discuss a methodological pitfall in contemporary schizophrenia research inherent in the attempt to link mental phenomena with the brain: we claim that the time-honored phenomenological method of defining mental symptoms should not be contaminated with the naturalistic approach of modern neuroscience. We then describe our Systems Neuroscience of Psychosis (SyNoPsis) project, which aims to overcome this intrinsic problem of psychiatric research. Considering schizophrenia primarily as a disorder of interindividual communication, we developed a neurobiologically informed semiotics of psychotic disorders, as well as an operational clinical rating scale. The novel psychopathology allows disentangling the clinical manifestations of schizophrenia into behavioral domains matching the functions of three well-described higher-order corticobasal brain systems involved in interindividual human communication, namely, the limbic, associative, and motor loops, including their corticocortical sensorimotor connections. The results of several empirical studies support the hypothesis that the proposed three-dimensional symptom structure, segregated into the affective, the language, and the motor domain, can be specifically mapped onto structural and functional abnormalities of the respective brain systems. New pathophysiological hypotheses derived from this brain system-oriented approach have helped to develop and improve novel treatment strategies with noninvasive brain stimulation and practicable clinical parameters. In clinical practice, the novel psychopathology allows confining the communication deficits of the individual patient, shifting attention from the symptoms to the intact resources. We have studied this approach and observed important advantages for therapeutic alliances, personalized treatment, and de-escalation strategies. Future studies will further conjoin clinical definitions of psychotic symptoms with brain structures and functions, and disentangle structural and functional deficit patterns within these systems to identify neurobiologically distinct subsyndromes. Neurobiologically homogeneous patient groups may provide new momentum for treatment research. Finally, lessons learned from schizophrenia research may contribute to developing a comprehensive perspective on human experience and behavior that integrates methodologically distinct, but internally consistent, insights from humanities and neuroscience.

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“…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.…”

Section: Circuitrymentioning

confidence: 99%

“…[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. 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.…”

Section: Circuitrymentioning

confidence: 99%

“…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.…”

Section: Circuitrymentioning

confidence: 99%

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Neurosurgery for Refractory Schizophrenia: A Systematic Literature Review

Almeida

Aquino

Silva

2020

Arquivos Brasileiros de Neurocirurgia: Brazilian Neurosurgery

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Schizophrenia is a chronic and disabling psychiatric disease that can be refractory to conventional treatment. The present study aims to gather information about the circuitry related to schizophrenia to describe possible surgical targets, and to establish whether psychosurgery can be a safe and effective treatment option for refractory schizophrenia. A systematic review of the literature was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. An electronic search was performed in the Pubmed and BVSalud databases using medical subject headings (MeSH) combined with Boolean operators. Out of the 724 studies retrieved, 13 were included in the review. Regarding leucotomy without a stereotactic approach, we found side effects such as irritability, nervous excitement, cases of disinhibition, and compromised normal social control. In other stereotactic procedures, there was some improvement, mainly regarding aggressiveness and positive symptoms; an anterior capsulotomy had an efficacy rate of 74% according to the Clinical Global Impression (CGI) rating scales. The only deep brain stimulation (DBS) case report found in our study described a significant improvement in the positive and negative symptoms. The use of a stereotactic approach enables psychosurgery to be a safe and effective treatment option in cases of refractory schizophrenia, improving the quality of life and the symptoms. Cognitive and negative symptoms remain a challenge in the treatment of schizophrenia, revealing that more targets in the circuitry must be surgically explored. Furthermore, more clinical trials are needed to compare these many surgical techniques and targets, using a standard evaluation parameter. The results show that DBS has a promising future in the treatment of refractory schizophrenia.

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Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target

Cited by 44 publications

References 126 publications

Optogenetic stimulation of glutamatergic neuronal activity in the striatum enhances neurogenesis in the subventricular zone of normal and stroke mice

Optogenetic stimulation of glutamatergic neuronal activity in the striatum enhances neurogenesis in the subventricular zone of normal and stroke mice

Systems Neuroscience of Psychosis: Mapping Schizophrenia Symptoms onto Brain Systems

Neurosurgery for Refractory Schizophrenia: A Systematic Literature Review

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