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      Correlation between Motor Cortex Excitability Changes and Cognitive Impairment in Vascular Depression: Pathophysiological Insights from a Longitudinal TMS Study

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          Abstract

          Background. Transcranial magnetic stimulation (TMS) highlighted functional changes in dementia, whereas there are few data in patients with vascular cognitive impairment-no dementia (VCI-ND). Similarly, little is known about the neurophysiological impact of vascular depression (VD) on deterioration of cognitive functions. We test whether depression might affect not only cognition but also specific cortical circuits in subcortical vascular disease. Methods. Sixteen VCI-ND and 11 VD patients, age-matched with 15 controls, underwent a clinical-cognitive, neuroimaging, and TMS assessment. After approximately two years, all participants were prospectively reevaluated. Results. At baseline, a significant more pronounced intracortical facilitation (ICF) was found in VCI-ND patients. Reevaluation revealed an increase of the global excitability in both VCI-ND and VD subjects. At follow-up, the ICF of VCI-ND becomes similar to the other groups. Only VD patients showed cognitive deterioration. Conclusions. Unlike VD, the hyperfacilitation found at baseline in VCI-ND patients suggests enhanced glutamatergic neurotransmission that might contribute to the preservation of cognitive functioning. The hyperexcitability observed at follow-up in both groups of patients also indicates functional changes in glutamatergic neurotransmission. The mechanisms enhancing the risk of dementia in VD might be related either to subcortical vascular lesions or to the lack of compensatory functional cortical changes.

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          Most cited references51

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          Frontal-subcortical circuits and human behavior.

          This synthetic review was performed to demonstrate the utility of frontal-subcortical circuits in the explanation of a wide range of human behavioral disorders. Reports of patients with degenerative disorders or focal lesions involving frontal lobe or linked subcortical structures were chosen from the English literature. Individual case reports and group investigations from peer-reviewed journals were evaluated. Studies were included if they described patient behavior in detail or reported pertinent neuropsy-chological findings and had compelling evidence of a disorder affecting frontal-subcortical circuits. Information was used if the report from which it was taken met study selection criteria. Five parallel segregated circuits link the frontal lobe and subcortical structures. Clinical syndromes observed with frontal lobe injury are recapitulated with lesions of subcortical member structures of the circuits. Each prefrontal circuit has a signature behavioral syndrome: executive function deficits occur with lesions of the dorsolateral prefrontal circuit, disinhibition with lesions of the orbitofrontal circuit, and apathy with injury to the anterior cingulate circuit. Depression, mania, and obsessive-compulsive disorder may also be mediated by frontal-subcotical circuits. Movement disorders identify involvement of the basal ganglia component of frontal-subcortical circuits. Frontal-subcortical circuits mediate many aspects of human behavior.
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            Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial.

            Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.
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              VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants.

              The neural mechanisms underlying the cellular and behavioral responses to antidepressants are not yet known. Up-regulation of growth factors and adult neurogenesis suggest a role for one or more of these factors in the action of antidepressants. One candidate of interest is vascular endothelial growth factor (VEGF), which was initially characterized for its role in angiogenesis, but also exerts direct mitogenic effects on neural progenitors in vitro. Results of this study demonstrate that VEGF is induced by multiple classes of antidepressants at time points consistent with the induction of cell proliferation and therapeutic action of these treatments. We find that VEGF signaling through the Flk-1 receptor is required for antidepressant-induced cell proliferation. We also show that VEGF-Flk-1 signaling is required and sufficient for behavioral responses in two chronic and two subchronic antidepressant models. Taken together, these studies identify VEGF and VEGF-Flk-1 signaling as mediators of antidepressant actions and potential targets for therapeutic intervention.
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                Author and article information

                Journal
                Neural Plast
                Neural Plast
                NP
                Neural Plasticity
                Hindawi Publishing Corporation
                2090-5904
                1687-5443
                2016
                20 July 2016
                : 2016
                : 8154969
                Affiliations
                1Spinal Unit, Emergency Hospital “Cannizzaro”, 95126 Catania, Italy
                2Department of Neurology I.C., “Oasi” Institute for Research on Mental Retardation and Brain Aging (I.R.C.C.S.), 94018 Troina, Italy
                3Department of Medical and Surgical Sciences and Advanced Technologies, Section of Neurosciences, University of Catania, 95125 Catania, Italy
                4Department of Electrical, Electronics and Informatics Engineering, University of Catania, 95125 Catania, Italy
                5Department of Surgery and Medical-Surgical Specialties, University of Catania, 95125 Catania, Italy
                6Department of Medicine, Unit of Neurology, Neurophysiology, Neurobiology, Campus Bio-Medico University of Rome, 00128 Rome, Italy
                Author notes

                Academic Editor: Zygmun Galdzicki

                Author information
                http://orcid.org/0000-0003-0776-1411
                http://orcid.org/0000-0002-5659-662X
                http://orcid.org/0000-0001-9751-4478
                http://orcid.org/0000-0002-0911-2370
                http://orcid.org/0000-0002-9113-5925
                http://orcid.org/0000-0001-8332-6863
                Article
                10.1155/2016/8154969
                4971324
                27525127
                827572e0-4044-4dfb-b867-60321650c655
                Copyright © 2016 Manuela Pennisi et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 January 2016
                : 14 March 2016
                : 30 May 2016
                Categories
                Research Article

                Neurosciences
                Neurosciences

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