Photobiomodulation in the aging brain: a systematic review from animal models to humans.

Aging is a multifactorial biological process that may be associated with cognitive decline. Photobiomodulation (PBM) is a non-pharmacological therapy that shows promising results in the treatment or prevention of age-related cognitive impairments. The aim of this review is to compile the preclinical and clinical evidence of the effect of PBM during aging in healthy and pathological conditions, including behavioral analysis and neuropsychological assessment, as well as brain-related modifications. 37 studies were identified by searching in PubMed, Scopus, and PsycInfo databases. Most studies use wavelengths of 800, 810, or 1064 nm but intensity and days of application were highly variable. In animal studies, it has been shown improvements in spatial memory, episodic-like memory, social memory, while different results have been found in recognition memory. Locomotor activity improved in Parkinson disease models. In healthy aged humans, it has been outlined improvements in working memory, cognitive inhibition, and lexical/semantic access, while general cognition was mainly enhanced on Alzheimer disease or mild cognitive impairment. Anxiety assessment is scarce and shows mixed results. As for brain activity, results outline promising effects of PBM in reversing metabolic alterations and enhancing mitochondrial function, as evidenced by restored CCO activity and ATP levels. Additionally, PBM demonstrated neuroprotective, anti-inflammatory, immunomodulatory and hemodynamic effects. The findings suggest that PBM holds promise as a non-invasive intervention for enhancing cognitive function, and in the modulation of brain functional reorganization. It is necessary to develop standardized protocols for the correct, beneficial, and homogeneous use of PBM.

Sleep-slow oscillation-spindle coupling precedes spindle-ripple coupling during development.

STUDY OBJECTIVES: Sleep supports systems memory consolidation through the precise temporal coordination of specific oscillatory events during slow-wave sleep, i.e. the neocortical slow oscillations (SOs), thalamic spindles, and hippocampal ripples. Beneficial effects of sleep on memory are also observed in infants, although the contributing regions, especially hippocampus and frontal cortex, are immature. Here, we examined in rats the development of these oscillatory events and their coupling during early life. METHODS: EEG and hippocampal local field potentials were recorded during sleep in male rats at postnatal days (PD)26 and 32, roughly corresponding to early (1-2 years) and late (9-10 years) human childhood, and in a group of adult rats (14-18 weeks, corresponding to ~22-29 years in humans). RESULTS: SO and spindle amplitudes generally increased from PD26 to PD32. In parallel, frontocortical EEG spindles increased in density and frequency, while changes in hippocampal ripples remained nonsignificant. The proportion of SOs co-occurring with spindles also increased from PD26 to PD32. Whereas parietal cortical spindles were phase-locked to the depolarizing SO-upstate already at PD26, over frontal cortex SO-spindle phase-locking emerged not until PD32. Co-occurrence of hippocampal ripples with spindles was higher during childhood than in adult rats, but significant phase-locking of ripples to the excitable spindle troughs was observed only in adult rats. CONCLUSIONS: Results indicate a protracted development of synchronized thalamocortical processing specifically in frontocortical networks (i.e. frontal SO-spindle coupling). However, synchronization within thalamocortical networks generally precedes synchronization of thalamocortical with hippocampal processing as reflected by the delayed occurrence of spindle-ripple phase-coupling.

Dosimetry in cranial photobiomodulation therapy: effect of cranial thickness and bone density.

This research aims to examine the influence of human skull bone thickness and density on light penetration in PBM therapy across different wavelengths, focusing on how these bone characteristics affect the absorption of therapeutic light. Analyses explored the effect of skull bone density and thickness on light penetration in PBM, specifically using Low-Level Laser Therapy (LLLT) for efficacy prediction. Measurements of bone thickness and density were taken using precise tools. This approach emphasizes LLLT's significance in enhancing PBM outcomes by assessing how bone characteristics influence light penetration. The study revealed no significant correlation between skull bone density and thickness and light penetration capability in photobiomodulation (PBM) therapy, challenging initial expectations. Wavelengths of 405 nm and 665 nm showed stronger correlations with bone density, suggesting a significant yet weak impact. Conversely, wavelengths of 532 nm, 785 nm, 810 nm, 830 nm, 980 nm, and 1064 nm showed low correlations, indicating minimal impact from bone density variations. However, data variability (R2 < 0.4) suggests that neither density nor thickness robustly predicts light power traversing the bone, indicating penetration capability might be more influenced by bone thickness at certain wavelengths. The study finds that the effectiveness of photobiomodulation (PBM) therapy with bone isn't just based on bone density and thickness but involves a complex interplay of factors. These include the bone's chemical and mineral composition, light's wavelength and energy dose, treatment duration and frequency, and the precise location where light is applied on the skull.

Photobiomodulation increases brain metabolic activity through a combination of 810 and 660 wavelengths: a comparative study in male and female rats.

Photobiomodulation (PBM), an emerging and non-invasive intervention, has been shown to benefit the nervous system by modifying the mitochondrial cytochrome c-oxidase (CCO) enzyme, which has red (620-680 nm) or infrared (760-825 nm) spectral absorption peaks. The effect of a single 810-nm wavelength with a combination of 810 nm and 660 nm lights in the brain metabolic activity of male and female rats was compared. PBM, with a wavelength of 810 nm and a combination of 810 nm and 660 nm, was applied for 5 days on the prefrontal cortex. Then, brain metabolic activity in the prefrontal area, hippocampus, retrosplenial, and parietal cortex was explored. Sex differences were found in cortical and subcortical regions, indicating higher male brain oxidative metabolism, regardless of treatment. CCO activity in the cingulate and prelimbic area, dentate gyrus, retrosplenial and parietal cortex was enhanced in both treatments (810 + 660 nm and 810 nm). Moreover, using the combination of waves, CCO increased in the infralimbic area, and in CA1 and CA3 of the hippocampus. Thus, employment of a single NIR treatment or a combination of red to NIR treatment led to slight differences in CCO activity across the limbic system, suggesting that a combination of lights of the spectrum may be relevant.

Differential approach to stroke aphasia and primary progressive aphasia using transcranial magnetic stimulation: A systematic review.

Language disorders can occur as a consequence of stroke or neurodegenerative disorders, among other causes. Post­stroke aphasia (PSA) and primary progressive aphasia (PPA) are syndromes that, despite having common features, differ in the brain mechanisms that cause their symptoms. These differences in the underlying functional neuroanatomical changes may influence the way they are addressed by different non­invasive brain stimulation techniques and, in particular, by repetitive transcranial magnetic stimulation (rTMS). The aim of this systematic review is to evaluate the efficacy of rTMS in the treatment of PSA and PPA, as well as the differences in the approach to these disorders using rTMS. To this end, a total of 36 articles were found in the Web of Science, Scopus, and PubMed. The results obtained suggest that whereas in PSA, the selection of the stimulation paradigm is based on bi­hemispheric functional reorganisation models with a tendency towards the application of inhibitory rTMS in the contralateral right hemisphere, in PPA, the application of excitatory rTMS in functionally compromised areas seems to show promising changes. It is concluded that rTMS is a potential treatment in the therapy of both disorders, although differences in the underlying brain mechanisms differentiate the rTMS approach in each case.

Are there sex differences in spatial reference memory in the Morris water maze? A large-sample experimental study.

Sex differences have been found in allocentric spatial learning and memory tasks, with the literature indicating that males outperform females, although this issue is still controversial. This study aimed to explore the behavior of male and female rats during the habituation and learning of a spatial memory task performed in the Morris Water Maze (MWM). The study included a large sample of 89 males and 85 females. We found that females searched slightly faster than males during habituation with a visible platform. During learning, both male and female rats decreased the latency and distance traveled to find the hidden platform over the days, with males outperforming females in the distance traveled. Females swam faster but did not find the platform earlier, suggesting a less directed navigational strategy. Both sexes increased time spent in the target zone over the days, with no sex differences. Although females swam more in the periphery during the first days of the task, both sexes decreased the time spent in this area. Finally, only males increased swimming in the pool's center over the days, spending more time than females in this area across the entire training. In conclusion, we need to register several variables in the MWM and analyze path strategies to obtain more robust results concerning sex differences. Research on spatial learning should include both sexes to achieve a more equitable, representative, and translational science.

Hippocampal alterations after SARS-CoV-2 infection: A systematic review.

SARS-CoV-2 infection produces a wide range of symptoms. Some of the structural changes caused by the virus in the nervous system are found in the medial temporal lobe, and several neuropsychological sequelae of COVID-19 are related to the function of the hippocampus. The main objective of the systematic review is to update and further analyze the existing evidence of hippocampal and related cortices' structural and functional alterations due to SARS-CoV-2 infection. Both clinical and preclinical studies that used different methodologies to explore the effects of this disease at different stages and grades of severity were considered, besides exploring related cognitive and emotional symptomatology. A total of 24 studies were identified by searching in SCOPUS, Web Of Science (WOS), PubMed, and PsycInfo databases up to October 3rd, 2022. Thirteen studies were performed in clinical human samples, 9 included preclinical animal models, 3 were performed post-mortem, and 1 included both post-mortem and preclinical samples. Alterations in the hippocampus were detected in the acute stage and after several months of infection. Clinical studies revealed alterations in hippocampal connectivity and metabolism. Memory alterations correlated with altered metabolic profiles or changes in grey matter volumes. Hippocampal human postmortem and animal studies observed alterations in neurogenesis, dendrites, and immune response, besides high apoptosis and neuroinflammation. Preclinical studies reported the viral load in the hippocampus. Olfactory dysfunction was associated with alterations in brain functionality. Several clinical studies revealed cognitive complaints, neuropsychological alterations, and depressive and anxious symptomatology.

Anosmia in COVID-19 could be associated with long-term deficits in the consolidation of procedural and verbal declarative memories.

Background and purpose: Long-COVID describes the long-term effects of the coronavirus disease 2019 (COVID-19). In long-COVID patients, neuropsychological alterations are frequently reported symptoms. Research points to medial temporal lobe dysfunction and its association with anosmia in long-COVID patients. This study aims to investigate the acquisition and consolidation of declarative and procedural memory in long-COVID patients and to explore whether anosmia is related to these dissociated memory functions. Methods: Forty-two long-COVID participants and 30 controls (C) were recruited. The sample of long-COVID patients was divided into two groups based on the presence or absence of anosmia, group A and group NA, respectively. Objective performance in verbal declarative memory (Paired-Associate Learning, PAL), procedural memory (Mirror Tracing Test, MTT), general cognitive function (Montreal Cognitive Assessment scale), psychomotor speed, and incidental learning (Digit Symbol Substitution Test) were assessed and compared among the A, NA, and C groups. Long-term retention of PAL and MTT were assessed 24 h after acquisition. Results: Lower scores in general cognition, psychomotor speed, and sustained attention were found in A and NA compared with C. However, incidental learning, both cue-guided and free-recalled, was diminished in group A compared with C, with no differences with group NA. General cognition and incidental learning were related to declarative memory function exclusively in long-COVID groups. Long-COVID groups presented lower long-term retention of verbal declarative memory than controls in recall tests but no differences in recognition tests. No group differences were found in the acquisition of procedural memory. However, long-term retention of this memory was worse in group A as compared to the NA and C groups, respectively, when errors and time of execution were considered. Conclusion: Findings support that consolidation of both procedural and declarative memories is more affected than the acquisition of these memories in long-COVID patients, who are also more vulnerable to deficits in delayed recall than in recognition of declarative memories. Deficits in the consolidation of procedural memory and immediate recall of declarative information are especially relevant in long-COVID participants with anosmia. This indicates that anosmia in COVID-19 could be associated with a long-term dysfunction of the limbic system.

Memory alterations after COVID-19 infection: a systematic review.

SARS-CoV-2 infection has a wide range of both acute and long-term symptoms. Memory alterations have been frequently reported in studies that explore cognition. The main objective of the systematic review is to update and further analyze the existing evidence of objective memory impairments in long-COVID-19 considering sample and study design characteristics, as well as to explore associations between memory performance and their epidemiological, clinical, and pathological features. A total of 13 studies were identified by searching in PubMed, Web of Science, and PsycInfo databases up to May 6, 2022. Most studies evaluated verbal component of memory in the short-term and long-term recall up to 30 min and mainly performed a single assessment completed at 4-6 months after the infection. The samples mainly consisted of middle-aged adults that required hospitalization. Samples were not stratified by sex, age, and severity. Poor verbal learning was reported in most cases (6-58%), followed by deficits in long-term (4-58%) and short-term (4-37%) verbal memory. Visuospatial component of memory was studied less than verbal component, showing impairment of long-term retention of visual items (10-49%). COVID-19 severity in the acute stage was not systematically associated with poor memory performance. Verbal memory deficits were associated with anxiety and depression. The existing literature on objective memory assessment in long-COVID suggests further research is warranted to confirm memory dysfunction in association with epidemiological, pathological, and clinical factors, using both verbal and visuospatial tests, and exploring in deep long-term memory deficits.

The removal and addition of cues does not impair spatial retrieval and leads to a different metabolic activity of the limbic network in female rats.

The retrieval of spatial memories does not always occur in an environment with the same stimuli configuration where the memory was first formed. However, re-exposure to a partial portion of the previously encountered cues can elicit memory successfully. Navigation with contextual changes has received little attention, especially in females. Thus, we aimed to assess memory retrieval using the Morris Water Maze spatial reference protocol in female adult Wistar rats. Rats were trained with five allocentric cues, and retrieval was explored one week later either with the same cues, or with four removed, or with three added cues. We studied the underlying brain oxidative metabolism of the hippocampus, prefrontal, parietal, retrosplenial, entorhinal, and perirhinal cortices through cytochrome c oxidase (CCO) histochemistry. Neither cue removal nor cue addition impaired retrieval performance. Retrieval with a degraded subset of cues led to increased prefrontal, hippocampal, retrosplenial, parietal, and perirhinal CCO activity. Retrieval with extra cues led to an enhancement of CCO activity in the hippocampus and retrosplenial cortex. Different patterns of network intercorrelations were found. The cue-removal group presented a closed reciprocal network, while the group with extra cues had separate parallel networks. Both groups showed a simpler network than the group with no cue modifications. Future research is needed to delve into behavioral and brain-related functions of spatial memory processes under modified environmental conditions.

Functional neuroanatomy of allocentric remote spatial memory in rodents.

Successful spatial cognition involves learning, consolidation, storage, and later retrieval of a spatial memory trace. The functional contributions of specific brain areas and their interactions during retrieval of past spatial events are unclear. This systematic review collects studies about allocentric remote spatial retrieval assessed at least two weeks post-acquisition in rodents. Results including non-invasive interventions, brain lesion and inactivation experiments, pharmacological treatments, chemical agent administration, and genetic manipulations revealed that there is a normal forgetting when time-periods are close to or exceed one month. Moreover, changes in the morphology and functionality of neocortical areas, hippocampus, and other subcortical structures, such as the thalamus, have been extensively observed as a result of spatial memory retrieval. In conclusion, apart from an increasingly neocortical recruitment in remote spatial retrieval, the hippocampus seems to participate in the retrieval of fine spatial details. These results help to better understand the timing of memory maintenance and normal forgetting, outlining the underlying brain areas implicated.

Repetitive transcranial magnetic stimulation during a spatial memory task leads to a decrease in brain metabolic activity.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is able to generate causal-based interferences between brain networks and cognitive or behavioral responses. It has been used to improve cognition in several disease models. However, although its exploration in healthy animals is essential to attribute its pure effect in learning and memory processes, studies in this regard are scarce. We aimed to evaluate whether rTMS leads to memory facilitation in healthy rats, and to explore the brain-related oxidative metabolism. We stimulated healthy Wistar rats with a high-frequency (100 Hz) and low-intensity (0.33 T) protocol during three consecutive days and evaluated the effect on the performance of an allocentric spatial reference learning and memory task. Following the last day of learning, we assessed oxidative brain metabolism through quantitative cytochrome c oxidase (CCO) histochemistry. The results showed that rTMS did not improve spatial memory in healthy rats, but the behavioral outcome was accompanied by a CCO reduction in the prefrontal, retrosplenial, parietal, and rhinal cortices, as well as in the striatum, amygdala, septum, mammillary bodies, and the hippocampus, reflecting a lower metabolic activity. In conclusion, rTMS induces a highly efficient use of brain regions associated with spatial memory.

Hippocampus and cortex are involved in the retrieval of a spatial memory under full and partial cue availability.

Retaking routes after a period of time usually occurs in an environment which has suffered from spatial configuration modifications. Thus, the original visual stimuli that allowed us to establish cognitive mapping using an allocentric strategy during the acquisition phase may not remain physically identical at the time of retrieval. However, in the standard experimental paradigms the cues are typically maintained constant. In this study, we explored memory retrieval with spatial modifications from learning in the Morris Water Maze. We trained rats on a reference memory protocol with five cues placed on black curtains that surrounded the pool, and seven days later, we tested memory retrieval under different conditions: maintenance of the five cues, removal of two and four of them, and the addition of three extra ones. Under full-cue and partial cue-conditions, rats showed successful memory retrieval, whereas adding extra cues resulted in impaired retrieval. Furthermore, we assessed brain oxidative metabolism through cytochrome c oxidase (CCO) histochemistry and found that, under full- and partial-cue conditions, there is an enhancement of the hippocampal, prefrontal, retrosplenial, parietal, and rhinal cortex metabolism. Rats that failed to retrieve spatial information in the extra cues condition showed similar or lower CCO activity than controls across many limbic areas. It is suggested that the presence of a partial portion of visual stimuli from learning makes it possible to reactivate the entire memory trace, but extra spatial information hinders retrieval, making it difficult to disengage the novel information from the older knowledge and establish a contextual generalization.

Recovering Spatial Information through Reactivation: Brain Oxidative Metabolism Involvement in Males and Females.

Memory involves a complex network system of interconnected brain areas in which labile trace memories are transformed into enduring ones and reorganized in a time-dependant manner. Although it has been observed that remote memories are less prone to destabilizing, they can become fragile and lead to behavioural decline. We explored the behavioural outcomes of male and female rats in response to the reactivation of a previously acquired allocentric spatial reference memory, under conditions in which animals have shown a retrieval decay. In addition, we assessed their brain metabolic activity through cytochrome c oxidase (CCO) histochemistry. Our results show that a spatial memory amnesia-like behaviour with a time interval of 45 days can be recovered after re-exposure to the environmental configuration with the reinforced contingencies. Moreover, we observed that, following reactivation, male rats reveal a decrease in metabolic activity in septal nuclei and thalamic structures, whereas female rats add a metabolic reduction in the hippocampus, amygdala, mPFC, and retrosplenial, parietal and rhinal cortices, suggesting that they efficiently employ these brain areas when reactivation a memory that has suffered a decay with time. Finally, although male and female rats perform the behavioural task equally, we found sex differences at the brain metabolism level, revealing the differential contribution of brain limbic system energy demands by sex, even when their performance is similar. In conclusion, our work provides behavioural and brain data about remote spatial retrieval and memory reactivation processes.

Retrieval of allocentric spatial memories is preserved up to thirty days and does not require higher brain metabolic demands.

Spatial orientation is a cognitive ability that is indispensable for survival. Several visual distal cues present in the context can be integrated, establishing a cognitive map. Although there is cumulative evidence about the neural substrate involved in spatial memory acquisition, the brain networks mediating the processes involved in the retrieval of allocentric spatial memories have been studied less. Here, we aimed to explore the role of neuronal oxidative metabolism in the retrieval of allocentric spatial memories through cytochrome c oxidase (CCO) histochemistry seven, 15, 30, 45, and 60 days after task acquisition. Our behavioural results show that spatial memory retrieval in male and female rats is preserved seven, 15, and 30 days post-acquisition, but there is forgetfulness after this time, with subjects not being able to remember the position of the hidden platform after 45 and 60 dfearays. Regarding the study of male brain metabolism, we observed reduced CCO activity in the medial prefrontal cortex, the parietal, retrosplenial, rhinal cortex, and the hippocampal regions in all the groups that failed to solve the task. Similar results were found for female brain oxidative metabolism, in addition to certain differences between succefearssful-retrieval female groups. In conclusion, our work adds information about the behavioural retrieval of an allocentric spatial reference task, suggesting that recovering spatial information seven, 15, and 30days after acquisition is a simple task that does not require a high metabolic demand, in both male and female rats.

Equipment for Repetitive Transcranial Magnetic Stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique used for the treatment of a great variety of neurological disorders. The technique involves applying a magnetic field in certain areas of the cerebral cortex in order to modify neuronal excitability outside the skull. However, the exact brain mechanisms underlying rTMS effects are not completely elucidated. For that purpose, and in order to generate a pulsed magnetic field, a half-bridge converter controlled by a microcontroller has been designed to apply rTMS in small animals. Moreover, the small size of the rodent head makes it necessary to design a magnetic transducer, with the aim of focusing the magnetic field on selected brain areas using a specific and a small magnetic head. Using such devices, our purpose was to compare the effects of five different rTMS dosages on rat brain metabolic activity. The experimental results showed that one day of stimulation leads to an enhancement of brain metabolic activity in cortical areas, meanwhile with three days of stimulation it is possible to also modify subcortical zones, results that were not found when extending the number of rTMS applications up to seven days. In consequence, the number of pulses delivered might be an important parameter in rTMS protocols, highlighting its importance in rTMS impact.

Current State of Transcranial Magnetic Stimulation and its use in Psychiatry.

INTRODUCTION: Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that could be used as a therapeutic intervention in order to treat psychiatric disorders. AIM: Reviewing the effectiveness of TMS in the modulation of cognitive functions and also detailing its potential applications in psychiatric treatments. DEVELOPMENT: TMS has been traditionally used for the treatment of a great variety of neurological or psychiatric conditions by modulating the activity in brain areas and networks. Therapeutic benefit has been found in depressive disorders, anxiety, schizophrenia, addiction, and neurodevelopmental disorders as well as in brain damage and neurodegenerative disorders. Moreover, TMS is a technique which offers great tolerance and can be used as complement with other therapies. However, it is not easy to define an optimal treatment for every pathology: the parameters of stimulation are variable, and its effects at the cellular level of the nervous system are not well-known. CONCLUSION: While it is true that TMS provides many therapeutic benefits, it requires further investigation. It is necessary to detail the action mechanism of the stimulation and the long-term side effects, if any. This information would allow the design of specific treatment protocols for different psychiatric disorders.

Estado actual de la estimulación magnética transcraneal y sus aplicaciones en psiquiatría / Current State of Transcranial Magnetic Stimulation and its use in Psychiatry

Introducción. La estimulación magnética transcraneal (EMT) es una técnica de estimulación cerebral no invasiva que puede constituir una intervención terapéutica en multitud de trastornos psiquiátricos. Objetivo. Revisar la eficacia de la EMT en la modulación de las funciones cognitivas, así como detallar las potenciales aplicaciones en tratamientos de trastornos psiquiátricos. Desarrollo. La EMT ha sido empleada tradicionalmente para el tratamiento de diversas condiciones neurológicas o psiquiátricas debido a la modulación de la actividad de distintas áreas y redes cerebrales. Se observa beneficio terapéutico en trastornos depresivos, de ansiedad, de la esquizofrenia, de adicción, del neurodesarrollo, así como en daño cerebral adquirido y trastornos que cursan con neurodegeneración. Asimismo, constituye una técnica que presenta gran tolerancia y complementariedad con otras terapias. Sin embargo, existen dificultades para definir un tratamiento óptimo según qué patología: los parámetros de estimulación son muy variables y no se conocen en detalle los efectos a nivel celular en el sistema nervioso. Conclusión. Si bien es cierto que los beneficios terapéuticos de esta técnica son numerosos, precisa de una mayor investigación. Es necesario detallar el mecanismo de acción que induce la terapia, así como los posibles efectos secundarios a largo plazo, si los hubiera. Ello permitiría diseñar protocolos de tratamiento específicos para diferentes alteraciones neurológicas

Introduction. Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that could be used as a therapeutic intervention in order to treat psychiatric disorders. Aim. Reviewing the effectiveness of TMS in the modulation of cognitive functions and also detailing its potential applications in psychiatric treatments. Development. TMS has been traditionally used for the treatment of a great variety of neurological or psychiatric conditions by modulating the activity in brain areas and networks. Therapeutic benefit has been found in depressive disorders, anxiety, schizophrenia, addiction, and neurodevelopmental disorders as well as in brain damage and neurodegenerative disorders. Moreover, TMS is a technique which offers great tolerance and can be used as complement with other therapies. However, it is not easy to define an optimal treatment for every pathology: the parameters of stimulation are variable, and its effects at the cellular level of the nervous system are not well-known. Conclusion. While it is true that TMS provides many therapeutic benefits, it requires further investigation. It is necessary to detail the action mechanism of the stimulation and the long-term side effects, if any. This information would allow the design of specific treatment protocols for different psychiatric disorders

High frequency repetitive transcranial magnetic stimulation improves neuronal activity without affecting astrocytes and microglia density.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique capable of producing changes in the electrical potential of neurons. Currently, the application of rTMS in clinical practice and as a neurophysiological tool is increasing. However, the exact cellular mechanisms underlying rTMS-based therapies are not completely clear. Additionally, glial cells have been studied less. Our aim was to investigate the effect of three days of high-frequency rTMS on neuronal metabolism and neuronal activation, in addition to its effect on glial cells. For this purpose, we performed histochemistry and immunohistochemistry procedures: the histochemistry of cytochrome oxidase (COx) to assess neuronal metabolic activity, and the immunohistochemistry of c-Fos (marker of neuronal activity), GFAP (marker of astrocytic reactivity), and Iba1 (selective marker of reactive microglia). Our results showed enhanced metabolic activity after rTMS in the retrosplenial and parietal cortex and CA1 and CA3 subfields of the hippocampus. Moreover, higher c-Fos activity was found in the agranular retrosplenial cortex. Finally, we did not find changes between groups in the induction of astrocyte and microglia reactivity in any of the immunostained regions. In conclusion, we can assume that three days of high-frequency rTMS applied in healthy rats does not alter astroglia reactivity or inflammatory responses, such as microglia proliferation. Because we have shown an upregulation of neuronal metabolic activity in many limbic brain structures, in addition to higher c-Fos levels in the nearest cortical area to the rTMS, our work provides novel insight into the effectiveness and safety of rTMS as a brain modulation therapy.

Social dominance differentially alters gene expression in the medial prefrontal cortex without affecting adult hippocampal neurogenesis or stress and anxiety-like behavior.

Social hierarchies are crucial for a group's survival and can influence the way an individual behaves and relates to a given social context. The study of social rank has been classically based on ethological and observational paradigms, but it recently has taken advantage of the use of other approaches, such as the tube test that measures territorial dominance without the display of in situ aggression and is executable in group-living animals. However, little is known about how previous basal individual differences affect the development of dominance hierarchy measured in the tube test. We have analyzed in male mice body weight, locomotion, anxiety, and serum corticosterone both before and after the tube test, as well as adult hippocampal neurogenesis and transcriptome in the prefrontal cortex after the hierarchy had been established. We found differential gene expression between dominants and subordinates but no association between the other parameters and social status, neither pre- nor posttest. Our findings reveal that social rank in mice is stable along time and is not related to basal differences in stress, mood, or physical features. Lastly, real-time quantitative PCR analysis confirmed differential expression of vomeronasal and olfactory receptors in the cerebral cortex between dominant and subordinate individuals, suggesting that differential brain gene expression in the medial prefrontal cortex could potentially be used as a biomarker of social dominance.-Pallé, A., Zorzo, C., Luskey, V. E., McGreevy, K. R., Fernández, S., Trejo, J. L. Social dominance differentially alters gene expression in the medial prefrontal cortex without affecting adult hippocampal neurogenesis or stress and anxiety-like behavior.