Deep brain stimulation improves behavior and modulates neural circuits in a rodent model of schizophrenia

Abstract

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Deep brain stimulation (DBS) is a surgical technique currently investigated for medically-refractory psychiatric disorders. Here, we use the poly I:C rat model of schizophrenia to study the effects of medial prefrontal cortex (mPFC) and nucleus accumbens (Nacc) DBS on two behavioral schizophrenia-like deficits, i.e. sensorimotor gating, as reflected by disrupted prepulse inhibition (PPI), and attentional selectivity, as reflected by disrupted latent inhibition (LI). In addition, the neurocircuitry influenced by DBS was studied using FDG PET. We found that mPFC-and Nacc-DBS alleviated PPI and LI abnormalities in poly I:C offspring, whereas Nacc-but not mPFC-DBS disrupted PPI and LI in saline offspring. In saline offspring, mPFC-DBS increased metabolism in the parietal cortex, striatum, ventral hippocampus and Nacc, while reducing it in the brainstem, cerebellum, hypothalamus and periaqueductal gray. Nacc-DBS, on the other hand, increased activity in the ventral hippocampus CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptand olfactory bulb and reduced it in the septal area, brainstem, periaqueductal gray and hypothalamus. In poly I:C offspring changes in metabolism following mPFC-DBS were similar to those recorded in saline offspring, except for a reduced activity in the brainstem and hypothalamus. In contrast, Nacc-DBS did not induce any statistical changes in brain metabolism in poly I:C offspring. Our study shows that mPFC-or Nacc-DBS delivered to the adult progeny of poly I:C treated dams improves deficits in PPI and LI. Despite common behavioral responses, stimulation in the two targets induced different metabolic effects.

Amotivation is associated with smaller ventral striatum volumes in older patients with schizophrenia

“…A better understanding of the biological mechanisms underlying reduced VS volume and activity may help guide future treatments for amotivation in schizophrenia. For example, these findings support theories that deep-brain stimulation of the VS may improve motivational deficits in schizophrenia, [57][58][59] as in depression. 60 Volumetric reductions are usually interpreted as reflecting neurodegeneration.…”

Response to Deep Brain Stimulation in Three Brain Targets with Implications in Mental Disorders: A PET Study in Rats

“…We show that the effects of high frequency DBS on neuronal activity, reflected as the differences in regional glucose metabolism between DBS on and off conditions, involve modifications of complex networks rather than global or isolated regions. This is in agreement with our previous study for mPFC and NAcc stimulation in an animal model of schizophrenia [12]. Its capability to either increase or decrease activity supports the notion that DBS induces several mechanisms that lead to net inhibitory and excitatory effects irrespective of the function [48], suggesting a complex modulation of activity along cortico-basal ganglia-thalamo-cortical and the cerebello-thalamo-cortical circuits.…”

“…The idea to extend DBS to the treatment of psychiatric disorders was based on the notion that psychiatric disorders are the clinical presentation of dysfunctional brain networks and the observation that DBS induces depressive and hypomanic states in Parkinson’s disease patients [4]. Meanwhile, DBS in the ventral capsule/ventral striatum (VC/VS), which contains the nucleus accumbens (NAcc), has received FDA approval for treatment of obsessive compulsive disorders, is being tested for treatment of depressive disorders [5–7] and addiction [8–11] and the first preclinical report on successful DBS in the context of schizophrenia has just been published [12]. The only double-blind sham-controlled trials for chronic treatment-resistant depression stimulated the VC/VS[13] and Brodmann area 25[14], obtaining little success.…”

“…Positron emission tomography (PET) with 2-deoxy-2-[ 18 F]fluoro-D-glucose ( 18 FDG) constitutes the traditional technique for in vivo direct quantification of regional brain glucose metabolism in humans and rodents [12, 18, 31–35]. The method has proven itself as an excellent tool for promoting our understanding of the neurobiological processes in healthy as well as diseased brains and allows for reliable comparative studies [36–40].…”

Prepulse inhibition of the blink reflex is abnormal in functional movement disorders

“…PPI is regulated by specific neurochemical and anatomical substrates within the prefrontal cortex, thalamus, amygdala, hippocampus, striatum, pallidum, and the pedunculopontine nucleus, with a central role of the ventral striatum/nucleus accumbens . Lack of differences between FMD patients and controls in the unconditioned blink reflex suggest that there is normal integrity of brainstem circuits.…”