Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study.

Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.

Combining Trauma Script Exposure With rTMS to Reduce Symptoms of Post-Traumatic Stress Disorder: Randomized Controlled Trial.

BACKGROUND: Innovative therapeutic interventions for post-traumatic stress disorder (PTSD) are required. We opted to facilitate fear extinction by combining trauma script exposure with repetitive transcranial magnetic stimulation (rTMS) to reduce symptoms of PTSD. OBJECTIVE: The efficacy and safety of 10 Hz rTMS of the right dorsolateral prefrontal cortex simultaneously with exposure to personal traumatic narrative were studied in patients with PTSD. MATERIALS AND METHODS: This trial was a single-center randomized controlled trial (NCT02584894). Patients were randomly assigned 1:1 to receive eight daily sessions of 110% of motor threshold high frequency (HF) 10 Hz rTMS (110% HF rTMS) or 70% low frequency (LF) 1 Hz rTMS (70% LF rTMS) with trauma script exposure in both groups. Severity of PTSD, depression, and anxiety were assessed before and after study treatment (one month, three months) by an assessor masked to the trial group assignment. The primary outcome was the severity of PTSD assessed by the Clinician Administered PTSD Scale (CAPS). We used mixed linear regression models for statistical comparisons. RESULTS: Thirty-eight patients (65.8% females) were randomly assigned to 110% HF rTMS (n = 18, 31.3 ± 10.0 years, 13 females) or 70% LF rTMS (n = 20, 33.5 ± 11.1 years, 12 females). From baseline to three months, mean CAPS scores decreased by 51% in the 110% HF rTMS group (from 83.7 ± 14.4 to 41.8 ± 31.9) and by 36.9% in the 70% LF rTMS group (from 81.8 ± 15.6 to 51.6 ± 23.7), but with no significant difference in improvement (time by treatment interaction -3.61 [95% confidence interval (CI), -9.70 to 2.47]; p = 0.24; effect size 0.53). One serious adverse event occurred during the study (psychogenic nonepileptic seizure). CONCLUSION: We found no evidence of difference in clinical improvement or remission rates between the 110% HF and 70% LF stimulation. These findings may reflect the importance of exposure procedure and that larger number of participants is needed.

Neuroinflammation and depression: A review.

Some recent clinical and preclinical evidence suggests that neuroinflammation is a key factor that interacts with the three neurobiological correlates of major depressive disorder: depletion of brain serotonin, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and alteration of the continuous production of adult-generated neurons in the dentate gyrus of the hippocampus. This review discusses the main players in brain immunity as well as how inflammation interacts with the above three mechanisms. It is reported that kynurenine (KYN) pathway alteration in favour of its excitotoxic component and HPA axis dysregulation have the common effect of increasing extracellular glutamate levels and glutamate neurotransmission, which can impact hippocampal neurogenesis. This pathophysiological cascade appears to be triggered or sustained and reinforced by any chronic inflammatory condition involving increased circulating markers of inflammation that are able to cross the blood-brain barrier and activate microglia; it can also be the consequence of primary brain neuroinflammation, such as in neurodegenerative disorders with early manifestations that are frequently depressive symptoms. Further recent data indicate that primary microglial activation may also result from a direct impact of chronic stress on vascular function. The intricated dynamic crosstalk between neuroinflammation and other relevant neurobiological correlates of depression add to evidence that neuroinflammation may be a key therapeutic target for future therapeutic strategies in major depressive disorder.

Brain immune cells characterization in UCMS exposed P2X7 knock-out mouse.

BACKGROUND: Several lines of evidence suggest that neuroinflammation might be a key neurobiological mechanism of depression. In particular, the P2X7 receptor (P2X7R), an ATP-gated ion channel involved in activation of the pro-inflammatory interleukin IL-1ß, has been shown to be a potential new pharmacological target in depression. The aim of this study was to explore the impact of unpredictable chronic mild stress (UCMS) on behavioural changes, hippocampal neurogenesis, and cellular characterisation of brain immune cells, in P2X7R Knock-Out (KO) mice. METHODS: P2X7R KO and wild-type (WT) mice were subjected to a 6-week UCMS protocol and received a conventional oral antidepressant (15 mg.kg-1 fluoxetine) or water per os. The mice then underwent behavioural tests consisting of the tail suspension test (TST), the elevated plus maze (EPM) test, the open field test, the splash test and the nest building test (week 7). Doublecortin immunostaining (DCX) of brain slices was used to assess neurogenesis in the dentate gyrus. Iba1 and TMEM119 immunostaining was used to characterise brain immune cells, Iba1 as a macrophage marker (including microglial cells) and TMEM119 as a potential specific resident microglial cells marker. RESULTS: After a 6-week UCMS exposure, P2X7R KO mice exhibited less deterioration of their coat state, spent a significantly smaller amount of time immobile in the TST and spent a larger amount of time in the open arms of the EPM. As expected, adult ventral hippocampal neurogenesis was significantly decreased by UCMS in WT mice, while P2X7R KO mice maintained ventral hippocampal neurogenesis at similar levels in both control and UCMS conditions. In stress-related brain regions, P2X7R KO mice also exhibited less recruitment of Iba1+/TMEM119+ and Iba1+/TMEM119- cells in the brain. The ratio between these two staining patterns revealed that brain immune cells were mostly composed of Iba1+/TMEM119+ cells (87 to 99%), and this ratio was affected neither by P2X7R genetic depletion nor by antidepressant treatment. DISCUSSION: Behavioural patterns, neurogenesis levels and density of brain immune cells in P2X7R KO mice after exposure to UCMS significantly differed from control conditions. Brain immune cells were mostly increased in brain regions known to be sensitive to UCMS exposure in WT but not in P2X7R KO mice. Considering Iba1+/TMEM119- staining might characterize peripheral immune cells, the ratio between Iba1+/TMEM119+ cells and IBA1+/TMEM119- cells, suggests that the rate of peripheral immune cells recruitment may not be modified neither by P2X7R gene expression nor by antidepressant treatment.

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

BACKGROUND: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. METHODS: Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. RESULTS: Relative to the control group, the survivors group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivors group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivors group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. LIMITATIONS: The small sample size was the main limitation of this study. CONCLUSION: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

BACKGROUND: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. METHODS: Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. RESULTS: Relative to the control group, the survivor group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivor group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivor group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. LIMITATIONS: The small sample size was the main limitation of this study. CONCLUSION: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.

Fluoxetine induces paradoxical effects in C57BL6/J mice: comparison with BALB/c mice.

The C57BL6/J mouse is the most commonly used strain in genetic investigations and behavioural tests. However, only a few studies have used C57BL6/J mice to assess the effects of antidepressant compounds. We carried out a study to compare the behavioural effects of fluoxetine (FLX) in a model of depression in two mice strains: C57BL6/J and BALB/c. We used an 8-week unpredictable chronic mild stress (UCMS) protocol during which FLX was administered (15 mg/kg, oral) from the third week to the end of the protocol. We found that UCMS induced degradation of the coat state in the two strains. Moreover, as expected, we observed that FLX elicited antidepressant-like effects in the BALB/c mice by reducing the coat state deterioration and the latency of grooming in splash test. However, in the C57BL6/J mice, it did not induce this action, but instead triggered an opposite effect: an increased sniffing latency in the novelty suppression of feeding test. We conclude that FLX exerts a paradoxical effect in the C57Bl6/J strain. This observation is consistent with some clinical features of hyper-reactivity to FLX observed in humans. Therefore, the UCMS protocol used in C57Bl6/J mice could be a good model to study the mechanisms of the paradoxical effects caused by selective serotonin reuptake inhibitors.

Influence of Stress Severity on Contextual Fear Extinction and Avoidance in a Posttraumatic-like Mouse Model.

Posttraumatic stress disorder (PTSD) is a widespread fear-related psychiatric affection associated with fear extinction impairments and important avoidance behaviors. Trauma-related exposure therapy is the current first-hand treatment for PTSD, yet it needs to be improved to shorten the time necessary to reach remission and increase responsiveness. Additional studies to decipher the neurobiological bases of extinction and effects on PTSD-like symptoms could therefore be of use. However, a PTSD-like animal model exhibiting pronounced PTSD-related phenotypes even after an extinction training directly linked to the fearful event is necessary. Thus, using a contextual fear conditioning model of PTSD, we increased the severity of stress during conditioning to search for effects on extinction acquisition and on pre- and post-extinction behaviors. During conditioning, mice received either two or four electrical shocks while a control group was constituted of mice only exposed to the context. Stressed mice exhibited important fear generalization, high fear reaction to the context and selective avoidance of a contextual reminder even after the extinction protocol. Increasing the number of footshocks did not induce major changes on these behaviors.

Region-dependent and stage-specific effects of stress, environmental enrichment, and antidepressant treatment on hippocampal neurogenesis.

Chronic stress and depression are associated with decreased levels of hippocampal neurogenesis. On the other hand, antidepressants as well as environmental enrichment may rely in part on their pro-neurogenic effects to improve cognition and mood. Because a functional heterogeneity has been consistently reported along the septo-temporal axis of the hippocampus, regional changes in neurogenesis could differentially contribute to these effects and affect distinct hippocampal functions. Mapping these regional changes could therefore provide a better understanding of the function of newborn neurons. While some studies report region-specific effects of stress and antidepressants on neurogenesis, it is unclear whether these changes affect distinct populations of newborn neurons according to their developmental stage in a region-specific manner. By using endogenous markers and BrdU labeling we quantified the regional changes in cell proliferation and survival as well as in the number of neuronal progenitors and immature neurons following unpredictable chronic mild stress (UCMS), environmental enrichment (EE) and chronic fluoxetine (20 mg/kg/day) treatment along the septo-temporal axis of the hippocampus. EE promoted cell proliferation and survival of 4-week-old newborn cells as well as increased the number and proportion of post-mitotic immature neurons specifically within the septal hippocampus. By contrast, UCMS uniformly decreased cell proliferation, survival and immature newborn neurons but differentially affected progenitor cells with a decrease restricted to the temporal regions of the hippocampus. Whereas fluoxetine treatment in control mice affected proliferation and survival specifically in the temporal hippocampus, it reversed most of the UCMS-induced alterations all along the septo-temporal axis. These results highlight that different factors known for exerting a mood improving effect differentially regulate neurogenesis along the septo-temporal axis of the hippocampus. Such region and stage specific effects may correlate to distinct functional properties of newborn neurons along the septo-temporal axis of the hippocampus which may contribute differently to the pathophysiology of affective disorders.

Guidelines for successful motor cortex ultrasonic neurostimulation in mice.

BACKGROUND: Ultrasound neurostimulation (USNS) is a non-invasive neuromodulation technique that might hold promise for treating neuropsychiatric disorders with regards to its noninvasiveness, penetration depth, and high resolution. OBJECTIVE: We sought in this experimental study to provide detailed and optimized protocol and methodology for a successful ultrasonic neurostimulation of the Primary Motor Cortex (M1) in mice addressed to young researchers/students beginning their research in the field of ultrasonic neurostimulation and encountering practical challenges. METHODS: A 500 kHz single-element transducer was used for stimulating the primary motor cortex at different acoustic pressures in C57BL/6 mice at various anesthesia levels. To further illustrate the effect of anesthesia, real time visual observations of motor responses validated with video recordings as well as electromyography were employed for evaluating the success and reliability of the stimulations. RESULTS: Detailed experimental procedure for a successful stimulations including targeting and anesthesia is presented. Our study demonstrates that we can achieve high stimulation success rates (91 % to 100 %) at acoustic pressures ranging from 330 kPa to 550 kPa at anesthesia washout period. CONCLUSIONS: This study shows a reliable and detailed methodology for successful USNS in mice addressed to beginners in ultrasonic brain stimulation topic. We showed an effective USNS protocol. We offered a simple and consistent non-invasive technique for locating and targeting brain zones. Moreover, we illustrated the acoustic pressure and stimulation success relationship and focused on the effect of anesthesia level for successful stimulation.

An ecological animal model of subthreshold depression in adolescence: behavioral and resting state 18F-FDG PET imaging characterization.

The different depressive disorders that exist can take root at adolescence. For instance, some functional and structural changes in several brain regions have been observed from adolescence in subjects that display either high vulnerability to depressive symptoms or subthreshold depression. For instance, adolescents with depressive disorder have been shown to exhibit hyperactivity in hippocampus, amygdala and prefrontal cortex as well as volume reductions in hippocampus and amygdala (prefrontal cortex showing more variable results). However, no animal model of adolescent subthreshold depression has been developed so far. Our objective was to design an animal model of adolescent subthreshold depression and to characterize the neural changes associated to this phenotype. For this purpose, we used adolescent Swiss mice that were evaluated on 4 tests assessing cognitive abilities (Morris water maze), anhedonia (sucrose preference), anxiety (open-field) and stress-coping strategies (forced swim test) at postnatal day (PND) 28-35. In order to identify neural alterations associated to behavioral profiles, we assessed brain resting state metabolic activity in vivo using 18F-FDG PET imaging at PND 37. We selected three profiles of mice distinguished in a composite Z-score computed from performances in the behavioral tests: High, Intermediate and Low Depressive Risk (HDR, IDR and LDR). Compared to both IDR and LDR, HDR mice were characterized by passive stress-coping behaviors, low cognition and high anhedonia and anxiety and were associated with significant changes of 18F-FDG uptakes in several cortical and subcortical areas including prelimbic cortex, infralimbic cortex, nucleus accumbens, amygdala, periaqueductal gray and superior colliculus, all displaying higher metabolic activity, while only the thalamus was associated with lower metabolic activity (compared to IDR). LDR displayed an opposing behavioral phenotype and were associated with significant changes of 18F-FDG uptakes in the dorsal striatum and thalamus that both exhibited markedly lower metabolic activity in LDR. In conclusion, our study revealed changes in metabolic activities that can represent neural signatures for behavioral profiles predicting subthreshold depression at adolescence in a mouse model.

Decrease in ultrasound Brain Tissue Pulsations as a potential surrogate marker of response to antidepressant.

Previous cross-sectional studies found excessive Brain Tissue Pulsations (BTP) in mid-life depression, which could constitute a mechanism of brain damage in depression. However, it remains unclear whether successful antidepressant therapy restores BTP amplitudes. In this prospective study, we investigated longitudinal changes in BTP in patients with a major depressive episode (MDE), among responders and non-responders to escitalopram. Fifty-two individuals with a MDE, free of antidepressants at baseline, were included in an 8-week open-labeled escitalopram trial. Ultrasound Tissue Pulsatility Imaging (TPI) was applied to measure resting BTP and BTP reactivity in an orthostatic challenge, at baseline and at week 8. TPI data were available for 48 participants divided into responders (n = 28, 58.3%) and non-responders (n = 20, 41.7%) according to change in the MADRS score. MaxBTP significantly decreased between baseline and week 8, only in responders. In addition, changes in MaxBTP during the orthostatic challenge were no longer significant at week 8 but only in responders. Because excessive BTP constitutes a potential mechanism for brain damage, our results suggest that a successful pharmacotherapy could benefit patients to lower the risk of brain damage in individuals with depression, a population exposed to stroke, small arteries disease and brain atrophy. TPI could provide a surrogate biomarker to monitor antidepressant response and brain health in depression in clinical routine.

Adult neurogenesis augmentation attenuates anhedonia and HPA axis dysregulation in a mouse model of chronic stress and depression.

Major depressive disorder is a common debilitating mental health problem that represents one of the leading causes of disability. Up to date, the therapeutic targets and approaches are still limited. Adult hippocampal neurogenesis (AHN) has been proposed as a critical contributor to the pathophysiology and treatment of depression, altering the hippocampal control over stress response at network, neuroendocrine and behavioral levels. These findings together have suggested that manipulating AHN may be a promising therapeutic strategy for depression. To investigate this question, we assessed whether increasing adult neurogenesis would be sufficient to produce antidepressant-like effects at behavioral and neuroendocrine levels in a mouse model of depression; the unpredictable chronic mild stress (UCMS). For this purpose, we used a bi-transgenic mouse line (iBax) in which AHN increase was induced by deletion of the pro-apoptotic gene Bax from the neural progenitors following the tamoxifen-dependent action of CreERT2 recombinases. UCMS induced a syndrome that is reminiscent of depression-like states, including anhedonia (cookie test), physical changes (coat deterioration, reduced weight gain), anxiety-like behaviors (higher latency in the novelty-supressed feeding -NSF- test), passive stress-coping behaviors (immobility in the forced swim test -FST-) and a blunted hypothalamo-pituitary-adrenal (HPA) axis reactivity to acute stress in addition to AHN decrease. Tamoxifen injection reversed the AHN decrease as well as partly counteracted UCMS effects on the cookie test and HPA axis but not for the coat state, weight gain, NSF test and FST. Taken together, our results suggest that a strategy directing at increasing AHN may be able to alleviate some depression-related behavioral and neuroendocrine dimensions of UCMS, such as anhedonia and HPA axis reactivity deficits, but may be hardly sufficient to produce a complete recovery.

Left amygdala volume and brain tissue pulsatility are associated with neuroticism: an MRI and ultrasound study.

Brain changes associated with the personality trait of neuroticism have been partly elucidated. While subcortical brain volume changes, especially a larger amygdala, appear consistent in high neuroticism, functional changes, such as cerebral blood flow (CBF) differences, have shown conflicting results, possibly because of the limitations in methods of CBF measurement. In our study, we investigated changes in amygdala volume and CBF-related function associated with neuroticism in healthy and depressed subjects using both conventional magnetic resonance imaging (MRI) measures of brain volume and the innovative technique of ultrasound Tissue Pulsatility Imaging (TPI), which has a high level of detection in measuring brain tissue pulsatility (BTP). Middle-aged females with depression (n = 25) and without depression (n = 25) underwent clinical examination, magnetic resonance imaging (MRI) and ultrasound assessment (TPI). Neuroticism was positively associated with left amygdala volume and mean BTP in individuals without depression, in both simple and multiple regressions that included potential confounding factors such as age and body mass index. No association was found in the depressed group. We confirmed the role of the left amygdala in the brain physiology of neuroticism in nondepressed individuals. Moreover, we identified a novel mechanism associated with high neuroticism, namely BTP, that may reflect greater CBF and account for the increased risk of cerebrovascular disease in individuals with high neuroticism. Because neuroticism is considered a risk factor for depression, our paper provides potential objective biomarkers for the identification of subjects at risk for depression.

A systematic review of ultrasound imaging and therapy in mental disorders.

BACKGROUND: Increasing evidence suggests that ultrasound (US) imaging may provide biomarkers and therapeutic options in mental disorders. We systematically reviewed the literature to provide a global overview of the possibilities of US for psychiatry. METHODS: Original English language articles published between January 2000 and September 2019 were identified through databases searching and analyzed to summarize existing evidence according to PRISMA methodology. RESULTS: A total of 81 articles were included. Various US techniques and markers have been used in mental disorders, including Transcranial Doppler and Intima-Media Thickness. Most of the studies have focused on characterizing the pathophysiology of mental disorders, especially vascular physiology. Studies on therapeutic applications are still scarce. DISCUSSION: US imaging has proved to be useful in characterizing vascular impairment and structural and functional brain changes in mental disorders. Preliminary findings also suggest potential interests for therapeutic applications. Growing evidence suggests that US imaging could provide a non-invasive, portable and low-cost tool for pathophysiological characterization, prognostic assessment and therapeutic applications in mental disorders.

When classical music relaxes the brain: An experimental study using Ultrasound Brain Tissue Pulsatility Imaging.

INTRODUCTION: Recent evidence suggests that biomechanical parameters of the brain, such as Brain Tissue Pulsatility (BTP), could be involved in emotional reactivity. However, no study has investigated the impact of an emotional task on BTP. We used the ultrasound method of Tissue Pulsatility Imaging (TPI) to assess changes in BTP to exciting and relaxing classical music, in a musical perception task, as a validated paradigm to assess emotional reactivity. METHODS: 25 healthy volunteers were exposed via earphones to four 5-minute musical excerpts (two exciting and two relaxing musical excerpts) presented in a randomized order and intersected by 5 silence periods. Measures of BTP, Heart Rate (HR) and Skin Conductance (SC) were collected during the entire task. RESULTS: The BTP significantly decreased with relaxing music compared to silence, and especially with the excerpt 'Entrance of the Shades' by Minkus. The HR and SC, but not Heart Rate Variability, were also decreased with relaxing music. We found no significant effect of exciting music. DISCUSSION: We report, for the first time, that classical relaxing music decreases the amplitude of the brain pulsatile movements related to cerebral blood flow and mechanical properties of the brain parenchyma, which provides further evidence of the involvement of BTP in emotional reactivity. In addition, we validate the use of TPI as a non-invasive, portable and low cost tool for studies in psychophysiology, with the potential to be implemented as a biomarker in musicotherapy trials notably.

Prefrontal cortex rTMS reverses behavioral impairments and differentially activates c-Fos in a mouse model of post-traumatic stress disorder.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a severe mental illness correlated with alterations in fear extinction neurocircuits that involve prefrontal, amygdala and hippocampal structures. Current treatments indirectly restore prefrontal control of fear responses, but still cannot achieve full remission in all patients. OBJECTIVE/HYPOTHESIS: Repetitive TMS (rTMS) can directly and chronically act on subparts of the prefrontal cortex (PFC) as a potential alternative treatment. However, preclinical studies are needed to further the comprehension of its mechanisms and thus enhance its efficacy. METHODS: A 40-mm coil is used on a stereotaxic frame to apply 12-Hz high-intensity rTMS of the ventromedial PFC (vmPFC) in a foot-shock mouse model of PTSD. Chronic rTMS treatment was applied 7 days after the shocks every day up to day 12 (5 sessions, 3750 pulses). RESULTS: One session of rTMS (750 pulses) was able to precisely evoke immediate c-Fos activity in an area of the vmPFC (0.5 mm2) in preliminary control mice. When used in the foot-shock model, chronic rTMS treatment (n = 19) counteracted short-term episodic memory deficits at day 18, and enhanced extinction dynamics when reexposed to the shocking chamber at day 22. Associated c-Fos activity was found increased in the rodent's vmPFC (infralimbic cortex), the basolateral amygdala and the ventral CA1 (hippocampal output). CONCLUSIONS: This study is the first to use prefrontal cortex rTMS in a mouse model of PTSD. Chronic rTMS of the vmPFC reversed stress-induced behavioral impairments and acted on distributed networks of fear extinction up to 10 days after treatment.

Cerebral blood flow velocity positively correlates with brain volumes in long-term remitted depression.

BACKGROUND: Mechanisms involved in brain changes observed in major depression have been poorly investigated in clinical populations. Changes in cerebral blood flow (CBF) have been found in depressed patients and constitute a potential mechanism by which brain volume varies in depression. We have tested the association of cerebral blood flow velocity (CBFV) as assessed with Transcranial Doppler (TCD) and cerebral blood flow (CBF) as assessed with Arterial Spin Labeling Magnetic Resonance Imaging (ASL-MRI) with Total Brain Volume (TBV) and the volume of seven subcortical regions, in currently depressed and long-term remitted patients. In addition, we have evaluated other potential confounders for the association depression/brain volume, including dimensional symptoms of depression, cardiovascular risk factors (CVRF) and antidepressants. METHODS: Seventy-five individuals were recruited, divided in 3 equal groups (currently depressed, remitted individuals and healthy controls) and were submitted to clinical assessment, MRI and Transcranial Doppler. RESULTS: CBFV was positively correlated with TBV, Hippocampus and Thalamus volume, but only in remitted patients, who tend to have larger brains compared to both currently depressed and controls. CVRF were negatively associated with brain volumes in the 3 groups and antidepressant use was associated with larger Thalamus. We found no association between brain volumes and CBF as assessed with ASL-MRI, anhedonia, anxiety or psychomotor retardation. DISCUSSION: Greater CBFV may be a physiological mechanism by which brain is enlarged in remitted patients. Future studies should consider CBFV, CVRF and antidepressants as possible confounders for the association depression/brain volumes, especially in remitted patients.