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      Neuromodulation Strategies in Post-Traumatic Stress Disorder: From Preclinical Models to Clinical Applications

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          Abstract

          Post-traumatic stress disorder (PTSD) is an often debilitating disease with a lifetime prevalence rate between 5–8%. In war veterans, these numbers are even higher, reaching approximately 10% to 25%. Although most patients benefit from the use of medications and psychotherapy, approximately 20% to 30% do not have an adequate response to conventional treatments. Neuromodulation strategies have been investigated for various psychiatric disorders with promising results, and may represent an important treatment option for individuals with difficult-to-treat forms of PTSD. We review the relevant neurocircuitry and preclinical stimulation studies in models of fear and anxiety, as well as clinical data on the use of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) for the treatment of PTSD.

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          Most cited references79

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          Neurons in medial prefrontal cortex signal memory for fear extinction.

          Conditioned fear responses to a tone previously paired with a shock diminish if the tone is repeatedly presented without the shock, a process known as extinction. Since Pavlov it has been hypothesized that extinction does not erase conditioning, but forms a new memory. Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinction, indicating that medial prefrontal cortex might store long-term extinction memory. Here we show that infralimbic neurons recorded during fear conditioning and extinction fire to the tone only when rats are recalling extinction on the following day. Rats that froze the least showed the greatest increase in infralimbic tone responses. We also show that conditioned tones paired with brief electrical stimulation of infralimbic cortex elicit low freezing in rats that had not been extinguished. Thus, stimulation resembling extinction-induced infralimbic tone responses is able to simulate extinction memory. We suggest that consolidation of extinction learning potentiates infralimbic activity, which inhibits fear during subsequent encounters with fear stimuli.
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            Traumatic events and posttraumatic stress disorder in an urban population of young adults.

            To ascertain the prevalence of posttraumatic stress disorder (PTSD) and risk factors associated with it, we studied a random sample of 1007 young adults from a large health maintenance organization in the Detroit, Mich, area. The lifetime prevalence of exposure to traumatic events was 39.1%. The rate of PTSD in those who were exposed was 23.6%, yielding a lifetime prevalence in the sample of 9.2%. Persons with PTSD were at increased risk for other psychiatric disorders; PTSD had stronger associations with anxiety and affective disorders than with substance abuse or dependence. Risk factors for exposure to traumatic events included low education, male sex, early conduct problems, extraversion, and family history of psychiatric disorder or substance problems. Risk factors for PTSD following exposure included early separation from parents, neuroticism, preexisting anxiety or depression, and family history of anxiety. Life-style differences associated with differential exposure to situations that have a high risk for traumatic events and personal predispositions to the PTSD effects of traumatic events might be responsible for a substantial part of PTSD in this population.
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              Which elements are excited in electrical stimulation of mammalian central nervous system: a review.

              J Ranck (1975)
              (1) There are data on the amount of current necessary to stimulate a myelinated fiber or cell body and/or its axon a given distance away from a monopolar electrode over the entire range of practical interest for intracranial stimulation. Data do not exist for other electrode configurations. (2) Currents from a monopolar cathode of more than 8 times threshold may block action potentials in axons. Therefore, only axons lying in a shell around the electrode are stimulated. Elements very close to the electrode may not be stimulated. Close to an electrode small diameter axons may be stimulated and larger ones may not be. (3) Most, and perhaps all, CNS myelinated fibers have chronaxies of 50-100 musec. When gray matter is stimulated, the chronaxie is often 200-700 musec. It is not clear what is being stimulated in this case. Current-duration relations should be determined for many more responses. (4) There are no current-distance or current-duration data for central finely myelinated or unmyelinated fibers. (5) It takes less cathodal current than anodal to stimulate a myelinated fiber passing by a monopolar electrode. When a monopolar electrode is near a cell body, on the opposite side from the axon, often the lowest threshold is anodal, but sometimes cathodal. Stimulation of a neuron near its cell body is not well understood, but in many cases the axon is probably stimulated. (6) Orientation of cell body and axons with respect to current flow is important. For an axon it is the component of the voltage gradient parallel to the fiber that is important. (7) The pia has a significant resistance and capacitance. Gray matter, white matter, and cerebrospinal fluid have different resistivities, which affect patterns of current flow. (8) More is known about stimulation of mammalian CNS than most workers are aware of. Much of what is unknown seems solvable with current methods.
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                Author and article information

                Journal
                Brain Sci
                Brain Sci
                brainsci
                Brain Sciences
                MDPI
                2076-3425
                19 February 2019
                February 2019
                : 9
                : 2
                : 45
                Affiliations
                [1 ]Sunnybrook Research Institute, Toronto, ON M4N3M5, Canada; flavia.venetuccigouveia@ 123456sunnybrook.ca (F.V.G.); darryl.gidyk@ 123456sri.utoronto.ca (D.C.G.); peter.giacobbe@ 123456sunnybrook.ca (P.G.); Nir.Lipsman@ 123456sunnybrook.ca (N.L.)
                [2 ]Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada; ying.meng@ 123456mail.utoronto.ca (Y.M.); benjamin.davidson@ 123456mail.utoronto.ca (B.D.); agessandro.abrahao@ 123456sunnybrook.ca (A.A.)
                [3 ]Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada; enoch.ng@ 123456utoronto.ca
                [4 ]Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada
                Author notes
                [* ]Correspondence: Clement.Hamani@ 123456sunnybrook.ca ; Tel.: +1-416-480-6100 (ext. 3318)
                Author information
                https://orcid.org/0000-0003-0029-1269
                https://orcid.org/0000-0003-1142-2842
                Article
                brainsci-09-00045
                10.3390/brainsci9020045
                6406551
                30791469
                f3641535-105c-47e2-b815-31cca5d77f0d
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 January 2019
                : 15 February 2019
                Categories
                Review

                deep brain stimulation,fear extinction,post-traumatic stress disorder,transcranial direct current stimulation,transcranial magnetic stimulation

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