Disruption of Rich-Club Connectivity in Cushing Disease.

OBJECTIVE: Cushing disease (CD) is a rare clinical disease in which brain structural and function are impaired as the result of excessive cortisol. However, little is known whether rich-club organization changes in patients with CD, as visualized on resting-state magnetic resonance imaging (fMRI), can reverse to normal conditions after transsphenoidal surgery (TSS). In this study, we aimed to investigate whether the functional connectivity of rich-club organization is affected and whether any abnormal changes may reverse after TSS. METHODS: In this study, 38 patients with active CD, 33 with patients with CD in remission, and 41 age-, sex-, and education-matched healthy control participants underwent resting-state fMRI. Brain functional connectivity was constructed based on fMRI and rich club was calculated with graph theory approach. We constructed the functional brain networks for all participants and calculated rich-club connectivity based on fMRI. RESULTS: We identified left precuneus, right precuneus, left middle cingulum, right middle cingulum, right inferior temporal, right middle temporal, right lingual, right postcentral, right middle occipital, and right precentral regions as rich club nodes. Compared with healthy control participants, rich-club connectivity was significantly lower in patients with active CD (P < 0.001). Moreover, abnormal rich-club connectivity improved to normal after TSS. CONCLUSIONS: Our results show rich-club organization was disrupted in patients with active CD with excessive cortisol production. TSS can reverse abnormal rich-club connectivity. Rich club may be a new indicator to investigate the outcomes of TSS and to increase our understanding of the effect of excessive cortisol on brain functional connectivity in patients with CD.

Lnc-THOR silencing inhibits human glioma cell survival by activating MAGEA6-AMPK signaling.

Long non-coding RNA THOR (Lnc-THOR) binds to IGF2BP1, essential for its function. We here show that Lnc-THOR is expressed in human glioma tissues and cells. Its expression is extremely low or even undetected in normal brain tissues, as well as in human neuronal cells and astrocytes. We show that Lnc-THOR directly binds to IGF2BP1 in established and primary human glioma cells. shRNA-mediated Lnc-THOR knockdown or CRISPR/Cas9-induced Lnc-THOR knockout potently inhibited cell survival and proliferation, while provoking glioma cell apoptosis. Contrarily, forced overexpression of Lnc-THOR promoted glioma cell growth and migration. Importantly, Lnc-THOR shRNA or knockout activated MAGEA6-AMPK signaling in glioma cells. AMPK inactivation, by AMPKα1 shRNA, knockout, or dominant-negative mutation (T172A), attenuated Lnc-THOR shRNA-induced A172 glioma cell apoptosis. Moreover, CRISPR/Cas9-induced IGF2BP1 knockout activated MAGEA6-AMPK signaling as well, causing A172 glioma cell apoptosis. Significantly, Lnc-THOR shRNA was ineffective in IGF2BP1 KO A172 cells. In vivo, Lnc-THOR silencing or knockout potently inhibited subcutaneous A172 xenograft tumor growth in mice. MAGEA6 downregulation and AMPK activation were detected in Lnc-THOR-silenced/-KO A172 tumor tissues. Taken together, Lnc-THOR depletion inhibits human glioma cell survival possibly by activating MAGEA6-AMPK signaling.

Deep brain stimulation in post-traumatic dystonia: A case series study.

AIMS: Deep brain stimulation (DBS) has been proposed as an effective treatment for drug-intolerant isolated dystonia, but whether it is also efficacious for posttraumatic dystonia (PTD) is unknown. Reports are few in number and have reached controversial conclusions regarding the efficacy of DBS for PTD treatment. Here, we report a case series of five PTD patients with improved clinical benefit following DBS treatment. METHODS: Five patients with disabling PTD underwent DBS therapy. The clinical outcomes were assessed with the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) at baseline and the last follow-up visit (at more than 12 months). RESULTS: Patients 1 and 3 received unilateral globus pallidus internus (GPi) DBS for contralateral dystonia. The subthalamic nucleus (STN) was chosen as target for patients 2 and 4, due to a lesion located in the globus pallidus. Patient 5 had an electrode in the ventral intermediate nucleus (VIM) for treating predominant tremor of left upper extremity, with unexpected improvement of focal hand dystonia. The scores of BFMDRS movement exhibited favorable improvement in all five patients at the last follow-up, ranging from 52.4% to 78.6%. CONCLUSIONS: Deep brain stimulation may be an effective and safe treatment for medically refractory PTD, but this needs to be confirmed by further studies.

Bilateral anterior capsulotomy enhances medication compliance in patients with epilepsy and psychiatric comorbidities.

OBJECTIVES: Patients with epilepsy and refractory comorbid psychiatric disorders often experience functional impairments and a lower quality of life as well as showing a lack of compliance with anti-epileptic medication regimens. We reasoned that widespread clinical benefits could be gained if the psychiatric comorbidities among these patients were reduced. In this study, we assessed the utility of anterior capsulotomy in managing medication-refractory comorbid psychotic symptoms and aggression in patients with epilepsy. METHODS: In this retrospective case series, we evaluated the clinical outcomes of 13 epilepsy patients with severe psychiatric comorbidities who had received bilateral anterior capsulotomy. Clinical outcome assessments were performed at 1 week, 6 months, 1 year, and several years after surgery focusing on: (a) severity of psychotic symptoms, as assessed by the 18-item Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale; (b) severity of impulsivity and aggression, measured by the Barratt Impulsiveness Scale-11 and the Buss-Perry Aggression Scale; and (c) social function and quality of life, assessed by the Social Disability Screening Scale and the Quality of Life in Epilepsy. RESULTS: After anterior capsulotomy, patients displayed significant improvements of psychotic symptoms, as well as of impulsivity and aggression, along with improvements of social function and quality of life. The clinical benefits to patients were evident within 6 months after surgery and remained stable or continued to improve at a much slower rate thereafter. Furthermore, after anterior capsulotomy all patients complied with epilepsy interventions that they did not comply with prior to surgery. No significant side effects or complications occurred during the study. CONCLUSION: Anterior capsulotomy seems to be a safe and effective treatment for epilepsy patients with otherwise intractable comorbid psychotic symptoms and aggression. Moreover, this neurosurgical treatment may improve the patients' social function, quality of life, and compliance with anti-epilepsy medication regimens.

The safety issues and hardware-related complications of deep brain stimulation therapy: a single-center retrospective analysis of 478 patients with Parkinson's disease.

INTRODUCTION: Deep brain stimulation (DBS) is a well-established therapy for the treatment of advanced Parkinson's disease (PD) in patients experiencing motor fluctuations and medication-refractory tremor. Despite the relative tolerability and safety of this procedure, associated complications and unnatural deaths are still unavoidable. METHODS: In this study, hardware-related complications and the causes of unnatural death were retrospectively analyzed in 478 patients with PD who were treated with DBS. RESULTS: The results showed a 3-year survival rate of 98.6% and a 5-year survival rate of 96.4% for patients with PD who underwent DBS treatment at the study center. Pneumonia was the cause of death with the highest frequency. Prophylactic antibiotics and steroids or antihistamine drugs were adopted to reduce the risk of infection. Twenty-two patients (4.6%) experienced hardware-related complications. CONCLUSION: Deaths of PD patients who receive DBS are typically unrelated to the disease itself or complications associated with the surgery. Pneumonia, malignant tumors, asphyxia, and multiple-organ failure are the common causes of death. Swallowing-related problems may be the most important clinical symptom in late-stage PD, as they cannot be stabilized or improved by DBS alone, and are potentially lethal. Although prophylactic antibiotics and steroids or antihistamine drugs may reduce the risk of infection, it is imperative to identify high-risk patients for whom a therapeutic approach not requiring an implantable device is more suitable, for example, pallidotomy and potentially transcranial ultrasound.

Long-term follow-up of bilateral subthalamic deep brain stimulation for refractory tardive dystonia.

BACKGROUND: No effective treatment for tardive dystonia (TD) has been well established. Deep brain stimulation (DBS) can ameliorate motor manifestations in primary dystonia, and may also be an effective approach for TD. OBJECTIVES: This study aimed to illuminate the long-term efficacy and safety of subthalamic nucleus (STN)-DBS in treating TD. METHODS: Ten patients with refractory TD underwent STN-DBS therapy and were assessed by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS), Abnormal Involuntary Movement Scale (AIMS), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and the Short Form (36) Health Survey (SF-36) at four time points: pre-operation, 1 week post-operation, 6 months post-operation, and at a final long-term postsurgical follow-up time point. RESULTS: The mean follow-up time was 65.6 ± 30.4 months (range, 12-105 months). At the first follow-up, BFMDRS motor and disability scores had improved by 55.9± 28.3% and 62.6± 32.0%, respectively, while AIMS scores improved by 53.3± 26.7%. At the second follow-up, BFMDRS motor and disability scores improved further, by 87.3± 17.0% and 84.3% ± 22.9%, respectively, while AIMS scores improved by 88.4 ± 16.1%. At the last follow-up, this benefit was sustained and had plateaued. Quality of life was improved significantly at the long-term follow-up, and the HAMA and HAMD scores displayed a significant reduction that persisted after the first follow-up. CONCLUSION: STN-DBS may be an effective and acceptable procedure for TD, leading to persistent and significant improvement in both movement and psychiatric symptoms.

Modulations on cortical oscillations by subthalamic deep brain stimulation in patients with Parkinson disease: A MEG study.

OBJECTIVE: The study aimed to explore the modification to cortical oscillations of Parkinson disease (PD) patients by subthalamic nucleus deep brain stimulation (STN DBS). METHODS: With Magnetoencephalogram (MEG) detection, we examined the changes in absolute power spectrum of cortical oscillations in the PD patients with the treatment of STN DBS. RESULTS: The power analysis of PD patients showed a dominant over-synchronization of alpha and beta bands in temporal and occipital areas relative to the healthy control subjects. STN DBS on-state showed marked power increase in the gamma band of PD patients in the frontal and parietal relative to the DBS off-state. The alleviation of motor symptoms by STN DBS negatively correlated to the increase of high gamma oscillation in the right frontal cortex, and also correlated to the suppression of the alpha and beta oscillations in the right temporal cortex. CONCLUSION: The treatment of STN DBS to PD patients might involve the augmentation of gamma activity and suppression of alpha and beta activities in cortical oscillations.

Influence of deep brain stimulation of the subthalamic nucleus on cognitive function in patients with Parkinson's disease.

Deep brain stimulation (DBS) is an effective technique for treating Parkinson's disease (PD) in the middle and advanced stages. The subthalamic nucleus (STN) is the most common target for clinical treatment using DBS. While STN-DBS can significantly improve motor symptoms in PD patients, adverse cognitive effects have also been reported. The specific effects of STN-DBS on cognitive function and the related mechanisms remain unclear. Thus, it is imperative to identify the influence of STN-DBS on cognition and investigate the potential mechanisms to provide a clearer view of the various cognitive sequelae in PD patients. For this review, a literature search was performed using the following inclusion criteria: (1) at least 10 patients followed for a mean of at least 6 months after surgery since the year 2006; (2) pre- and postoperative cognitive data using at least one standardized neuropsychological scale; and (3) adequate reporting of study results using means and standard deviations. Of ∼170 clinical studies identified, 25 cohort studies (including 15 self-controlled studies, nine intergroup controlled studies, and one multi-center, randomized control experiment) and one meta-analysis were eligible for inclusion. The results suggest that the precise mechanism of the changes in cognitive function after STN-DBS remains obscure, but STN-DBS certainly has effects on cognition. In particular, a progressive decrease in verbal fluency after STN-DBS is consistently reported and although executive function is unchanged in the intermediate stage postoperatively, it tends to decline in the early and later stages. However, these changes do not affect the improvements in quality of life. STN-DBS seems to be safe with respect to cognitive effects in carefully-selected patients during a follow-up period from 6 months to 9 years.

Metabolic imaging of deep brain stimulation in anorexia nervosa: a 18F-FDG PET/CT study.

OBJECTIVES: Anorexia nervosa (AN), a disorder of unknown etiology, has the highest mortality rate of any psychiatric disorder. Drawing the brain metabolic pattern of AN may help to target the core biological and psychological features of the disorder and to perfect the diagnosis and recovery criteria. In this study, we used 18F-FDG PET to show brain metabolic network for AN. METHODS: Glucose metabolism in 6 AN patients and 12 age-matched healthy controls was studied using 18F-FDG PET. SPM2 was used to compare brain metabolism in AN patients with that in healthy controls. Four of 6 AN patients took deep brain stimulation (DBS) targeted in nucleus accumbens (NAcc). About 3 to 6 months after the surgery, the 4 AN patients took another 18F-FDG PET scan to assess the change in brain glucose metabolism. RESULTS: The SPM (statistical parametric mapping ) analysis showed hypermetabolism in the frontal lobe (bilateral, BA10, BA11, BA47), the limbic lobe (bilateral, hippocampus, and amygdala), lentiform nucleus (bilateral), left insula (BA13), and left subcallosal gyrus (BA25). It also showed hypometabolism in the parietal lobe (bilateral, BA7, BA40). The hypermetabolism in frontal lobe, hippocampus, and lentiform nucleus decreased after NAcc-DBS. CONCLUSIONS: The changes in brain glucose metabolism illustrated the brain metabolic pattern in AN patients. Furthermore, the pattern can be modulated by NAcc-DBS, which confirmed specificity of the pattern. The regions with altered metabolism could interconnect to form a network and integrate information related to appetite. Our study may provide information for targeting the potential candidate brain regions for understanding the pathophysiology of AN and assessing the effects of existing and future treatment approaches.

Changes of procedural learning in Chinese patients with non-demented Parkinson disease.

To study procedural learning changes in patients with non-demented Parkinson disease (PD) but without depression. The Nissen serial reaction time task (SRTT) software version II (as a task of procedural learning), the Wechsler Memory Scale-Chinese version (WMS-CR), and two tasks of implicit memory were applied to 20 PD patients with a Hoehn-Yahr score at I-II degrees and 20 matched healthy controls were enrolled for the Nissen Version test. In the explicit WMS-CR and the implicit (word stem completion and degraded picture naming) tasks, the patients' scores fell within normal limits. In the SRTT, healthy controls displayed significantly reduced response times and error rates across the blocks of repeated sequence trials. In contrast, PD patients only showed a reduction in error rates but no change in response times. Impairment of nigrostriatal pathways selectively affects the performance in visuo-motor learning tasks such as the SRTT, but not in both the explicit tasks of WMS-CR and the implicit tasks.

Economic burden of Parkinson's disease in a developing country: a retrospective cost analysis in Shanghai, China.

We investigated economic costs from patients with Parkinson's disease (PD) in Shanghai, China, which could be used as a baseline for future evaluations. Data were collected from 190 patients by interview during 1-year period. Direct medical care costs averaged approximately Chinese yuan, renminbi (RMB) 4,305 (USD 519, or EUR 410) per year per patient, of which drugs (RMB 2,677) accounted for the major costly component. Nonmedical direct costs were much less than direct health care costs, averaging approximately RMB 3,301 (USD 398, or EUR 314). Costs due to loss of productivity averaged approximately RMB 73 (USD 8.8, or EUR 7.0) per patient per year. Taken together, the overall mean annual cost for PD in our series was approximately RMB 7,679 (USD 925, or EUR 731), and these costs accounted for around half of the mean annual income. Total cost was significantly associated with the disease severity and the frequency of outpatient visits. In addition, levodopa equivalent dose (LED) and the number of drugs being taken were also closely related with the drug cost. The results indicate that the economic burden of Chinese PD patients is heavy.

Effects of bilateral subthalamic nucleus stimulation on resting-state cerebral glucose metabolism in advanced Parkinson's disease.

BACKGROUND: The major neuropathological symptoms of Parkinson's disease (PD) consist of a loss of pigmented dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. This study was to investigate the effects of bilateral subthalamic nucleus (STN) stimulation on resting-state cerebral glucose metabolism in advanced PD, and investigate the mechanism of deep brain stimulation (DBS). METHODS: Seven consecutive advanced PD patients (4 men and 3 women, mean age 64 +/- 4 years, mean H-Y disability rating 4.4 +/- 0.65) receiving bilateral STN DBS underwent 18F-fluorodeoxyglucose (18F-FDG)/positron-emission tomography (PET) examinations at rest both preoperatively and one month postoperatively, with STN stimulation still on. The unified PD rating scale was used to evaluate the clinical state under each condition. Statistical parametric mapping (SPM) was used to investigate the regional cerebral metabolic rates of glucose (rCMRGlu) during STN stimulation, and to compare these values to rCMRGlu preoperation. RESULTS: STN stimulation clearly improved clinical symptoms in all patients. A significant increase in rCMRGlu was found in the bilateral lentiform nucleus, brainstem (midbrain and pons), bilateral premotor area (BA6), parietal-occipital cortex, and anterior cingulated cortex, and a marked decrease in rCMRGlu was noted in the left limbic lobe and bilateral inferior frontal cortex (P < 0.05). CONCLUSION: Bilateral STN stimulation may activate the projection axon from the STN, improving clinical symptoms in advanced PD patients by improving both ascending and descending pathways from the basal ganglia and increasing the metabolism of higher-order motor control in the frontal cortex.

Aetiology of epilepsy in surgically treated patients in China.

The aim of this retrospective, multicenter clinical study was to evaluate the aetiology of epilepsy in surgically treated patients in China. The detailed clinical records of all intractable partial epilepsy (IPE) were reviewed in five tertiary referral centres from June 1991 to June 2000. 1650 patients (927 males, 723 females) were recruited. 41.4% had aetiological factors, including the histories of major brain trauma (20.9%), febrile seizure (6.5%), meningitis (5.4%), encephalitis (5.0%), prenatal distress (2.1%), birth trauma (0.8%) and family history of seizure (0.7%). The pathological lesions were divided into eight groups according to the nature of the lesion: scar (19.2%), vascular malformations (VM) (17.7%), hippocampal sclerosis (HS) (16.2%), tumours (15.0%), gliosis (12.1%), neuronal migration disorders (NMDs) (7.4%), intracranial infection (4.5%), and other lesions (7.9%). In conclusion, effective management of these aetiological factors and pathological lesions may be essential to deal with IPE. Scar, HS, VM, NMDs are the most likely consequences of antecedent morbid events.

Anticopper efficacy of captopril and sodium dimercaptosulphonate in patients with Wilson's disease.

The aim of this study was to explore and compare initial treatment effects of captopril (Tensiomin) and sodium dimercaptosulphonate (DMPS) on a relatively large series of Wilson's disease inpatients. Two important markers of anticopper efficacy: serum sulphydryl and 24 h urinary copper levels in the patients were evaluated before and after treatment. The patients were randomly subdivided into 4 groups to allow statistical analysis (ANOVA) of the values recorded. The protocol was an open-label study of all the patients treated for 8 weeks (i.e., all the patients except those in the no-drug group), and a further six-month follow-up (post hospitalization) of the 14 patients administered captopril. Several copper-related variables were studied to evaluate the effect of the drugs on copper, and several biochemical and clinical variables were studied to evaluate potential toxic effects. Captopril was found to have a significant anticopper effect and did not markedly raise serum sulphydryl levels within this limited patient sample; the anticopper efficacy of captopril was, however, found to be markedly lower than that of DMPS; DMPS was found to raise the patients' serum sulphydryl and urinary copper levels. Evaluation of data from individual patients revealed evidence of a toxic side effect in only 1 patient, treated with DMPS, who exhibited transiently raised serum alanine aminotransferases, while no serious adverse events, upstanding syncope, irritating cough and leukopenia induced by captopril were noted. The results obtained in this four-group sample suggest that captopril might be a mild anticopper agent for Wilson's disease, possibly relieving the hepatic portal hypertension, but that DMPS has a greater field of anticopper efficiency than captopril. The authors also discuss recent experience of the overall treatment in China.