Deep brain stimulation of the mediodorsal thalamic nucleus and its implications for the treatment of schizophrenia
Background: Whilst antipsychotic drugs treat the positive symptoms associated with schizophrenia they have limited effects against the negative symptoms and cognitive deficits. Here a deep brain stimulation (DBS) strategy analogous to that used in Parkinson's disease is proposed. Methods for the validation of this strategy in a phencyclidine (PCP) rat model of schizophrenia are described. Given the weight of evidence implicating disruption of the thalamo-cortical system, particularly the mediodorsal thalamic nucleus (MD) and prefrontal cortex (PFC), studies have focussed on investigation of the consequences of high frequency stimulation of the MD. Results are reported in terms of spectral analysis of the electrocorticogram (ECoG) and the expression of the immediate early genes (IEGs) zif-268 and c-fos.
Methods: In the study concerning the expression of IEGs, custom made bipolar stimulating electrodes were implanted bilaterally into the MD of isoflurane anaesthetised rats. Stimulation was delivered unilaterally to either the right or left MD whilst the contralateral hemisphere served as a control. High frequency stimulation stimulation (Frequency, 130 Hz; Amplitude, 200 μA; Pulse Width, 100 μs) was delivered for 3 hours via a custom designed and made deep brain stimulation device. Brains were then removed, sectioned and radio labelled for the immediate early genes zif-268 and c-fos before being exposed to X-ray film for 8 days. The relative optical density of the resultant autoradiograms were analysed with MCID, a computer based optical densitometer. In the study concerning the spectral analysis of the ECoG, custom made bipolar stimulating electrodes were implanted unilaterally into the left MD of rats treated sub-chronically with PCP (2.6 mg/kg for 5 days, 3 day washout) or saline. Animals were anaesthetised with isoflurane and 7 screw electrodes were implanted in the skull overlying the cortex of the left hemisphere and one in the skull overlying the cerebellum. Differential ECoG recordings were made between the 7 cortical electrodes and the cerebellar electrode. Baseline ECoG recordings were made for 30 minutes before delivering high frequency stimulation (Frequency, 130 Hz; Amplitude, 200 μA; Pulse Width, 100 μs) for 1 hour via a custom designed and made deep brain stimulation device. A bipolar montage was derived by subtracting the signals from adjacent electrodes. The power spectra of the derived signals was computed using Fourier methods and the absolute band power computed for the delta (1-4 Hz) and theta bands (4-8 Hz). In addition the coherence between electrodes was computed in the delta and theta bands.
Results: In isoflurane anaesthetised rats DBS of the MD produced robust increases in the expression of zif-268 but not c-fos localised to the efferent targets of the MD, indicating an increase in neural activity in the PFC. Increases in frontal delta power and parietal theta power were demonstrated in PCP treated animals when compared with saline treated controls. Furthermore PCP treated animals exhibited increased delta coherence at frontal electrode locations and reduced theta coherence at parietal/somatosensory electrode locations. High frequency stimulation of the MD yields transient increases in delta and theta power at frontal electrode locations.
Discussion: Impairment in the ability to recruit the prefrontal cortex is frequently reported in schizophrenia. The results of these experiments demonstrate activation of frontal cortical regions as a consequence of deep brain stimulation of the MD. Furthermore quantitative analysis of the ECoG demonstrates a spectral profile, in rats treated sub-chronically with PCP, similar to that seen in schizophrenic patients.
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