Efficacy of deep brain stimulation of the subthalamic nucleus versus globus pallidus internus on sensory complaints.

Pain control after deep brain stimulation (DBS) in Parkinson's disease (PD) remains unclear. Following six months, subthalamic (STN)-DBS reduced sensory complaints related to parkinsonism and bodily discomfort, increasing central beta-endorphin level. Pallidal GPi-DBS decreased bodily discomfort and beta-endorphin levels. Unexplained pain by other conditions and bodily discomfort were negatively correlated with beta-endorphin levels. Thus, DBS regulates central opioids, and prioritizing STN is important for PD patients with significant sensory complications.

Reduction of aggressive behaviour following hypothalamic deep brain stimulation: Involvement of 5-HT1A and testosterone.

BACKGROUND: Aggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB. OBJECTIVES: To test whether pHyp-DBS reduces aggressive behaviour in mice through mechanisms involving testosterone and 5-HT. METHODS: Male mice were housed with females for two weeks. These resident animals become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5 h/day for 8 consecutive encounters prior to the interaction with the intruder. After testing, blood and brains were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT1A antagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 encounters. RESULTS: DBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1A receptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS. CONCLUSIONS: This study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1A mechanisms.

One year follow-up on a randomized study investigating serratus anterior muscle and pectoral nerves type I block to reduced neuropathic pain descriptors after mastectomy.

Breast cancer is the second most common diagnosed type of cancer in women. Chronic neuropathic pain after mastectomy occurs frequently and is a serious health problem. In our previous single-center, prospective, randomized controlled clinical study, we demonstrated that the combination of serratus anterior plane block (SAM) and pectoral nerve block type I (PECS I) with general anesthesia reduced acute postoperative pain. The present report describes a prospective follow-up study of this published study to investigate the development of chronic neuropathic pain 12 months after mastectomy by comparing the use of general anesthesia alone and general anesthesia with SAM + PECS I. Additionally, the use of analgesic medication, quality of life, depressive symptoms, and possible correlations between plasma levels of interleukin (IL)-1 beta, IL-6, and IL-10 collected before and 24 h after surgery as predictors of pain and depression were evaluated. The results showed that the use of SAM + PECS I with general anesthesia reduced numbness, hypoesthesia to touch, the incidence of patients with chronic pain in other body regions and depressive symptoms, however, did not significantly reduce the incidence of chronic neuropathic pain after mastectomy. Additionally, there was no difference in the consumption of analgesic medication and quality of life. Furthermore, no correlation was observed between IL-1 beta, IL-6, and IL-10 levels and pain and depression. The combination of general anesthesia with SAM + PECS I reduced the occurrence of specific neuropathic pain descriptors and depressive symptoms. These results could promote the use of SAM + PECS I blocks for the prevention of specific neuropathic pain symptoms after mastectomy.Registration of clinical trial: The Research Ethics Board of the Hospital Sirio-Libanes/Brazil approved the study (CAAE 48721715.0.0000.5461). This study is registered at Registro Brasileiro de Ensaios Clinicos (ReBEC), and ClinicalTrials.gov, Identifier: NCT02647385.

Does TRODAT-1 SPECT Uptake Correlate with Cerebrospinal Fluid α-Synuclein Levels in Mid-Stage Parkinson's Disease?

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 α-synuclein levels in the cerebrospinal fluid (CSF). Therefore, this study aimed to understand the correlation between disease laterality, DAT-SPECT, cognition, and α-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 α-synuclein. RESULTS: We found that α-synuclein in the CSF was correlated with global cognition (positive correlation, r2 = 0.3, p = 0.05) and DAT-SPECT concentration in the putamen (positive correlation, r2 = 0.4, p = 0.005), and striatum (positive correlation, r2 = 0.2, p = 0.03), thus working as a neurodegenerative biomarker. No other correlations were found between DAT-SPECT, CSF α-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.

Unraveling the peripheral and local role of inflammatory cytokines in glioblastoma survival.

Glioblastoma (GBM) is a life-threatening disease that presents high morbidity and mortality. The standardized treatment protocol results in a global survival of less than three years in the majority of cases. Immunotherapies have gained wide recognition in cancer treatment; however, GBM has an immunosuppressive microenvironment diminishing the possible effectiveness of this therapy. In this sense, investigating the inflammatory settings and the tumoral nature of GBM patients are an important goal to create an individual plan of treatment to improve overall survival rate and quality of life of these patients. Thirty-two patients who underwent surgical resection of GBM were included in this study. Tumor samples and 10 mL of peripheral blood were collected and immediately frozen. TNF-a, IL-1a and IL-4 were evaluated in the tumor and TNF-a, IL-1a and TGF-b in the plasma by Luminex assay. Immunohistochemistry analysis to determine immune celular profile was done, including immunohistochemistry for CD20, CD68 and CD3. Three cases were excluded. Tumor topography, tumor nature, and tumor volume reconstructions were accurately analyzed by T1-weighted, T2-weighted, and FLAIR magnetic resonance imaging. We found that GBM patients with below median peripheral levels of TNF-a and IL-1a had a decreased survival rate when compared to above median patients. On the other hand, patients with below median peripheral levels of TGF-b increased overall survival rate. Intratumoral IL-1a above median was associated with higher number of macrophages and fewer with B cells. Furthermore, plasmatic TNF-a levels were correlated with intratumoral TNF-a levels, suggesting that peripheral cytokines are related to the tumoral microenvironment. Even though tumor size has no difference regarding survival rate, we found a negative correlation between intratumoral IL-4 and tumor size, where larger tumors have less IL-4 expression. Nevertheless, the tumoral nature had a significant effect in overall survival rate, considering that infiltrative tumors showed decreased survival rate and intratumoral TNF-a. Moreover, expansive tumors revealed fewer macrophages and higher T cells. In multiple variation analyzes, we demonstrated that infiltrative tumors and below median peripheral IL-1a expression represent 3 times and 5 times hazard ratio, respectively, demonstrating a poor prognosis. Here we found that peripheral cytokines had a critical role as prognostic tools in a small cohort of GBM patients.

Transcranial Direct Current Stimulation Reduces Anxiety, Depression and Plasmatic Corticosterone in a Rat Model of Atypical Generalized Epilepsy.

Affective disorders (i.e. anxiety and depression) are commonly observed in patients with epilepsy and induce seizure aggravation. Animal models of epilepsy that exhibit affective disorder features are essential in developing new neuromodulatory treatments. GEAS-W rats (Generalized Epilepsy with Absence Seizures, Wistar background) are an inbred model of generalized epilepsy showing spontaneous spike-wave discharges concomitant with immobility. Transcranial Direct Current Stimulation (tDCS) is a safe non-invasive neuromodulatory therapy used to modulate dysfunctional circuitries frequently and successfully applied in affective disorders for symptom alleviation. Here we investigated anxiolytic and antidepressant effects of tDCS in GEAS-W rats and the role of corticosterone as a possible mechanism of action. GEAS-W and Wistar rats were randomly divided into control, sham-tDCS and active-tDCS groups. Both tDCS groups received 15 sessions of sham or active-tDCS (1 mA, cathode). Behavioural tests included the Open Field and Forced Swimming tests followed by corticosterone analysis. We observed a main effect of treatment and a significant treatment by strain interaction on anxiety-like and depressive-like behaviours, with active-tDCS GEAS-W rats entering the center of the open field more often and showing less immobility in the forced swimming test. Furthermore, there was a main effect of treatment on corticosterone with active-tDCS animals showing marked reduction in plasmatic levels. This study described preclinical evidence to support tDCS treatment of affective disorders in epilepsy and highlights corticosterone as a possible mechanism of action.

Directional Deep Brain Stimulation of the Posteromedial Hypothalamus for Refractory Intermittent Explosive Disorder: A Case Series Using a Novel Neurostimulation Device and Intraoperative Microdialysis.

BACKGROUND: Intermittent explosive disorder (IED) is a psychiatric disorder characterized by recurrent outbursts of aggressive behavior. Deep brain stimulation (DBS) in the posteromedial nucleus of the hypothalamus (pHyp) is an alternative therapy for extreme cases and shows promising results. Intraoperative microdialysis can help elucidate the neurobiological mechanism of pHyp-DBS. We sought to evaluate efficacy and safety of pHyp-DBS using 8-contact directional leads in patients with refractory IED (rIED) and the accompanying changes in neurotransmitters. METHODS: This was a prospective study in which patients with a diagnosis of rIED were treated with pHyp-DBS for symptom alleviation. Bilateral pHyp-DBS was performed with 8-contact directional electrodes. Follow-up was performed at 3, 6, and 12 months after surgery. RESULTS: Four patients (3 men, mean age 27 ± 2.8 years) were included. All patients were diagnosed with rIED and severe intellectual disability. Two patients had congenital rubella, one had a co-diagnosis of infantile autism, and the fourth presented with drug-resistant epilepsy. There was a marked increase in the levels of gamma-aminobutyric acid and glycine during intraoperative stimulation. The average improvement in aggressive behavior in the last follow-up was 6 points (Δ: 50%, P = 0.003) while also documenting an important improvement of the Short Form Health Survey in all domains except bodily pain. No adverse events associated with pHyp-DBS were observed. CONCLUSIONS: This is the first study to show the safety and beneficial effect of directional lead pHyp-DBS in patients with rIED and to demonstrate the corresponding mechanism of action through increases in gamma-aminobutyric acid and glycine concentration in the pHyp.

Bilateral Amygdala Radio-Frequency Ablation for Refractory Aggressive Behavior Alters Local Cortical Thickness to a Pattern Found in Non-refractory Patients.

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.

Beneficial nonmotor effects of subthalamic and pallidal neurostimulation in Parkinson's disease.

BACKGROUND: Subthalamic (STN) and pallidal (GPi) deep brain stimulation (DBS) improve quality of life, motor, and nonmotor symptoms (NMS) in advanced Parkinson's disease (PD). However, few studies have compared their nonmotor effects. OBJECTIVE: To compare nonmotor effects of STN-DBS and GPi-DBS. METHODS: In this prospective, observational, multicenter study including 60 PD patients undergoing bilateral STN-DBS (n = 40) or GPi-DBS (n = 20), we examined PDQuestionnaire (PDQ), NMSScale (NMSS), Unified PD Rating Scale-activities of daily living, -motor impairment, -complications (UPDRS-II, -III, -IV), Hoehn&Yahr, Schwab&England Scale, and levodopa-equivalent daily dose (LEDD) preoperatively and at 6-month follow-up. Intra-group changes at follow-up were analyzed with Wilcoxon signed-rank or paired t-test, if parametric tests were applicable, and corrected for multiple comparisons. Inter-group differences were explored with Mann-Whitney-U/unpaired t-tests. Analyses were performed before and after propensity score matching which balanced out demographic and preoperative clinical characteristics. Strength of clinical changes was assessed with effect size. RESULTS: In both groups, PDQ, UPDRS-II, -IV, Schwab&England Scale, and NMSS improved significantly at follow-up. STN-DBS was significantly better for LEDD reduction, GPi-DBS for UPDRS-IV. While NMSS total score outcomes were similar, explorative NMSS domain analyses revealed distinct profiles: Both targets improved sleep/fatigue and mood/cognition, but only STN-DBS the miscellaneous (pain/olfaction) and attention/memory and only GPi-DBS cardiovascular and sexual function domains. CONCLUSIONS: To our knowledge, this is the first study to report distinct patterns of beneficial nonmotor effects of STN-DBS and GPi-DBS in PD. This study highlights the importance of NMS assessments to tailor DBS target choices to patients' individual motor and nonmotor profiles.

Refractoriness of aggressive behaviour to pharmacological treatment: cortical thickness analysis in autism spectrum disorder.

Aggressive behaviour is a highly prevalent and devastating condition in autism spectrum disorder resulting in impoverished quality of life. Gold-standard therapies are ineffective in about 30% of patients leading to greater suffering. We investigated cortical thickness in individuals with autism spectrum disorder with pharmacological-treatment-refractory aggressive behaviour compared with those with non-refractory aggressive behaviour and observed a brain-wide pattern of local increased thickness in key areas related to emotional control and overall decreased cortical thickness in those with refractory aggressive behaviour, suggesting refractoriness could be related to specific morphological patterns. Elucidating the neurobiology of refractory aggressive behaviour is crucial to provide insights and potential avenues for new interventions.

Fully Automated Habenula Segmentation Provides Robust and Reliable Volume Estimation Across Large Magnetic Resonance Imaging Datasets, Suggesting Intriguing Developmental Trajectories in Psychiatric Disease.

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/semiautomated 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.

Amygdala and Hypothalamus: Historical Overview With Focus on Aggression.

Aggressiveness has a high prevalence in psychiatric patients and is a major health problem. Two brain areas involved in the neural network of aggressive behavior are the amygdala and the hypothalamus. While pharmacological treatments are effective in most patients, some do not properly respond to conventional therapies and are considered medically refractory. In this population, surgical procedures (ie, stereotactic lesions and deep brain stimulation) have been performed in an attempt to improve symptomatology and quality of life. Clinical results obtained after surgery are difficult to interpret, and the mechanisms responsible for postoperative reductions in aggressive behavior are unknown. We review the rationale and neurobiological characteristics that may help to explain why functional neurosurgery has been proposed to control aggressive behavior.

Neurochemical effects of motor cortex stimulation in the periaqueductal gray during neuropathic pain.

OBJECTIVE: Motor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings. METHODS: Male Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS. RESULTS: MCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia. CONCLUSIONS: These results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.

The critical role of amygdala subnuclei in nociceptive and depressive-like behaviors in peripheral neuropathy.

The amygdala is an important component of the limbic system that participates in the control of the pain response and modulates the affective-motivational aspect of pain. Neuropathic pain is a serious public health problem and has a strong affective-motivational component that makes it difficult to treat. The central (CeA), basolateral (BLA) and lateral (LA) nuclei of the amygdala are involved in the processing and regulation of chronic pain. However, the roles of these nuclei in the maintenance of neuropathic pain, anxiety and depression remain unclear. Thus, the main objective of this study was to investigate the role of amygdala subnuclei in the modulation of neuropathic pain, including the affective-motivational axis, in an experimental model of peripheral neuropathy. The specific goals were as follows: (1) To evaluate the nociceptive responses and the patterns of activation of the CeA, BLA and LA in neuropathic rats; and (2) To evaluate the effect of inactivating the amygdala nuclei on the nociceptive response, anxiety and depressive behaviors, motor activity, and plasma stress hormones in animals with neuropathic pain. Thus, mechanical hyperalgesia and allodynia, and the pattern of c-Fos staining in the amygdala subnuclei were evaluated in rats with chronic constriction of the sciatic nerve, as well as sham-operated and naïve rats. Once the amygdala subnuclei involved in neuropathic pain response were defined, those subnuclei were pharmacological inactivated. The effect of muscimol inactivation on the nociceptive response (hyperalgesia and allodynia), anxiety (elevated plus-maze), depressive-like behavior (forced swim test), motor activity (open field), and plasma stress hormone levels (corticosterone and adrenocorticotropic hormone) were evaluated in sham-operated and neuropathic animals. The results showed that the anterior and posterior portions of the BLA and the central portion of the CeA are involved in controlling neuropathic pain. The inactivation of these nuclei reversed hyperalgesia, allodynia and depressive-like behavior in animals with peripheral neuropathy. Taken together, our findings improve our understanding of the neurocircuitry involved in persistent pain and the roles of specific amygdala subnuclei in the modulation of neuropathic pain, including the neurocircuitry that processes the affective-motivational component of pain.

Benefits in radical mastectomy protocol: a randomized trial evaluating the use of regional anesthesia.

Surgery is the first-line treatment for early, localized, or operable breast cancer. Regional anesthesia during mastectomy may offer the prevention of postoperative pain. One potential protocol is the combination of serratus anterior plane block (SAM block) with pectoral nerve block I (PECS I), but the results and potential benefits are limited. Our study compared general anesthesia with or without SAM block + PECS I during radical mastectomy with axillary node dissection and breast reconstruction using evaluations of pain, opioid consumption, side effects and serum levels of interleukin (IL)-1beta, IL-6 and IL-10. This is a prospective, randomized controlled trial. Fifty patients were randomized to general anesthesia only or general anesthesia associated with SAM block + PECS I (25 per group). The association of SAM block + PECS I with general anesthesia reduced intraoperative fentanyl consumption, morphine use and visual analog pain scale scores in the post-anesthetic care unit (PACU) and at 24 h after surgery. In addition, the anesthetic protocol decreased side effects and sedation 24 h after surgery compared to patients who underwent general anesthesia only. IL-6 levels increased after the surgery compared to baseline levels in both groups, and no differences in IL-10 and IL-1 beta levels were observed. Our protocol improved the outcomes of mastectomy, which highlight the importance of improving mastectomy protocols and focusing on the benefits of regional anesthesia.

A Window on the Study of Aversive Instrumental Learning: Strains, Performance, Neuroendocrine, and Immunologic Systems.

The avoidance response is present in pathological anxiety and interferes with normal daily functions. The aim of this article is to shed light on performance markers of active avoidance (AA) using two different rat strains, Sprague-Dawley (SD) and Wistar. Specifically, good and poor performers were evaluated regarding anxiety traits exhibited in the elevated plus maze (EPM) and corticosterone levels and motor activity in the open field test. In addition, the plasma levels of Interleukin-6 (IL-6), Interleukin-1Beta (IL-1beta), Nerve Growth Factor Beta (NGF-beta), Tumor Necrosis Factor-Alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant 1 (CINC-1) were compared in the good and poor performers to better understand the role of the immunologic system in aversive learning. Behavioral criteria were employed to identify subpopulations of SD and Wistar rats based on their behavioral scores during a two-way AA test. The animals were tested for anxiety-like behavior in the EPM and motor activity in the open-field test. Plasma corticosterone levels were measured at the end of the avoidance test. Cytokine levels of IL-6, IL-1beta, NGF-beta, TNF-alpha, and CINC-1 were measured in the plasma of the Wistar rats. Sixty-six percent of the Wistar rats and 35% of the SD rats exhibited a poor performance. This feature was associated with a decrease in anxiety-like behavior in the EPM. The poor and good performers exhibited lower levels of corticosterone compared with the control animals, which suggests that training alters corticosterone levels, thereby leading to hypocortisolism, independent of the performance. The CINC-1 levels were increased in the poor performers, which reinforces the role of immunologic system activation in learning deficits. Our study provides a better understanding of the complex interactions that underlie neuroimmune consequences and their implications for performance.

Intraoperative dopamine release during globus pallidus internus stimulation in Parkinson's disease.

BACKGROUND: It is still unclear whether dopamine (DA) levels correlate with Parkinson's disease (PD) severity or play a role in the mechanisms of high-frequency stimulation (HFS). METHODS: We have used microdialysis to record pallidal DA in 5 patients with PD undergoing microelectrode-guided pallidotomy. RESULTS: We found that patients with more severe disease and, consequently, lower pallidal DA did poorly after pallidal lesions. In the operating room, 4 of 5 patients had a significant increase in DA levels during HFS (600%, on average). To test the hypothesis that DA was important for the effects of stimulation, we correlated the amelioration in rigidity observed in the operating room with pallidal DA release. Though rigidity was 56% better during stimulation, no correlation was found between such an improvement and DA release. CONCLUSIONS: These findings suggest that additional mechanisms not directly dependent on pallidal DA release may be involved in the clinical effects of HFS of the globus pallidus internus.

Active vs. reactive threat responding is associated with differential c-Fos expression in specific regions of amygdala and prefrontal cortex.

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.

Evidence for the thalamic targets of the medial hypothalamic defensive system mediating emotional memory to predatory threats.

Previous studies from our laboratory have documented that the medial hypothalamic defensive system is critically involved in processing actual and contextual predatory threats, and that the dorsal premammillary nucleus (PMd) represents the hypothalamic site most responsive to predatory threats. Anatomical findings suggest that the PMd is in a position to modulate memory processing through a projecting branch to specific thalamic nuclei, i.e., the nucleus reuniens (RE) and the ventral part of the anteromedial nucleus (AMv). In the present study, we investigated the role of these thalamic targets in both unconditioned (i.e., fear responses to predatory threat) and conditioned (i.e., contextual responses to predator-related cues) defensive behaviors. During cat exposure, all experimental groups exhibited intense defensive responses with the animals spending most of the time in the home cage displaying freezing behavior. However, during exposure to the environment previously associated with a cat, the animals with combined RE+AMv lesions, and to a lesser degree, animals with single AMv unilateral lesions, but not animals with single RE lesions, presented a reduction of contextual conditioned defensive responses. Overall, the present results provide clear evidence suggesting that the PMd's main thalamic targets (i.e., the nucleus reuniens and the AMv) seem to be critically involved in the emotional memory processing related to predator cues.