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Aim: Intermittent theta-burst stimulation (iTBS) delivered over the dorsomedial prefrontal cortex (DMPFC) has shown promise as a treatment for anhedonia and amotivation in patients with depression. Here, we investigated whether this protocol modulates cognitive performance and concurrent prefrontal blood oxygenation. We also examined whether depressed patients exhibit cognitive dysfunction and prefrontal hypoactivity at baseline compared to healthy controls. Methods: This sham-controlled study comprises 52 patients randomized to either active or sham accelerated iTBS over the DMPFC (applied twice daily) for 10 consecutive treatment days, and 55 healthy controls. Cognitive performance was assessed at baseline and once again 4 weeks later using a cognitive test battery targeting attention, inhibitory control, and numerical, verbal, and visual working memory. Concurrent prefrontal oxygenated hemoglobin (oxy-Hb) was captured with functional near-infrared spectroscopy. Results: Active iTBS over DMPFC did not affect cognitive performance or concurrent oxy-Hb change compared to sham iTBS in patients with depression. Compared to controls, patients at baseline showed impaired performance in the Trail Making Test,the Rey Auditory Verbal Learning Test, the Animal Naming Test, and the Digit Symbol Substitution Test, however no difference in prefrontal oxy-Hb was observed. Conclusion: Patients with treatment-resistant depression displayed cognitive deficits, however without prefrontal hypoactivity, compared to healthy controls at baseline. iTBS treatment did not alter cognitive performance, nor concurrent prefrontal blood oxygenation, in patients. Taken together, iTBS can likely be considered a cognitively safe treatment option in this sample of patients.

Aim: Intermittent theta-burst stimulation (iTBS) delivered over the dorsomedial prefrontal cortex (DMPFC) has shown promise as a treatment for anhedonia and amotivation in patients with depression. Here, we investigated whether this protocol modulates cognitive performance and concurrent prefrontal blood oxygenation. We also examined whether depressed patients exhibit cognitive dysfunction and prefrontal hypoactivity at baseline compared to healthy controls. Methods: This sham-controlled study comprises 52 patients randomized to either active or sham accelerated iTBS over the DMPFC (applied twice daily) for 10 consecutive treatment days, and 55 healthy controls. Cognitive performance was assessed at baseline and once again 4 weeks later using a cognitive test battery targeting attention, inhibitory control, and numerical, verbal, and visual working memory. Concurrent prefrontal oxygenated hemoglobin (oxy-Hb) was captured with functional near-infrared spectroscopy. Results: Active iTBS over DMPFC did not affect cognitive performance or concurrent oxy-Hb change compared to sham iTBS in patients with depression. Compared to controls, patients at baseline showed impaired performance in the Trail Making Test,the Rey Auditory Verbal Learning Test, the Animal Naming Test, and the Digit Symbol Substitution Test, however no difference in prefrontal oxy-Hb was observed. Conclusion: Patients with treatment-resistant depression displayed cognitive deficits, however without prefrontal hypoactivity, compared to healthy controls at baseline. iTBS treatment did not alter cognitive performance, nor concurrent prefrontal blood oxygenation, in patients. Taken together, iTBS can likely be considered a cognitively safe treatment option in this sample of patients.

Aim: Intermittent theta-burst stimulation (iTBS) delivered over the dorsomedial prefrontal cortex (DMPFC) has shown promise as a treatment for anhedonia and amotivation in patients with depression. Here, we investigated whether this protocol modulates cognitive performance and concurrent prefrontal blood oxygenation. We also examined whether depressed patients exhibit cognitive dysfunction and prefrontal hypoactivity at baseline compared to healthy controls. Methods: This sham-controlled study comprises 52 patients randomized to either active or sham accelerated iTBS over the DMPFC (applied twice daily) for 10 consecutive treatment days, and 55 healthy controls. Cognitive performance was assessed at baseline and once again 4 weeks later using a cognitive test battery targeting attention, inhibitory control, and numerical, verbal, and visual working memory. Concurrent prefrontal oxygenated hemoglobin (oxy-Hb) was captured with functional near-infrared spectroscopy. Results: Active iTBS over DMPFC did not affect cognitive performance or concurrent oxy-Hb change compared to sham iTBS in patients with depression. Compared to controls, patients at baseline showed impaired performance in the Trail Making Test,the Rey Auditory Verbal Learning Test, the Animal Naming Test, and the Digit Symbol Substitution Test, however no difference in prefrontal oxy-Hb was observed. Conclusion: Patients with treatment-resistant depression displayed cognitive deficits, however without prefrontal hypoactivity, compared to healthy controls at baseline. iTBS treatment did not alter cognitive performance, nor concurrent prefrontal blood oxygenation, in patients. Taken together, iTBS can likely be considered a cognitively safe treatment option in this sample of patients.

Aim: Intermittent theta-burst stimulation (iTBS) delivered over the dorsomedial prefrontal cortex (DMPFC) has shown promise as a treatment for anhedonia and amotivation in patients with depression. Here, we investigated whether this protocol modulates cognitive performance and concurrent prefrontal blood oxygenation. We also examined whether depressed patients exhibit cognitive dysfunction and prefrontal hypoactivity at baseline compared to healthy controls. Methods: This sham-controlled study comprises 52 patients randomized to either active or sham accelerated iTBS over the DMPFC (applied twice daily) for 10 consecutive treatment days, and 55 healthy controls. Cognitive performance was assessed at baseline and once again 4 weeks later using a cognitive test battery targeting attention, inhibitory control, and numerical, verbal, and visual working memory. Concurrent prefrontal oxygenated hemoglobin (oxy-Hb) was captured with functional near-infrared spectroscopy. Results: Active iTBS over DMPFC did not affect cognitive performance or concurrent oxy-Hb change compared to sham iTBS in patients with depression. Compared to controls, patients at baseline showed impaired performance in the Trail Making Test,the Rey Auditory Verbal Learning Test, the Animal Naming Test, and the Digit Symbol Substitution Test, however no difference in prefrontal oxy-Hb was observed. Conclusion: Patients with treatment-resistant depression displayed cognitive deficits, however without prefrontal hypoactivity, compared to healthy controls at baseline. iTBS treatment did not alter cognitive performance, nor concurrent prefrontal blood oxygenation, in patients. Taken together, iTBS can likely be considered a cognitively safe treatment option in this sample of patients.

Aim: Intermittent theta-burst stimulation (iTBS) delivered over the dorsomedial prefrontal cortex (DMPFC) has shown promise as a treatment for anhedonia and amotivation in patients with depression. Here, we investigated whether this protocol modulates cognitive performance and concurrent prefrontal blood oxygenation. We also examined whether depressed patients exhibit cognitive dysfunction and prefrontal hypoactivity at baseline compared to healthy controls. Methods: This sham-controlled study comprises 52 patients randomized to either active or sham accelerated iTBS over the DMPFC (applied twice daily) for 10 consecutive treatment days, and 55 healthy controls. Cognitive performance was assessed at baseline and once again 4 weeks later using a cognitive test battery targeting attention, inhibitory control, and numerical, verbal, and visual working memory. Concurrent prefrontal oxygenated hemoglobin (oxy-Hb) was captured with functional near-infrared spectroscopy. Results: Active iTBS over DMPFC did not affect cognitive performance or concurrent oxy-Hb change compared to sham iTBS in patients with depression. Compared to controls, patients at baseline showed impaired performance in the Trail Making Test,the Rey Auditory Verbal Learning Test, the Animal Naming Test, and the Digit Symbol Substitution Test, however no difference in prefrontal oxy-Hb was observed. Conclusion: Patients with treatment-resistant depression displayed cognitive deficits, however without prefrontal hypoactivity, compared to healthy controls at baseline. iTBS treatment did not alter cognitive performance, nor concurrent prefrontal blood oxygenation, in patients. Taken together, iTBS can likely be considered a cognitively safe treatment option in this sample of patients.

Negative symptoms in schizophrenia and core depressive symptoms share phenomenology and repetitive transcranial magnetic stimulation (rTMS) is a treatment modality for both conditions. The most common treatment site has been the dorsolateral prefrontal cortex (DLPFC) but there might be more optimal targets. Furthermore, the implementation of the currently approved protocols is hampered by the long duration. More intense stimulation protocols such as the theta burst stimulation (TBS) are significantly shorter and may be as effective and safe. The overall aim of this project is to evaluate the treatment effect of TBS on poor motivation and anhedonia in schizophrenia and depression and to explore the neurobiological correlates of these deficits. The dorsomedial prefrontal cortex (dmPFC) is a key cortical area in networks associated with motivation and anhedonia and it is affected in both schizophrenia and depression. The dmPFC has recently been identified as a possible site of stimulation and is now within reach by new angled coils that have deeper tissue penetration. Our study will enroll 38 patients with schizophrenia, 38 patients with depression and 38 healthy volunteers. Patients will be given daily TBS (totally 2400 pulses, 1200 on each hemisphere) over the dmPFC during 10 days. Target symptoms will be assessed with the Clinical Assessment Interview for Negative Symptoms (CAINS). We will also assess cortical excitability with paired-pulse stimulation and the pre-attentive memory function with mismatch negativity (MMN), spontaneous motor activity (assessed with 24 hours accelerometer) as well as autonomic nervous system tone (assessed by skin conductance, heart rate variability and breathing pattern). In addition, we will evaluate cognitive function (speed of processing, verbal fluency, auditory and working memory, visuospatial ability) during rest and stress.

A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.

Recent theories propose that both GABA and glutamate signaling are compromised in patients with schizophrenia. These deficits can be observed in several brain regions including the prefrontal cortex (PFC), an area extensively linked to the cognitive dysfunction in this disease and notably affected by NMDA receptor antagonists such as phencyclidine (PCP). We have previously demonstrated that inhibition of the nitric oxide (NO) pathways in the brain, particularly in the PFC, prevents a wide range of PCP-induced behavioral deficits including disruption of prepulse inhibition (PPI). This study investigated the role of GABAB receptor signaling and NO in the effects of PCP on PPI. Mice received systemic or prefrontal injections of the GABAB receptor agonist baclofen (2.5–5 mg/kg and 1 mM) before PCP treatment (5 mg/kg) and were thereafter tested for PPI. GABA/NO interactions were studied by combining baclofen and the NO synthase inhibitor L-NAME (20 mg/kg) in subthreshold doses. The role of GABAB receptors for NO production in vivo was assessed using NO-sensors implanted into the rat PFC. PCP-induced PPI deficits were attenuated in an additive manner by systemic baclofen treatment, whereas prefrontal microinjections of baclofen completely blocked the effects of PCP, without affecting PPI per se. The combination of baclofen and L-NAME was more effective in preventing the effects of PCP than any compound by itself. Additionally, baclofen decreased NO release in the PFC in a dose-related manner. This study proposes a role for GABAB receptor signaling in the effects of PCP, with altered NO levels as a downstream consequence. Thus, prefrontal NO signaling mirrors an altered level of cortical inhibition that may be of importance for information processing deficits in schizophrenia.

Phencyclidine exerts psychotomimetic effects in humans and is used as a pharmacological animal model for schizophrenia. We, and others, have demonstrated that phencyclidine induces cognitive deficits in rats that are associated with schizophrenia. These cognitive deficits can be normalized by inhibition of nitric oxide synthase. The development of selective microelectrochemical nitric oxide sensors may provide direct evidence for the involvement of nitric oxide in these effects. The aim of the present study was to use LIVE (long term in vivo electrochemistry) to investigate the effect of phencyclidine, alone or in combination with the nitric oxide synthase inhibitor L-NAME, on nitric oxide levels in the medial prefrontal cortex of freely moving rats. Phencyclidine (2 mg kg21) produced an increase in cortical nitric oxide levels and this increase was ameliorated by L-NAME (10 mg kg21). Tentatively, the results from the present study provide a biochemical rationale for the involvement of nitric oxide in the phencyclidine model of schizophrenia.

Recent theories propose that both GABA and glutamate signaling are compromised in patients with schizophrenia. These deficits can be observed in several brain regions including the prefrontal cortex (PFC), an area extensively linked to the cognitive dysfunction in this disease and notably affected by NMDA receptor antagonists such as phencyclidine (PCP). We have previously demonstrated that inhibition of the nitric oxide (NO) pathways in the brain, particularly in the PFC, prevents a wide range of PCP-induced behavioral deficits including disruption of prepulse inhibition (PPI). This study investigated the role of GABAB receptor signaling and NO in the effects of PCP on PPI. Mice received systemic or prefrontal injections of the GABAB receptor agonist baclofen (2.5–5 mg/kg and 1 mM) before PCP treatment (5 mg/kg) and were thereafter tested for PPI. GABA/NO interactions were studied by combining baclofen and the NO synthase inhibitor L-NAME (20 mg/kg) in subthreshold doses. The role of GABAB receptors for NO production in vivo was assessed using NO-sensors implanted into the rat PFC. PCP-induced PPI deficits were attenuated in an additive manner by systemic baclofen treatment, whereas prefrontal microinjections of baclofen completely blocked the effects of PCP, without affecting PPI per se. The combination of baclofen and L-NAME was more effective in preventing the effects of PCP than any compound by itself. Additionally, baclofen decreased NO release in the PFC in a dose-related manner. This study proposes a role for GABAB receptor signaling in the effects of PCP, with altered NO levels as a downstream consequence. Thus, prefrontal NO signaling mirrors an altered level of cortical inhibition that may be of importance for information processing deficits in schizophrenia.

Phencyclidine exerts psychotomimetic effects in humans and is used as a pharmacological animal model for schizophrenia. We, and others, have demonstrated that phencyclidine induces cognitive deficits in rats that are associated with schizophrenia. These cognitive deficits can be normalized by inhibition of nitric oxide synthase. The development of selective microelectrochemical nitric oxide sensors may provide direct evidence for the involvement of nitric oxide in these effects. The aim of the present study was to use LIVE (long term in vivo electrochemistry) to investigate the effect of phencyclidine, alone or in combination with the nitric oxide synthase inhibitor L-NAME, on nitric oxide levels in the medial prefrontal cortex of freely moving rats. Phencyclidine (2 mg kg21) produced an increase in cortical nitric oxide levels and this increase was ameliorated by L-NAME (10 mg kg21). Tentatively, the results from the present study provide a biochemical rationale for the involvement of nitric oxide in the phencyclidine model of schizophrenia.