Ultrasound neurostimulation (USNS) offers non-invasive access to deep mood-regulating circuits, but most protocols rely on arbitrary parameters and lack mechanistic evaluation. We first optimised single-pulse USNS in healthy mice by mapping pressure–response curves during motor cortex stimulation with behavioural scoring, electromyography and hydrophone measurements to define a focal, reproducible setting. We then applied repeated USNS to the infralimbic cortex, the rodent homologue of ventromedial prefrontal cortex, for five days during unpredictable chronic mild stress. Behavioural outcomes (nest-building, open-field exploration), whole-brain 18F-FDG microPET and targeted metabolomics in infralimbic cortex, amygdala and hippocampus were assessed. Optimised infralimbic USNS selectively activated local neurons, reversed self-care and anxiety-like deficits to near baseline and outperformed chronic fluoxetine. PET revealed sustained hypermetabolism in vmPFC, dorsal hippocampus, periaqueductal grey and raphe nuclei, while metabolomics showed coordinated down-regulation of glutamate-centred pathways, supporting USNS as a precise, non-destructive antidepressant-like intervention.

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.

Many studies evaluated the functional role of adult hippocampal neurogenesis (AHN) and its key role in cognitive functions and mood regulation. The effects of promoting AHN on the recovery of stress-induced symptoms have been well studied, but its involvement in stress resilience remains elusive. We used a mouse model enabling us to foster AHN before the exposure to unpredictable chronic mild stress (UCMS) to evaluate the potential protective effects of AHN on stress, assessing the depressive-like phenotype and executive functions. For this purpose, an inducible transgenic mouse model was used to delete the pro-apoptotic gene Bax from neural progenitors four weeks before UCMS, whereby increasing the survival of adult-generated neurons. Our results showed that UCMS elicited a depressive-like phenotype, highlighted by a deteriorated coat state, a higher immobility duration in the tail suspension test (TST), and a delayed reversal learning in a water maze procedure. Promoting AHN before UCMS was sufficient to prevent the development of stressed-induced behavioral changes in the TST and the water maze, reflecting an effect of AHN on stress resilience. Taken together, our data suggest that increasing AHN promotes stress resilience on some depressive-like symptoms but also in cognitive symptoms, which are often observed in MD.

Major depression is one of the main factors contributing to the Global Burden of Disease. Current treatment strategies ( antidepressants and neurostimulation techniques) of major depression show some limitations including inaccuracy and invasiveness. Ultrasound neurostimulation (USNS) has been recently introduced as a physical non-invasive method for brain tissue stimulation and has gained increasing interest. In this study, we sought to evaluate the efficacy of transcranial USNS in an unpredictable chronic mild stress (UCMS) mouse model. The results show that transcranial USNS of the infralimbic cortex reduced anxiety-related behaviors as well as some, but not all, depression-related parameters. [F]-FDG microPET imaging and brain metabolomic analyses showed that USNS triggered the activation of targeted brain region in addition to brain areas at a distance from the targeted zone, alleviating anxiety and depression-related behaviors induced by the UCMS regimen. Transcranial ultrasound neurostimulation show therapeutic potential in some aspects of major depression.

Posttraumatic stress disorder (PTSD) is associated with brain changes that commonly involve the fear network including the prefrontal cortex (PFC), hippocampus and amygdala. Neurostimulation can been recommended as an adjunct to psychotherapy in order to facilitate extinction of fear in PTSD. Repetitive transcranial magnetic stimulation (rTMS) can thus target the PFC to provide promising treatment responses. However, preclinical rodent-based studies need to be performed to enhance the comprehension and empirical-driven efficacy of rTMS.We used a focal 40-mm coil to apply a high frequency/intensity rTMS pattern (5 daily sessions) to the ventromedial PFC (vmPFC) in a mouse model of PTSD. This procedure was assessed against fluoxetine (SSRI treatment).Through spatially precise stereotaxic framing, one session of rTMS (750 pulses) was able to focally increase c-Fos functional maps in the vmPFC immediately after stimulation. When used as a chronic treatment (5 daily sessions for 3750 pulses) in a foot-shock PTSD model, rTMS counteracted PTSD-related behavioural deficit in the object recognition task 6 days after the last treatment session and enhanced extinction dynamics in a reexposure task (4 days afterward) compared to sham treatment. Reexposure-associated c-Fos activity was found increased in the infralimbic cortex, the basolateral amygdala and the CA1 of ventral hippocampus of mice exposed to the trauma and treated with rTMS.In conclusion, chronic rTMS treatment reversed PTSD-induced impairments by acting on distributed networks of fear neurocircuitry that self-sustained 10 days post-treatment in the infralimbic cortex, the basolateral amygdala and the ventral CA1.

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.