Deep brain stimulation of the corticolimbothalamic loop: implications for the treatment of schizophrenia
Schizophrenia affects 1% of the population ranking as the ninth most prevalent cause of disability worldwide. Whilst effective pharmacological treatments exist for the positive symptoms associated with this disease the negative symptoms and cognitive deficits remain untreated. Here we propose a deep brain stimulation (DBS) strategy analogous to that used to great success in Parkinson's disease and describe methods for validation of this strategy in a rodent model of schizophrenia (Cochran et al. 2003; Neuropsychopharmacol. 28: 265-275; Pratt et al. 2008; Brit. J. Pharmacol. 153: S465-S470). Bipolar electrodes were fabricated by affixing pairs of 25µm, teflon insulated, nichrome wire to a supporting 100µm, stainless steel insect pin. These were implanted, bilaterally, into the medial-dorsal nucleus of the thalamus or the ventral pallidum of anaesthetised male Hooded Lister rats. High frequency stimulation (130Hz, 220µA, 100µs) was delivered unilaterally via a remotely controlled custom built DBS device whilst the “silent”, contralateral electrode served as a control. Cortical electrodes were fabricated by soldering wires to anchor screws and affixed to the skull above the prelimbic cortex (PrL) and referenced to an electrode implanted above the cerebellum. EEG recordings were taken throughout. Brains were removed and 20µm coronal sections were radio labelled for the immediate early genes (IEG) c-fos and zif-268 via hybridisation with a 45-mer oligonucleotide probe labelled with 33P-dATP overnight. The labelled sections were exposed to film for several days and a semi-quantitative comparison between the stimulated and control hemispheres was made by examination of the optical density of the resultant autoradiograms. Signals were processed to remove the stimulation artifact and noise and analysed to determine changes in delta and gamma power. This approach demonstrates our ability to explore DBS as a potential therapy for the cognitive dysfunction associated with the hypofrontality (reduced blood flow and metabolism in the prefrontal cortex) seen in schizophrenia. By analysis of changes in IEG and EEG activity we are able to identify the neural signatures evoked by DBS of various subcortical nuclei.
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