Neuroimaging Research Section

Toronto, Canada

Neuroimaging Research Section

Toronto, Canada
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Hamani C.,Neuroimaging Research Section | Hamani C.,Toronto Western Hospital | Nobrega J. N.,Neuroimaging Research Section
European Journal of Neuroscience | Year: 2010

Deep brain stimulation (DBS) is currently being investigated as a therapy for the treatment of depression. Despite promising results of recent clinical trials, neural and chemical mechanisms responsible for the effects of stimulation are still unclear. In this article, we review clinical and laboratory findings on DBS for depression. Particular emphasis will be given to aspects involved in the translation of data from animal models to humans and in our findings on the potential substrates involved in the antidepressant effects of DBS in rats.


Brown Z.J.,University of Toronto | Nobrega J.N.,University of Toronto | Nobrega J.N.,Neuroimaging Research Section | Erb S.,University of Toronto
Behavioural Brain Research | Year: 2011

We recently reported that central injections of noradrenaline (NA) induce reinstatement of cocaine seeking in rats. Here, we replicate and extend our finding to an additional dose of NA and show that it is associated with the induction of c-fos mRNA expression (a marker of neuronal activation) in functionally relevant brain regions, including the bed nucleus of the stria terminalis and central nucleus of the amygdala. © 2010 Elsevier B.V.


Creed-Carson M.,Neuroimaging Research Section | Creed-Carson M.,University of Toronto | Oraha A.,Neuroimaging Research Section | Oraha A.,University of Toronto | And 2 more authors.
Behavioural Brain Research | Year: 2011

An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT 2) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT 2A antagonist M100,907, the 5-HT 2C antagonist SB242,084 and the mixed 5-HT 2A/C antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT 2 receptor subtypes in both acute and chronic motor effects induced by HAL. Acutely, SB242,084 (0.5mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5mg/kg) and ketanserin (1mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT 2C but not 5-HT 2A mRNA levels were altered in several brain regions after chronic HAL. These results highlight the importance of 5-HT2 2C receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT 2C antagonism could be targeted as a key property in the development of new antipsychotic medications. © 2011 Elsevier B.V.


Dubiela F.P.,University of Sao Paulo | Queiroz C.M.,Federal University of Rio Grande do Norte | Moreira K.D.M.,University of Sao Paulo | Nobrega J.N.,Neuroimaging Research Section | And 3 more authors.
Behavioural Brain Research | Year: 2013

The present study addressed the effects of sleep deprivation (SD) on AMPA receptor (AMPAR) binding in brain regions associated with learning and memory, and investigated whether treatment with drugs acting on AMPAR could prevent passive avoidance deficits in sleep deprived animals. [3H]AMPA binding and GluR1 in situ hybridization signals were quantified in different brain regions of male Wistar rats either immediately after 96h of sleep deprivation or after 24h of sleep recovery following 96h of sleep deprivation. Another group of animals were sleep deprived and then treated with either the AMPAR potentiator, aniracetam (25, 50 and 100mg/kg, acute administration) or the AMPAR antagonist GYKI-52466 (5 and 10mg/kg, acute and chronic administration) before passive avoidance training. Task performance was evaluated 2h and 24h after training. A significant reduction in [3H]AMPA binding was found in the hippocampal formation of SD animals, while no alterations were observed in GluR1 mRNA levels. The highest dose of aniracetam (100mg/kg) reverted SD-induced impairment of passive avoidance performance in both retention tests, whereas GYKI-52466 treatment had no effect. Pharmacological enhancement of AMPAR function may revert hippocampal-dependent learning impairments produced after SD. We argue that such effects might be associated with reduced AMPAR binding in the hippocampus of sleep deprived animals. © 2013 Elsevier B.V.


Hamani C.,Neuroimaging Research Section | Hamani C.,Toronto Western Hospital | Diwan M.,Neuroimaging Research Section | Macedo C.E.,Laboratorio Of Psicobiologia | And 7 more authors.
Biological Psychiatry | Year: 2010

Background: Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). Methods: The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. Results: Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. Conclusions: Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS. © 2010 Society of Biological Psychiatry.


Natesan S.,King's College London | Reckless G.E.,Schizophrenia Program and the Center | Barlow K.B.L.,Neuroimaging Research Section | Nobrega J.N.,Neuroimaging Research Section | And 2 more authors.
International Journal of Neuropsychopharmacology | Year: 2011

While dopamine D2 receptor partial agonists (PAs) have been long considered for treating schizophrenia, only one, aripiprazole, is clinically available for therapeutic use. This raises critically important questions as to what is unique about aripiprazole and to what extent animal models can predict therapeutic success. A number of PAs whose clinical fate is known: aripiprazole, preclamol, terguride, OPC-4392 and bifeprunox were compared to haloperidol (a reference antipsychotic) in several convergent preclinical animal models; i.e. amphetamine-induced locomotion (AIL) and conditioned avoidance response (CAR), predictive of antipsychotic effects; unilateral nigrostriatal lesioned rats, a model of hypo-dopaminergia; striatal Fos induction, a molecular marker for antipsychotic activity; and side-effects common to this class of drugs: catalepsy (motor side-effects) and prolactaemia. The results were compared across drugs with reference to their measured striatal D2 receptor occupancy. All the PAs occupied striatal D2 receptors in a dose dependent manner, inhibited AIL and CAR, and lacked motor side-effects or prolactinaemia despite D 2 receptor occupancy exceeding 80%. At comparative doses, aripiprazole distinguished itself from the other PAs by causing the least rotation in the hypo-dopaminergic model (indicating the least intrinsic activity) and showed the highest Fos expression in the nucleus accumbens (indicating functional D 2 antagonism). Although a number of PAs are active in antipsychotic animal models, not all of them succeed. Given that only aripiprazole is clinically available, it can be inferred that low functional intrinsic activity coupled with sufficient functional antagonism as reflected in the animal models may be a marker of success. © 2011 CINP.


Hamani C.,Toronto Western Hospital | Hamani C.,Neuroimaging Research Section | Nobrega J.N.,Neuroimaging Research Section | Lozano A.M.,Toronto Western Hospital
Clinical Pharmacology and Therapeutics | Year: 2010

Deep brain stimulation (DBS) has dramatically changed the landscape of neurosurgery. Overall, the technique consists of the delivery of current into the brain parenchyma through implanted electrodes (Figure 1). It is estimated that 60,000 patients worldwide have received DBS, with the rate of accrual currently approaching 8,000 to 10,000 new patients a year. Although electrical stimulation has been used for more than 50 years to treat psychiatric disorders and pain, the technique as conducted today reemerged some 25 years ago, in the field of movement disorders. The striking clinical effects of DBS in these conditions and the similarities in outcome between stimulation and lesions soon prompted the investigation of the technique for various diseases previously treated by functional neurosurgeons. Equally important for the development of the therapy were imaging and electrophysiological studies. Because DBS modulates local neuronal activity and influences regions at a distance from the stimulated site, dysfunctional anatomic circuits and structures have been regarded as potential targets. Animal research has provided the rationale for the use of DBS in some applications of the therapy, although most experimental studies have been conducted to explore potential mechanisms for the effects of stimulation.


Bregman T.,Neuroimaging Research Section | Diwan M.,Neuroimaging Research Section | Nobrega J.N.,Neuroimaging Research Section | Hamani C.,Neuroimaging Research Section | Hamani C.,University of Toronto
Brain Stimulation | Year: 2014

Background Neuromodulation therapies are currently being investigated as potential treatments for depression. One of these treatments involves the stimulation of supraorbital branches of the trigeminal nerve. Objective To show that supraorbital stimulation is effective in preclinical models. Methods Rats were given supraorbital stimulation at different settings in the forced swim test (FST) and open field. Results Supraorbital stimulation did not induce an antidepressant-like response in rats undergoing the FST. This is in contrast to other neuromodulation treatments, such as deep brain stimulation, vagus nerve stimulation and electroconvulsive therapy, which are all effective in this paradigm. Conclusions Supraorbital stimulation was ineffective in rats undergoing the FST. Such findings do not invalidate results of recent clinical trials. © 2014 Elsevier Inc.


Hamani C.,Neuroimaging Research Section | Hamani C.,Toronto Western Hospital | Diwan M.,Neuroimaging Research Section | Isabella S.,Neuroimaging Research Section | And 2 more authors.
Journal of Psychiatric Research | Year: 2010

Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is currently being investigated as a treatment for major depression. Despite the encouraging findings of the initial clinical series, several questions remain unanswered, including the most effective stimulation parameters (i.e., current intensity and frequency) and whether unilateral stimulation is also beneficial. We have recently found that some of the effects of SCG DBS could be modeled by stimulating the ventromedial prefrontal cortex (vmPFC) of rats undergoing the forced swim test (FST). Here we investigate whether changes in a number of DBS parameters, including electrode placement, influence outcome in this paradigm. Overall, we found that the antidepressant-like effects of DBS varied as a function of stimulation settings and target. The strongest response was observed with a current intensity of 200μA, followed by 100μA, and 300μA. In contrast, 400μA produced no effect. Using 200μA, a frequency of 130. Hz was more effective than 20. Hz. An intriguing finding was that left unilateral stimulation was as effective as bilateral DBS. When different targets within the vmPFC were considered, a significant antidepressant-like response was observed after PL DBS, whereas IL stimulation was associated with a non-significant reduction in immobility scores. In summary, vmPFC DBS at high frequency and moderate intensity led to a maximal response in the FST. © 2010 Elsevier Ltd.


Creed M.,University of Toronto | Hamani C.,Neuroimaging Research Section | Hamani C.,Toronto Western Hospital | Nobrega J.N.,University of Toronto | Nobrega J.N.,Neuroimaging Research Section
European Neuropsychopharmacology | Year: 2011

Deep brain stimulation (DBS) has recently emerged as a potential intervention for treatment-resistant tardive dyskinesia (TD). Despite promising case reports, no consensus exists as yet regarding optimal stimulation parameters or neuroanatomical target for DBS in TD. Here we report the use of DBS in an animal model of TD. We applied DBS (100 μA) acutely to the entopeduncular nucleus (EPN) or subthalamic nucleus (STN) in rats with well established vacuous chewing movements (VCMs) induced by 12. weeks of haloperidol (HAL) treatment. Stimulation of the STN or EPN resulted in significant reductions in VCM counts at frequencies of 30, 60 or 130. Hz. In the STN DBS groups, effects were significantly more pronounced at 130. Hz than at lower frequencies, whereas at the EPN the three frequencies were equipotent. Unilateral stimulation at 130. Hz was also effective when applied to either nucleus. These results suggest that stimulation of either the EPN or STN significantly alleviates oral dyskinesias induced by chronic HAL. The chronic HAL VCM model preparation may be useful to explore mechanisms underlying DBS effects in drug-induced dyskinesias. © 2010 Elsevier B.V.

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