Effect of Subthalamic Stimulation and Electrode Implantation in the Striatal Microenvironment in a Parkinson's Disease Rat Model.

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.

Unraveling the Role of Astrocytes in Subthalamic Nucleus Deep Brain Stimulation in a Parkinson's Disease Rat Model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for motor symptoms of Parkinson's disease (PD) when L-DOPA therapy induces disabling side effects. Classical inflammatory activation of glial cells is well established in PD, contributing to the progressive neurodegenerative state; however, the role of DBS in regulating the inflammatory response remains largely unknown. To understand the involvement of astrocytes in the mechanisms of action of DBS, we evaluated the effect of STN-DBS in regulating motor symptoms, astrocyte reactivity, and cytokine expression in a 6-OHDA-induced PD rat model. To mimic in vivo DBS, we investigate the effect of high-frequency stimulation (HFS) in cultured astrocytes regulating cytokine induction and NF-κB activation. We found that STN-DBS improved motor impairment, induced astrocytic hyperplasia, and reversed increased IFN-γ and IL-10 levels in the globus pallidus (GP) of lesioned rats. Moreover, HFS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. Our results indicate that DBS/HFS may act as a regulator of the inflammatory response in PD states, attenuating classical activation of astrocytes and cytokine induction, potentially through its ability to regulate NF-κB activation. These findings may help us understand the role of astrocyte signaling in HFS, highlighting its possible relationship with the effectiveness of DBS in neurodegenerative disorders.

Evolution of gamma knife capsulotomy for intractable obsessive-compulsive disorder.

For more than half a century, stereotactic neurosurgical procedures have been available to treat patients with severe, debilitating symptoms of obsessive-compulsive disorder (OCD) that have proven refractory to extensive, appropriate pharmacological, and psychological treatment. Although reliable predictors of outcome remain elusive, the establishment of narrower selection criteria for neurosurgical candidacy, together with a better understanding of the functional neuroanatomy implicated in OCD, has resulted in improved clinical efficacy for an array of ablative and non-ablative intervention techniques targeting the cingulum, internal capsule, and other limbic regions. It was against this backdrop that gamma knife capsulotomy (GKC) for OCD was developed. In this paper, we review the history of this stereotactic radiosurgical procedure, from its inception to recent advances. We perform a systematic review of the existing literature and also provide a narrative account of the evolution of the procedure, detailing how the procedure has changed over time, and has been shaped by forces of evidence and innovation. As the procedure has evolved and adverse events have decreased considerably, favorable response rates have remained attainable for approximately one-half to two-thirds of individuals treated at experienced centers. A reduction in obsessive-compulsive symptom severity may result not only from direct modulation of OCD neural pathways but also from enhanced efficacy of pharmacological and psychological therapies working in a synergistic fashion with GKC. Possible complications include frontal lobe edema and even the rare formation of delayed radionecrotic cysts. These adverse events have become much less common with new radiation dose and targeting strategies. Detailed neuropsychological assessments from recent studies suggest that cognitive function is not impaired, and in some domains may even improve following treatment. We conclude this review with discussions covering topics essential for further progress of this therapy, including suggestions for future trial design given the unique features of GKC therapy, considerations for optimizing stereotactic targeting and dose planning using biophysical models, and the use of advanced imaging techniques to understand circuitry and predict response. GKC, and in particular its modern variant, gamma ventral capsulotomy, continues to be a reliable treatment option for selected cases of otherwise highly refractory OCD.

EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson's disease.

OBJECTIVE: Real-life observational report of clinical efficacy of bilateral subthalamic stimulation (STN-DBS), apomorphine (APO), and intrajejunal levodopa infusion (IJLI) on quality of life, motor, and nonmotor symptoms (NMS) in Parkinson's disease (PD). METHODS: In this prospective, multicenter, international, real-life cohort observation study of 173 PD patients undergoing STN-DBS (n = 101), IJLI (n = 33), or APO (n = 39) were followed-up using PDQuestionnaire-8, NMSScale (NMSS), Unified PD Rating Scale (UPDRS)-III, UPDRS-IV, and levodopa equivalent daily dose (LEDD) before and 6 months after intervention. Outcome changes were analyzed with Wilcoxon signed-rank or paired t test when parametric tests were applicable. Multiple comparisons were corrected (multiple treatments/scales). Effect strengths were quantified with relative changes, effect size, and number needed to treat. Analyses were computed before and after propensity score matching, balancing demographic and clinical characteristics. RESULTS: In all groups, PDQuestionnaire-8, UPDRS-IV, and NMSS total scores improved significantly at follow-up. Levodopa equivalent daily dose was significantly reduced after STN-DBS. Explorative NMSS domain analyses resulted in distinct profiles: STN-DBS improved urinary/sexual functions, mood/cognition, sleep/fatigue, and the miscellaneous domain. IJLI improved the 3 latter domains and gastrointestinal symptoms. APO improved mood/cognition, perceptual problems/hallucinations, attention/memory, and the miscellaneous domain. Overall, STN-DBS and IJLI seemed favorable for NMSS total score, and APO favorable for neuropsychological/neuropsychiatric NMS and PDQuestionnaire-8 outcome. CONCLUSIONS: This is the first comparison of quality of life, nonmotor. and motor outcomes in PD patients undergoing STN-DBS, IJLI, and APO in a real-life cohort. Distinct effect profiles were identified for each treatment option. Our results highlight the importance of holistic nonmotor and motor symptoms assessments to personalize treatment choices. © 2019 International Parkinson and Movement Disorder Society.

Motor cortex and pain control: exploring the descending relay analgesic pathways and spinal nociceptive neurons in healthy conscious rats.

Motor cortex stimulation (MCS) is an effective therapy for refractory neuropathic pain. MCS increases the nociceptive threshold in healthy rats via endogenous opioids, inhibiting thalamic nuclei and activating the periaqueductal gray. It remains unclear how the motor cortex induces top-down modulation of pain in the absence of persistent pain. Here, we investigated the main nuclei involved in the descending analgesic pathways and the spinal nociceptive neurons in rats that underwent one session of MCS and were evaluated with the paw pressure nociceptive test. The pattern of neuronal activation in the dorsal raphe nucleus (DRN), nucleus raphe magnus (NRM), locus coeruleus (LC), and dorsal horn of the spinal cord (DHSC) was assessed by immunoreactivity (IR) for Egr-1 (a marker of activated neuronal nuclei). IR for serotonin (5HT) in the DRN and NRM, tyrosine hydroxylase (TH) in the LC, and substance P (SP) and enkephalin (ENK) in the DHSC was also evaluated. MCS increased the nociceptive threshold of the animals; this increase was accompanied by activation of the NRM, while DRN activation was unchanged. However, cortical stimulation induced an increase in 5HT-IR in both serotonergic nuclei. MCS did not change the activation pattern or TH-IR in the LC, and it inhibited neuronal activation in the DHSC without altering SP or ENK-IR. Taken together, our results suggest that MCS induces the activation of serotonergic nuclei as well as the inhibition of spinal neurons, and such effects may contribute to the elevation of the nociceptive threshold in healthy rats. These results allow a better understanding of the circuitry involved in the antinociceptive top-down effect induced by MCS under basal conditions, reinforcing the role of primary motor cortex in pain control.

Peripheral Nerve Stimulation for Painful Mononeuropathy Secondary to Leprosy: A 12-Month Follow-Up Study.

OBJECTIVE: Leprosy affects approximately 10-15 million patients worldwide and remains a relevant public health issue. Chronic pain secondary to leprosy is a primary cause of morbidity, and its treatment remains a challenge. We evaluated the feasibility and safety of peripheral nerve stimulation (PNS) for painful mononeuropathy secondary to leprosy that is refractory to pharmacological therapy and surgical intervention (decompression). METHODS: Between 2011 and 2013 twenty-three patients with painful mononeuropathy secondary to leprosy were recruited to this prospective case series. All patients were considered to be refractory to optimized conservative treatment and neurosurgical decompression. Pain was evaluated over the course of the study using the neuropathic pain scale and the visual analog scale for pain. In the first stage, patients were implanted with a temporary electrode that was connected to an external stimulator, and were treated with PNS for seven days. Patients with 50% or greater pain relief received a definitive implantation in the second stage. Follow-ups in the second stage were conducted at 1, 3, 6, and 12 months. RESULTS: After seven days of trial in the first stage, 10 patients showed a pain reduction of 50% or greater. At 12-month follow-up in the second stage, 6 of the 10 patients who underwent permanent device implantation showed a pain reduction of 50% or greater (75% reduction on average), and two patients showed a 30% reduction in pain. Two patients presented with electrode migration that required repositioning during the 12-month follow-up period. CONCLUSIONS: Our data suggest that PNS might have significant long-term utility for the treatment of painful mononeuropathy secondary to leprosy. Future studies should be performed in order to corroborate our findings in a larger population and encourage the clinical implementation of this technique.

Evaluation of GX1 and RGD-GX1 peptides as new radiotracers for angiogenesis evaluation in experimental glioma models.

Gliomas are the most common type among all central nervous system tumors. The aggressiveness of gliomas is correlated with the level of angiogenesis and is often associated with prognosis. The aim of this study is to evaluate the novel GX1 peptide and the heterodimer RGD-GX1 radiolabeled with technetium-99m, for angiogenesis detection in glioma models. Radiolabeling and radiochemical controls were assessed for both radioconjugates. In vitro binding studies in glioma tumor cells were performed, as well as biodistribution in SCID mice bearing tumor cells, in order to evaluate the biological behavior and tumor uptake of the radiocomplexes. Blocking and imaging studies were also conducted. MicroSPECT/CT images were acquired in animals with experimentally implanted intracranial tumor. Open field activity was performed to evaluate behavior, as well as perfusion and histology analysis. The radiochemical purity of both radiotracers was greater than 96 %. In vitro binding studies revealed rather similar binding profi le for each molecule. The highest binding was for RGD-GX1 peptide at 120 min in U87MG cells (1.14 ± 0.35 %). Tumor uptake was also favorable for RGD-GX1 peptide in U87MG cells, reaching 2.96 ± 0.70 % at 1 h p.i. with 47 % of blocking. Imaging studies also indicated better visualization for RGD-GX1 peptide in U87MG cells. Behavior evaluation pointed brain damage and histology studies confirmed actual tumor in the uptake site. The results with the angiogenesis seeking molecule (99m)Tc-HYNIC-E-[c(RGDfk)-c(GX1)] were successful, and better than with (99m)Tc-HYNIC-PEG4-c(GX1). Future studies targeting angiogenesis in other glioma and nonglioma tumor models are recommended.

Spinal cord stimulation for Parkinson's disease: a systematic review.

Axial symptoms are a late-developing phenomenon in the course of Parkinson's disease (PD) and represent a therapeutic challenge given their poor response to levodopa therapy and deep brain stimulation. Spinal cord stimulation (SCS) may be a new therapeutic approach for the alleviation of levodopa-resistant motor symptoms of PD. Our purpose was to systematically review the effectiveness of SCS for the treatment of motor symptoms of PD and to evaluate the technical and pathophysiological mechanisms that may influence the outcome efficacy of SCS. A comprehensive literature search was conducted using electronic databases for the period from January 1966 through April 2014. The methodology utilized in this work follows a review process derived from evidence-based systematic review and meta-analysis of randomized trials described in the PRISMA statement. Reports examining SCS for the treatment of PD are limited. Eight studies with a total of 24 patients were included in this review. The overall motor score of the Unified Parkinson's Disease Rating Scale in the on/off-stimulation condition remained unchanged in 6 patients and improved in 18 patients after SCS. SCS appears to yield positive results for PD symptoms, especially for impairments in gait function and postural stability. However, evidence is limited and long-term prospective studies will be required to identify the optimal candidates for SCS and the best parameters of stimulation and to fully characterize the effects of stimulation on motor and nonmotor symptoms of PD.

Correlation between impulsivity and executive function in patients with Parkinson disease experiencing depression and anxiety symptoms.

BACKGROUND: Depression and anxiety are comorbidities often associated with Parkinson disease (PD). Recent studies debate on how affective disorders can influence the cognition of patients with PD. This study sought to investigate how depression and anxiety affect specific executive functions and impulsivity traits in these patients. METHODS: Twenty-eight patients with advanced PD and 28 closely matched healthy volunteers (HV) were assessed for depressive and anxiety symptoms, impulsivity, executive function and control attention and behavioral response. RESULTS: Compared to the HV group, the PD group showed significantly higher perseverative responses and slowness to adapt to changes in environmental stimuli and longer reaction time for inter-stimulus interval change. Depression symptoms were significantly correlated to motor impulsivity score and total Barratt Impulsiveness Scale (BIS -11) score. Moreover, there was also significant correlation between anxiety symptoms and attentional impulsivity score and total BIS-11 score. Correlation analysis between impulsivity and control attention indicated a positive correlation in commission and a negative correlation in reaction time and detectability in the PD group. CONCLUSIONS: The present results suggest that depression and anxiety were highly correlated to impulsivity but not to executive functions changes in these PD patients.

Chronic spinal and oral morphine-induced neuroendocrine and metabolic changes in noncancer pain patients.

OBJECTIVE: Interactions between opioid use and hormonal function are documented in the literature. However, it is unclear if therapeutic intrathecal opioid therapy can induce hormonal changes, compared to oral opioid therapy. METHODS: The authors studied hormone and metabolic changes in 22 women (18-60 years) and 38 men (18-45 years) who were referred to a pain center. The patients were allocated to different treatment groups (based on assistant physicians' decision), as follows: 20 patients received oral morphine (60-120 mg/day); 20 patients, spinal morphine (0.2-10 mg/day); and 20 patients, nonopioid analgesic treatment. RESULTS: All three groups experienced substantial improvement in pain scores during the whole follow-up period. Significantly impaired libido, reduced potency, hot flashes, and menstrual cycle dysfunction occurred more often in both morphine groups than in the nonopioid group. Significantly low serum total testosterone levels were more prevalent in the spinal morphine group and the oral morphine group (58.3% and 70.0%, respectively) than in the control group (16.7%). Total cholesterol values above 200 mg/dL and higher ultrasensitive C-reactive protein levels were significantly more frequent in the morphine groups than in the controls. Total body bone mineral density was below normal in men receiving spinal morphine (P = 0.014). CONCLUSIONS: Hypogonadotrophic hypogonadism was more prevalent in the morphine groups and was correlated with clinical findings. Significant bone mass loss occurred in morphine users, even without hormone dysfunction when compared to nonopioid treatment. Growth hormone, thyroid stimulating hormone, adrenocorticotrophic hormones, and cardiovascular risk parameters were less compromised in morphine users.

Deep brain stimulation of the globus pallidus internus or ventralis intermedius nucleus of thalamus for Holmes tremor.

Holmes tremor (HT) is a difficult-to-treat, very disabling symptomatic condition which characteristically appears weeks to years after a brain lesion. It features a unique combination of rest, action, and postural tremors. Pharmacotherapy is mostly not effective. Chronic deep brain stimulation (DBS) of ventralis intermedius nucleus (Vim) of thalamus has been described as being the best surgical approach in singular case series; various authors observe, however, cases with partial responses only; therefore, alternatives are still needed. We report ten patients with HT unresponsive to best medical therapy who underwent DBS in our center from March 2002 to June 2012. Based in our previous experience dealing with cases of unsatisfactory Vim intraoperative tremor control and in order to optimize surgical results, presurgical target planning included two Nuclei: Vim and posteroventral Globus pallidus internus (GPi) (Espinoza et al. 2010; Espinoza et al. Stereotact Funct Neurosurg 90(suppl 1):1-202, p 61, 2012). Definitive chosen target was decided after single-cell microelectrode recording, intraoperative test stimulation, thresholds for stimulation-induced adverse effects and best clinical response compared to baseline status. Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) was used to evaluate outcome. The electrode was implanted in the nucleus with the best tremor suppression achievement; on the other hand, GPi DBS was initially decided if one of the following conditions was present: (a) If Vim nucleus anatomy was grossly altered; (b) when intraoperative tremor control was unsatisfactory despite Vim high-intensity stimulation; or (c) if unaffordable side effects or even tremor worsening occurred during intraoperative macrostimulation. Seven patients received definitive Gpi DBS implantation, while three patients received Vim DBS. In all observed cases, we observed an improvement on the TRS. In two cases where Vim thalamic anatomy was altered by the pathological insult GPI was planned from the beginning, and same was true in two additional cases where the Gpi nucleus showed major alterations allowing only Vim planning. Over all cases, the average improvement in tremor was of 2.55 points on the TRS or a 64 % increase in measured results; with a minimum of 1 point (25 %) improvement in one case and a maximum of 4 points (100 % improvement) also in one case. All the results were sustained at 2 years follow-up. One case with predominant resting component, implanted in the GPi, achieved the maximum possible tremor reduction (from 4 to 0 points, meaning 100 % tremor reduction); in the nine resting cases, the average reduction was of 3 points (or 75 %). DBS demonstrated in this case series adequate tremor control in 10 patients unresponsive to medical therapy. Presurgical planning of two targets allowed choosing best optimal response. Gpi stimulation could be considered as an alternative target for cases in which thalamic anatomy is considerably altered or Vim intraoperative stimulation does not produce satisfactory results.

Cerebral microdialysis in traumatic brain injury and subarachnoid hemorrhage: state of the art.

Cerebral microdialysis (CMD) is a laboratory tool that provides on-line analysis of brain biochemistry via a thin, fenestrated, double-lumen dialysis catheter that is inserted into the interstitium of the brain. A solute is slowly infused into the catheter at a constant velocity. The fenestrated membranes at the tip of the catheter permit free diffusion of molecules between the brain interstitium and the perfusate, which is subsequently collected for laboratory analysis. The major molecules studied using this method are glucose, lactate, pyruvate, glutamate, and glycerol. The collected substances provide insight into the neurochemical features of secondary injury following traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and valuable information about changes in brain metabolism within a short time frame. In this review, the authors detail the CMD technique and its associated markers and then describe pertinent findings from the literature about the clinical application of CMD in TBI and SAH.

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.

Decompressive craniectomy and head injury: brain morphometry, ICP, cerebral hemodynamics, cerebral microvascular reactivity, and neurochemistry.

There has been renewed interest in decompressive craniectomy as a surgical treatment for elevated intracranial pressure (ICP), although evidence-based clinical data are still lacking and some experimental results are conflicting. Ongoing clinical trials on the use of this operation after traumatic brain injury (TBI) may clarify the clinical application of this technique, however, some pathophysiological issues, such as the timing of this operation, its effect on brain edema formation, and its role for secondary brain damage, are still controversial. This review addresses recent clinical data on the influence of decompressive craniectomy on the brain pathophysiology in TBI. Decompressive craniectomy with dural augmentation enlarges intracranial space so that the swollen cerebral hemisphere could expand out of normal cranial limits, avoiding progression of brain herniation. The gain in intracranial volume results in both the improvement of cerebral compliance and a decrease in ICP; the latter favors a rise in both cerebral blood flow and cerebral microvascular perfusion, which can be accompanied by elevation in brain tissue oxygen tension (PbtO2) as well as the return of abnormal metabolic parameters to normal values in cases of cerebral ischemia. Enhancement of edema formation, impairment of cerebrovascular pressure reactivity, and non-restoration of brain aerobic metabolism due to metabolic crisis may occur after craniectomy and require further investigations. This review suggests that decompressive craniectomy as the sole treatment is likely to be insufficient; efforts must be made to maintain adequate brain hemodynamics, preferably coupled with brain metabolism, in addition to treating brain metabolic abnormalities, during postoperative stages.

Intra-operative transdural electric stimulation in awake patient: target refining for motor cortex stimulation.

INTRODUCTION: Most authors perform the implantation of epidural electrodes for motor cortex stimulation (MCS) under general anesthesia, using navigation merely based on anatomic landmarks or in combination with intra-operative sensory evoked potentials (SEP) for functional localization. However, intra-operative SEP can only provide the localization of central sulcus in patients who present sensory pathways which are at least partially preserved. Conversely, there are massive deafferentation pain syndromes (e.g., brachial plexus avulsion or amputation) in which the peripheral sensory pathways are severely or totally injured, precluding the use of intra-operative SEP. Objective. The authors present a simple technique for functional localization and intra-operative mapping of motor cortex by the implementation of transdural electrical stimulation of cerebral cortex for target refining of motor cortex during cortical electrode implantation procedures. METHODS: Thirteen patients with complete brachial plexus root avulsion suffering from severe neuropathic pain in the affected limb were included in this report. First, the anatomical location of the motor cortex of the hand was stereotactically determined by the hand knob within the central sulcus. Functional mapping of cortex was performed by transdural bipolar electrical stimulation under local anesthesia, so patients were fully awake during the whole time of cortical mapping. The cortical mapping oriented the placement of epidural electrodes for chronic cortical stimulation for treatment of neuropathic pain. RESULTS: Stereotactic MR images of the hand knob were considered a satisfactory landmark for the motor area of the hand in all patients. On top of the anatomical landmark, transdural electrical stimulation (4.0-6.0 mA, 30-60 Hz and pulse width of 1 ms) gave vivid sensations of movement in the deafferented hand, forearm, and arm. The phantom sensation was elicited with lower current than usual motor mapping in patients with intact limbs. It was possible to delineate the spatial map of the phantom hand on the cortical surface with acceptable resolution. The sensation of wrist flexion was elicited in all; most of the patients had clear distinction of the thumb and index. The remaining fingers were not perceived individually. The cortical area responsive to the thumb tended to occupy a lateral position related to the areas of the other fingers, following the maps of the normal homunculus. The evoked sensation was restricted to the period of stimulation, and it stopped as soon as that was discontinued. The stimulation also evoked emotional responses related to sensation of limb movement. CONCLUSION: The proposed technique was useful for target refining in implantation of epidural electrode for motor cortex stimulation. Further studies are required to investigate if target refining by intra-operative mapping will significantly improve the results in the treatment of refractory pain.

Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours.

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behavior, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fiber tracts and functionally connected with brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas - together with patient age - were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behavior, neuronal communication, plasticity and neuroinflammation might underlie this functional network.

Bilateral subthalamic nucleus stimulation for generalized dystonia after bilateral pallidotomy.

BACKGROUND: Thalamotomies and pallidotomies were commonly performed before the deep brain stimulation (DBS) era. Although ablative procedures can lead to significant dystonia improvement, longer periods of analysis reveal disease progression and functional deterioration. Today, the same patients seek additional treatment possibilities. METHODS: Four patients with generalized dystonia who previously had undergone bilateral pallidotomy came to our service seeking additional treatment because of dystonic symptom progression. Bilateral subthalamic nucleus DBS (B-STN-DBS) was the treatment of choice. The patients were evaluated with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Dystonia Rating Scale (UDRS) before and 2 years after surgery. RESULTS: All patients showed significant functional improvement, averaging 65.3% in BFMDRS (P = .014) and 69.2% in UDRS (P = .025). CONCLUSIONS: These results suggest that B-STN-DBS may be an interesting treatment option for generalized dystonia, even for patients who have already undergone bilateral pallidotomy.

Unilateral Campotomy of Forel for Acquired Hemidystonia: An Open-Label Clinical Trial.

BACKGROUND: Hemidystonia (HD) is characterized by unilateral involuntary torsion movements and fixed postures of the limbs and face. It often develops after deleterious neuroplastic changes secondary to injuries to the brain. This condition usually responds poorly to medical treatment, and deep brain stimulation often yields unsatisfactory results. We propose this study based on encouraging results from case reports of patients with HD treated by ablative procedures in the subthalamic region. OBJECTIVE: To compare the efficacy of stereotactic-guided radiofrequency lesioning of the subthalamic area vs available medical treatment in patients suffering from acquired HD. METHODS: This is an open-label study in patients with secondary HD allocated according to their treatment choice, either surgical or medical treatment; both groups were followed for one year. Patients assigned in the surgical group underwent unilateral campotomy of Forel. The efficacy was assessed using the Unified Dystonia Rating Scale, Fahn-Marsden Dystonia Scale, Arm Dystonia Disability Scale, and SF-36 questionnaire scores. RESULTS: Patients in the surgical group experienced significant improvement in the Unified Dystonia Rating Scale, Fahn-Marsden Dystonia Scale, and Arm Dystonia Disability Scale (39%, 35%, and 15%, respectively) 1 year after the surgery, with positive reflex in quality-of-life measures, such as bodily pain and role-emotional process. Patients kept on medical treatment did not experience significant changes during the follow-up. No infections were recorded, and no neurological adverse events were associated with either intervention. CONCLUSION: The unilateral stereotaxy-guided ablation of Forel H1 and H2 fields significantly improved in patients with HD compared with optimized clinical treatment.

Pain relief and functional recovery in patients with complex regional pain syndrome after motor cortex stimulation.

In addition to pain and neurovegetative symptoms, patients with severe forms of complex regional pain syndrome (CRPS) develop a broad range of symptoms, including sensory disturbances, motor impairment and dystonic posturing. While most patients respond to medical therapy, some are considered refractory and become surgical candidates. To date, the most commonly used surgical procedure for CRPS has been spinal cord stimulation. This therapy often leads to important analgesic effects, but no sensory or motor improvements. We report on 2 patients with pain related to CRPS and severe functional deficits treated with motor cortex stimulation (MCS) who not only had significant analgesic effects, but also improvements in sensory and motor symptoms. In the long term (27 and 36 months after surgery), visual analog scale pain scores were improved by 60-70% as compared to baseline. There was also a significant increase in the range of motion in the joints of the affected limbs and an improvement in allodynia, hyperpathia and hypoesthesia. Positron emission tomography scan in both subjects revealed that MCS influenced regions involved in the circuitry of pain.