RAQUEL CHACON RUIZ MARTINEZ

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Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina
LIM/23 - Laboratório de Psicopatologia e Terapêutica Psiquiátrica, Hospital das Clínicas, Faculdade de Medicina

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  • article 3 Citação(ões) na Scopus
    Long-Term Follow-Up on Bilateral Posterior Hypothalamic Deep Brain Stimulation for Treating Refractory Aggressive Behavior in a Patient with Cri du Chat Syndrome: Analysis of Clinical Data, Intraoperative Microdialysis, and Imaging Connectomics
    (2023) RIOS, Adriana Lucia Lopez; GERMANN, Jurgen; HUTCHISON, William D.; POSADA, Luis Fernando Botero; VELASQUEZ, Luisa Fernanda Ahunca; JIMENEZ, Francisco Aureliano Garcia; ESCOBAR, Jose Miguel Gloria; MARTINEZ, Raquel Chacon Ruiz; HAMANI, Clement; LEBRUN, Ivo; AUADA, Aline V. V.; BRAVO, Carlos Anibal Restrepo; GOUVEIA, Flavia Venetucci
    Posterior hypothalamic-deep brain stimulation (pHyp-DBS) has been reported as a successful treatment for reducing refractory aggressive behaviors in patients with distinct primary diagnoses. Here, we report on a patient with cri du chat syndrome presenting severe self-injury and aggressive behaviors toward others, who was treated with pHyp-DBS. Positive results were observed at long-term follow-up in aggressive behavior and quality of life. Intraoperative microdialysis and imaging connectomics analysis were performed to investigate possible mechanisms of action. Our results suggest the involvement of limbic and motor areas and alterations in main neurotransmitter levels in the targeted area that are associated with positive results following treatment.
  • article 72 Citação(ões) na Scopus
    Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortex
    (2013) MARTINEZ, Raquel C. R.; GUPTA, Nikita; LAZARO-MUNOZ, Gabriel; SEARS, Robert M.; KIM, Soojeong; MOSCARELLO, Justin M.; LEDOUX, Joseph E.; CAIN, Christopher K.
    Active avoidance (AA) is an important paradigm for studying mechanisms of aversive instrumental learning, pathological anxiety, and active coping. Unfortunately, AA neurocircuits are poorly understood, partly because behavior is highly variable and reflects a competition between Pavlovian reactions and instrumental actions. Here we exploited the behavioral differences between good and poor avoiders to elucidate the AA neurocircuit. Rats received Sidman AA training and expression of the activity-dependent immediate-early gene c-fos was measured after a shock-free AA test. Six brain regions with known or putative roles in AA were evaluated: amygdala, periaqueductal gray, nucleus accumbens, dorsal striatum, prefrontal cortex (PFC), and hippocampus. Good avoiders showed little Pavlovian freezing and high AA rates at test, the opposite of poor avoiders. Although c-Fos activation was observed throughout the brain, differential activation was found only in subregions of amygdala and PFC. Interestingly, c-Fos correlated with avoidance and freezing in only five of 20 distinct areas evaluated: lateral amygdala, central amygdala, medial amygdala, basal amygdala, and infralimbic PFC. Thus, activity in specific amygdala-PFC circuits likely mediates the competition between instrumental actions and Pavlovian reactions after AA training. Individual differences in AA behavior, long considered a nuisance by researchers, may be the key to elucidating the AA neurocircuit and understanding pathological response profiles.
  • article 16 Citação(ões) na Scopus
    Fully Automated Habenula Segmentation Provides Robust and Reliable Volume Estimation Across Large Magnetic Resonance Imaging Datasets, Suggesting Intriguing Developmental Trajectories in Psychiatric Disease
    (2020) GERMANN, Juergen; GOUVEIA, Flavia Venetucci; MARTINEZ, Raquel C. R.; ZANETTI, Marcus Vinicius; DURAN, Fabio Luis de Souza; CHAIM-AVANCINI, Tiffany M.; SERPA, Mauricio H.; CHAKRAVARTY, M. Mallar; DEVENYI, Gabriel A.
    Studies of habenula (Hb) function and structure provided evidence of its involvement in psychiatric disorders, including schizophrenia and bipolar disorder. Previous studies using magnetic resonance imaging (manual/semi-automated segmentation) have reported conflicting results. Aiming to improve Hb segmentation reliability and the study of large datasets, we describe a fully automated protocol that was validated against manual segmentations and applied to 3 datasets (childhood/adolescence and adult bipolar disorder and schizophrenia). It achieved reliable Hb segmentation, providing robust volume estimations across a large age range and varying image acquisition parameters. Applying it to clinically relevant datasets, we found smaller Hb volumes in the adult bipolar disorder dataset and larger volumes in the adult schizophrenia dataset compared with healthy control subjects. There are indications that Hb volume in both groups shows deviating developmental trajectories early in life. This technique sets a precedent for future studies, as it allows for fast and reliable Hb segmentation and will be publicly available.
  • article 7 Citação(ões) na Scopus
    Bilateral Amygdala Radio-Frequency Ablation for Refractory Aggressive Behavior Alters Local Cortical Thickness to a Pattern Found in Non-refractory Patients
    (2021) GOUVEIA, Flavia Venetucci; GERMANN, Jurgen; DEVENYI, Gabriel A.; FONOFF, Erich T.; MORAIS, Rosa M. C. B.; BRENTANI, Helena; CHAKRAVARTY, M. Mallar; MARTINEZ, Raquel C. R.
    Aggressive behaviors comprise verbal and/or physical aggression directed toward oneself, others, or objects and are highly prevalent among psychiatric patients, especially patients diagnosed with autism spectrum disorder and severe intellectual disabilities. Some of these patients are considered refractory to treatment, and functional neurosurgery targeting the amygdala can result in widespread plastic brain changes that might reflect ceasing of some abnormal brain function, offering symptom alleviation. This study investigated cortical thickness changes in refractory aggressive behavior patients that were treated with bilateral amygdala ablation and compared to control patients presenting non-refractory aggressive behavior [three refractory and seven non-refractory patients, all males diagnosed with autism spectrum disorder (ASD) and intellectual disabilities]. The Overt Aggression Scale (OAS) was used to quantify behavior and magnetic resonance imaging was performed to investigate cortical thickness. Before surgery, both groups presented similar total OAS score, however refractory patients presented higher physical aggression against others. After surgery the refractory group showed 88% average reduction of aggressive behavior. Imaging analysis showed that while refractory patients present an overall reduction in cortical thickness compared to non-refractory patients across both timepoints, the local pattern of thickness difference found in areas of the neurocircuitry of aggressive behavior present before surgery is diminished and no longer detected after surgery. These results corroborate the hypotheses on induction of widespread neuronal plasticity following functional neurosurgical procedures resulting in modifications in brain morphology and improvement in behavior. Further studies are necessary to determine the underlying cause of these morphological changes and to better understand and improve treatment options.
  • article 1 Citação(ões) na Scopus
    Does TRODAT-1 SPECT Uptake Correlate with Cerebrospinal Fluid alpha-Synuclein Levels in Mid-Stage Parkinson's Disease?
    (2023) COUTINHO, Artur M.; GHILARDI, Maria Gabriela; CAMPOS, Ana Carolina P.; ETCHEBEHERE, Elba; FONOFF, Fernanda C.; CURY, Rubens G.; PAGANO, Rosana L.; MARTINEZ, Raquel C. R.; FONOFF, Erich T.
    Background: Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons with impaired motor and non-motor symptoms. It has been suggested that motor asymmetry could be caused due to an imbalance in dopamine levels, as visualized by dopamine transporter single emission computed tomography test (DAT-SPECT), which might be related to indirect measures of neurodegeneration, evaluated by the Montreal Cognitive Assessment (MOCA) and alpha-synuclein levels in the cerebrospinal fluid (CSF). Therefore, this study aimed to understand the correlation between disease laterality, DAT-SPECT, cognition, and alpha-synuclein levels in PD. Methods: A total of 28 patients in the moderate-advanced stage of PD were subjected to neurological evaluation, TRODAT-1-SPECT/CT imaging, MOCA, and quantification of the levels of alpha-synuclein. Results: We found that alpha-synuclein in the CSF was correlated with global cognition (positive correlation, r(2) = 0.3, p = 0.05) and DAT-SPECT concentration in the putamen (positive correlation, r(2) = 0.4, p = 0.005), and striatum (positive correlation, r(2) = 0.2, p = 0.03), thus working as a neurodegenerative biomarker. No other correlations were found between DAT-SPECT, CSF alpha-synuclein, and cognition, thus suggesting that they may be lost with disease progression. Conclusions: Our data highlight the importance of understanding the dysfunction of the dopaminergic system in the basal ganglia and its complex interactions in modulating cognition.
  • article 5 Citação(ões) na Scopus
    Case report: 5 Years follow-up on posterior hypothalamus deep brain stimulation for intractable aggressive behaviour associated with drug-resistant epilepsy
    (2021) GOUVEIA, Flavia Venetucci; GERMANN, Jurgen; ELIAS, Gavin JB.; HAMANI, Clement; FONOFF, Erich Talamoni; MARTINEZ, Raquel Chacon Ruiz
  • article 7 Citação(ões) na Scopus
    Habenula activation patterns in a preclinical model of neuropathic pain accompanied by depressive-like behaviour
    (2022) ANTUNES, Geiza Fernanda; CAMPOS, Ana Carolina Pinheiro; ASSIS, Danielle Varin de; GOUVEIA, Flavia Venetucci; SENO, Midia Dias de Jesus; PAGANO, Rosana Lima; MARTINEZ, Raquel Chacon Ruiz
    Pain and depression are complex disorders that frequently co-occur, resulting in diminished quality of life. The habenula is an epithalamic structure considered to play a pivotal role in the neurocircuitry of both pain and depression. The habenula can be divided into two major areas, the lateral and medial habenula, that can be further subdivided, resulting in 6 main subregions. Here, we investigated habenula activation patterns in a rat model of neuropathic pain with accompanying depressive-like behaviour. Wistar rats received active surgery for the development of neuropathic pain (chronic constriction injury of the sciatic nerve; CCI), sham surgery (surgical control), or no surgery (behavioural control). All animals were evaluated for mechanical nociceptive threshold using the paw pressure test and depressive-like behaviour using the forced swimming test, followed by evaluation of the immunoreactivity to cFos-a marker of neuronal activity-in the habenula and subregions. The Open Field Test was used to evaluate locomotor activity. Animals with peripheral neuropathy (CCI) showed decreased mechanical nociceptive threshold and increased depressive-like behaviour compared to control groups. The CCI group presented decreased cFos immunoreactivity in the total habenula, total lateral habenula and lateral habenula subregions, compared to controls. No difference was found in cFos immunoreactivity in the total medial habenula, however when evaluating the subregions of the medial habenula, we observed distinct activation patterns, with increase cFos immunoreactivity in the superior subregion and decrease in the central subregion. Taken together, our data suggest an involvement of the habenula in neuropathic pain and accompanying depressive-like behaviour.
  • article 4 Citação(ões) na Scopus
    Increased Anxiety-Like Behavior in the Acute Phase of a Preclinical Model of Periodontal Disease
    (2020) VAROTTO, Bruna Luiza Roim; MARTINEZ, Raquel Chacon Ruiz; GOUVEIA, Flavia Venetucci; ANTUNES, Geiza Fernanda; FABRI, Gisele Maria de Campos; BALLESTER, Gerson; ANTEQUERA, Reynaldo; SIQUEIRA, Silvia Regina Dowgan Tesseroli de; FONOFF, Erich Talamoni; TEIXEIRA, Manoel Jacobsen; SIQUEIRA, Jose Tadeu Tesseroli de
    Periodontal disease (PD) is an infectious-inflammatory oral disease that is highly prevalent among adolescence and adulthood and can lead to chronic orofacial pain and be associated with anxiety, stress and depression. This study aimed to identify anxiety-like behaviors in the ligature-induced murine preclinical model of PD in different phases of the disease (i.e., acute vs. chronic). Also, we investigated orofacial mechanical allodynia thresholds and superficial cortical plasticity along the orofacial motor cortex in both disease phases. To this aim, 25 male Wistar rats were randomly allocated in acute (14 days) or chronic (28 days) ligature-induced-PD groups and further divided into active-PD or sham-PD. Anxiety-like behavior was evaluated using the elevated plus maze, mechanical allodynia assessed using the von Frey filaments test and superficial motor cortex mapping was performed with electrical transdural stimulation. We observed increased anxiety-like behavior in active-PD animals in the acute phase, characterized by decreased number of entries into the open arm extremities [t((1,7)) = 2.42, p = 0.04], and reduced time spent in the open arms [t((1,7)) = 3.56, p = 0.01] and in the open arm extremities [t((1,7)) = 2.75, p = 0.03]. There was also a reduction in the mechanical allodynia threshold in all active-PD animals [Acute: t((1,7)) = 8.81, p < 0.001; Chronic: t((1,6)) = 60.0, p < 0.001], that was positively correlated with anxiety-like behaviors in the acute group. No differences were observed in motor cortex mapping. Thus, our findings show the presence of anxiety-like behaviors in the acute phase of PD making this a suitable model to study the impact of anxiety in treatment response and treatment efficacy.
  • article 6 Citação(ões) na Scopus
    Effect of Subthalamic Stimulation and Electrode Implantation in the Striatal Microenvironment in a Parkinson's Disease Rat Model
    (2022) CAMPOS, Ana Carolina Pinheiro; MARTINEZ, Raquel Chacon Ruiz; AUADA, Aline Vivian Vatti; LEBRUN, Ivo; FONOFF, Erich Talamoni; HAMANI, Clement; PAGANO, Rosana Lima
    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is considered the gold-standard treatment for PD; however, underlying therapeutic mechanisms need to be comprehensively elucidated, especially in relation to glial cells. We aimed to understand the effects of STN-microlesions and STN-DBS on striatal glial cells, inflammation, and extracellular glutamate/GABAergic concentration in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Rats with unilateral striatal 6-OHDA and electrodes implanted in the STN were divided into two groups: DBS OFF and DBS ON (5 days/2 h/day). Saline and 6-OHDA animals were used as control. Akinesia, striatal reactivity for astrocytes, microglia, and inflammasome, and expression of cytokines, cell signaling, and excitatory amino acid transporter (EAAT)-2 were examined. Moreover, striatal microdialysis was performed to evaluate glutamate and GABA concentrations. The PD rat model exhibited akinesia, increased inflammation, glutamate release, and decreased glutamatergic clearance in the striatum. STN-DBS (DBS ON) completely abolished akinesia. Both STN-microlesion and STN-DBS decreased striatal cytokine expression and the relative concentration of extracellular glutamate. However, STN-DBS inhibited morphological changes in astrocytes, decreased inflammasome reactivity, and increased EAAT2 expression in the striatum. Collectively, these findings suggest that the beneficial effects of DBS are mediated by a combination of stimulation and local microlesions, both involving the inhibition of glial cell activation, neuroinflammation, and glutamate excitotoxicity.
  • article 16 Citação(ões) na Scopus
    Dopamine modulates individual differences in avoidance behavior: A pharmacological, immunohistochemical, neurochemical and volumetric investigation
    (2020) ANTUNES, Geiza Fernanda; GOUVEIA, Flavia Venetucci; REZENDE, Fabiana Strambio; SENO, Midia Dias de Jesus; CARVALHO, Milene Cristina de; OLIVEIRA, Caroline Cruz de; SANTOS, Lennon Cardoso Tosati dos; CASTRO, Marina Correia de; KUROKI, Mayra Akemi; TEIXEIRA, Manoel Jacobsen; OTOCH, Jose Pinhata; BRANDAO, Marcus Lira; FONOFF, Erich Talamoni; MARTINEZ, Raquel Chacon Ruiz
    Avoidance behavior is a hallmark in pathological anxiety disorders and results in impairment of daily activities. Individual differences in avoidance responses are critical in determining vulnerability or resistance to anxiety disorders. Dopaminergic activation is implicated in the processing of avoidance responses; however, the mechanisms underlying these responses are unknown. In this sense, we used a preclinical model of avoidance behavior to investigate the possibility of an intrinsic differential dopaminergic pattern between good and poor performers. The specific goal was to assess the participation of dopamine (DA) through pharmacological manipulation, and we further evaluated the effects of systemic injections of the dopaminergic receptor type 1 (D1 antagonist - SCH23390) and dopaminergic receptor type 2 (D2 antagonist - sulpiride) antagonists in the good performers. Additionally, we evaluated the effects of intra-amygdala microinjection of a D1 antagonist (SCH23390) and a D2 antagonist (sulpiride) in good performers as well as intra-amygdala microinjection of a D1 agonist (SKF38393) and D2 agonist (quinpirole) in poor performers. Furthermore, we quantified the contents of dopamine and metabolites (3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) in the amygdala, evaluated the basal levels of tyrosine hydroxylase expression (catecholamine synthesis enzyme) and measured the volume of the substantia nigra, ventral tegmental area and locus coeruleus. Our results showed that it could be possible to convert animals from good to poor performers, and vice versa, by intra-amygdala (basolateral and central nucleus) injections of D1 receptor antagonists in good performers or D2 receptor agonists in poor performers. Additionally, the good performers had lower levels of DOPAC and HVA in the amygdala, an increase in the total volume of the amygdala (AMG), substantia nigra (SN), ventral tegmental area (VTA) and locus coeruleus (LC), and an increase in the number of tyrosine hydroxylase-positive cells in SN, VTA and LC, which positively correlates with the avoidance behavior. Taken together, our data show evidence for a dopaminergic signature of avoidance performers, emphasizing the role of distinct dopaminergic receptors in individual differences in avoidance behavior based on pharmacological, immunohistochemical, neurochemical and volumetric analyses. Our findings provide a better understanding of the role of the dopaminergic system in the execution of avoidance behavior.