年轻人与老年人简单乘法运算之功能磁共振成像研究

目的应用fMRI技术探讨中国青年和老年人群在简单运算任务下脑激活模式及其与行为学之间的关系。方法分别对青年组(19例)和老年组(20例)健康志愿者进行对照任务和简单运算任务下的fMRI检查。结果两组受试者受教育程度(P=0.125)、智力水平(P=0.921),以及完成对照任务(P=0.142)和简单乘法运算任务(P=0.880)之正确率差异无统计学意义,但老年组受试者完成对照任务(P=0.000)和简单乘法运算任务(P=0.005)反应时间明显延长。青年组受试者在任务刺激下可激活右侧缘上回并向顶内沟和颞中上回后部延伸,中央前回和运动前区、前额叶,左侧缘上回并向颞上回后部和角回延伸,顶内沟区域、颞中下回,内侧后扣带回、楔前叶、辅助运动区、海马沟、海马旁回及前额叶内侧;老年组受试者则分别激活右侧缘上回和顶下区域并向颞中上回后部延伸,中央前回和运动前区、前额叶,左侧缘上回和角回并向顶下延伸,中央前回和运动前区、岛叶及前额叶,内侧后扣带回和中央旁小叶、前扣带回及前额叶内侧;两组受试者共激活脑区包括顶下区域、楔前叶、中央前后回和额顶叶网络,以及颞叶、海马旁回、钩回、屏状核和后扣带回等皮质下结构。结论数学事实提取相关网络的主要成分受年龄影响较小,老年人群的任务激活脑区主要向任务相关顶区集中。     

慢性失眠患者汉字工作记忆的功能磁共振研究

目的  探讨慢性失眠患者汉字任务下脑激活区改变。 方法  对40例慢性失眠患者和50例正常对照组进行汉字工作记忆功能磁共振扫描。 结果  慢性失眠组与正常组脑激活区存在差异：慢性失眠组编码期枕叶、右前额和右边缘叶激活增强;保持期左前额激活下降;提取期激活增强区为右枕叶,激活下降区为左尾状核和右侧丘脑。 结论  慢性失眠患者在文字记忆任务编码期及提取期均出现了右脑皮层的代偿激活,保持期出现了左前额激活下降,提取期出现了皮层下区域激活的下降,提示慢性失眠在文字记忆处理过程出现了相关脑区的损害和异常激活。     

帕金森病患者脑灰质变化的VBM-MRI研究

目的应用核磁共振的基于体素形态学(voxel-based morphometry method of magnetic resonanceimaging,VBM-MRI)技术,研究帕金森病(Parkinson disease,PD)患者大脑灰质变化的状况。方法 28例PD组与年龄、受教育年限相匹配32例健康对照组的VBM-MRI图像数据进行比较,PD组中,早期PD组(early Parkinson disease,EPD,n=14)与晚期PD组((late Parkinson disease,LPD,n=14)的VBM-MRI图像数据进行比较。结果与健康对照组比较,VBM-MRI显示PD组患者存在下列脑区灰质体积减少:额叶(双侧额上回、左额下回)、双侧颞叶(颞上回、颞中回)、右侧扣带回、右侧丘脑、双侧尾状核及左顶下小叶。与EPD比较,VBM-MRI显示LPD在下列脑区存在灰质体积减少:额叶(双侧额上回、右侧额下回、右侧额叶眶部、双侧内侧前额叶),颞叶(右侧颞上回、左侧颞中回),右侧海马旁回、右侧尾状核、右侧下丘脑,差异均有显著统计学意义。结论本组PD患者的脑灰质改变,主要集中在额叶、颞叶、右侧扣带回及皮质下的灰质。随着PD病程进展,这些部位的灰质减少加剧,并在边缘叶有进展的趋势。     

首发精神分裂症患者倒背数字作业的fMEI研究

目的利用功能磁共振成像(fMRI)探讨首发精神分裂症患者倒背数字作业激发图像的特点.方法 36例符合ICD-10诊断标准的(首发)精神分裂症患者及18名健康志愿者进行以倒背数字作业(backward digit span task, BDST)作为刺激模式、采用组块(block)设计的fMRI检查,经工作站处理后获功能图像.用阳性和阴性症状量表(PANSS)评价精神分裂症患者精神症状的严重程度. 结果 (1)健康志愿者与精神分裂症患者激活脑区的范围均较广泛,健康志愿者的左侧额上回、双侧额中回、左侧额下回、左侧中央前回、左侧顶上小叶、左侧缘上回、左侧颞下回及左侧枕颞外侧回等脑区均有明显激活.两组激活的脑区在额叶、颞叶、顶叶、枕叶及扣带回的分布,以及各脑区内部分布的差异均没有显著性(P>0.05).(2)健康志愿者与精神分裂症患者激活计数左侧额上回分别为16和11,左侧额下回分别为15和12,左侧中央前回分别为16和17,左侧颞下回分别为14和12,左侧顶上小叶分别为14和14,左侧缘上回分别为14和7,左侧枕颞外侧回分别为14和7,右侧中央前回分别为13和7,右侧枕颞外侧回分别为11和8,两组上述部位激活计数的差异均有显著性(P均＜0.05).(3)健康志愿者与精神分裂症患者左侧额叶背外侧的激活平均体积分别为(362±296)个体素和(79±101)个体素,差异有非常显著性(P=0.001);右侧顶叶后下部的激活平均体积分别为(448±273)个体素和(193±236)个体素,差异有显著性(P=0.039). 结论早期精神分裂症患者可能存在工作记忆缺陷,包括激活信息的保持及执行控制过程,激活信息的保持缺陷可能与左侧额叶腹外侧及顶叶后下部的功能低下有关,而执行控制缺陷可能与左侧额叶背外侧的功能低下有关.     

健康人倒背数字作业的脑功能磁共振成像研究

目的　利用功能磁共振成像(functionalmagneticresonanceimaging ,fMRI)技术探讨倒背数字作业认知功能的脑功能定位。方法　1 8名健康志愿者完成以倒背数字作业(backwarddigitspantask ,BDST)作为刺激模式、采用组块设计(block)的fMRI检查,经工作站处理后获功能图像。结果　健康志愿者的左侧额上回、额中回、额下回、中央前回、顶上小叶、缘上回、颞下回、枕颞外侧回及右侧额中回等脑区均有明显激活。结论　左侧额叶腹外侧及左侧项叶后下部可能参与工作记忆对语言材料激活信息的保持,而双侧额叶背外侧可能参与工作记忆对语言材料激活信息的执行控制。     

单相和双相抑郁障碍患者前扣带回功能连接特征差异观察北大核心CSCD

目的比较单、双相抑郁障碍前扣带回功能连接的差异,探讨前扣带回功能连接与抑郁症状严重程度的关系。方法利用fMRI技术,对符合DSM-Ⅳ诊断标准的30例单相抑郁障碍(unipolar depression)患者(单相抑郁组)、30例双相抑郁障碍(bipolar depression)患者(双相抑郁组)及年龄、性别、受教育程度相匹配的32名对照者(对照组)进行静息态fMRI扫描,以前扣带回为感兴趣区进行功能连接分析,比较组间差异,并对功能连接强度与抑郁症状的严重程度之间的关联进行Pearson相关分析。结果(1)与对照组相比,单相抑郁组左侧前扣带回与左侧三角部额下回(t=3.48)、左侧顶下缘角回(t=3.15)之间的功能连接增强,右侧前扣带回与左侧三角部额下回(t=3.52)之间的功能连接增强;(2)与对照组相比,双相抑郁组左侧前扣带回与右侧颞中回(t=-4.00)之间的功能连接减低,右侧前扣带回与左侧中央后回(t=-3.46)、右侧颞上回(t=-2.86)、右侧颞中回(t=-3.40)之间的功能连接减低;(3)与双相抑郁组相比,单相抑郁组左侧前扣带回与左侧三角部额下回(t=3.58)、右侧三角部额下回(t=4.06)、右侧颞中回(t=3.25)、左侧顶下缘角回(t=3.27)、右侧顶下缘角回(t=3.99)之间的功能连接增强;右侧前扣带回与左侧三角部额下回(t=3.13)、左侧顶下缘角回(t=3.42)、右侧顶下缘角回(t=3.78)之间的功能连接增强(均采用Alphasim校正,P<0.001);(4)Pearson相关分析显示,以上差异脑区功能连接强度与HAMD17总分均无相关性(-0.20.05)。结论静息态下单相抑郁患者前扣带回功能连接增强,双相抑郁患者前扣带回功能连接减弱;单、双相抑郁障碍差异脑区功能连接强度与临床症状无相关性。     

抑郁症患者对正性面部表情功能识别

目的：利用任务态功能核磁共振成像技术,初步探讨抗抑郁治疗对正性情绪识别脑区功能的影响。方法：检测19例抑郁症患者治疗前和治疗10周后在识别正性及中性面部表情视频时的激活脑区,并与19例匹配的健康者对照比较。结果：与正常对照组相比,治疗前抑郁症患者左右颞上回（BA39）、左后扣带回（BA23）、右后扣带回（BA30）、左丘脑、右岛叶（BA13）等脑区激活显著降低;治疗后患者左颞上回（BA39）、右颞上回（BA22）、左颞中回（BA37）、左右海马旁回（BA30）、右后扣带回（BA29）、右梭状回（BA36）、左额中回（BA8）、右额下回（BA47）、左顶下小叶（BA40）、右岛叶（BA13）等脑区激活较治疗前增强;但与正常组相比,左颞上回（BA22）、左额中回（BA10）、左梭状回（BA20）、左楔叶（BA19）、右顶上小叶（BA7）、右岛叶（BA13）等脑区激活仍存在一定程度的降低。结论：经抗抑郁治疗,抑郁症患者正性情绪识别脑区功能较治疗前有所改善,但与正常对照组相比,仍存在一定程度的功能损害。进一步证实了积极有效的抗抑郁治疗能够部分逆转正性情绪相关脑区损害。     

抑郁症患者情绪图片刺激早期低频脑磁图研究

目的：探讨抑郁症患者给予视觉情绪图片刺激早期0～100ms、100～200ms、200～300ms3个时段8～30Hz的神经磁场激活特征。方法：8例抑郁症患者及12例健康右利手对照者,在给予国际情绪图片库（IAPS）正性、中性、负性情绪图片刺激同时记录脑磁图信号,使用SPM8b软件进行数据分析：设两样本t检验P〈0.01（未校正）和K值≥10个体素范围为差异有统计学意义。结果：与对照组相比,抑郁组在正性情绪图片刺激下,100～200ms内的左侧额下回,右侧的终板旁回、额内侧回、海马回激活增强。在中性情绪图片刺激下,抑郁组在0～100ms的右侧豆状核、岛叶、额上回,左内侧额叶,100～200ms内的右侧岛叶、豆状核壳核及屏状核,左侧额下回、额上回、颞上回,200～300ms内的右侧岛叶、豆状核、尾状核体激活增强。负性情绪图片刺激下抑郁组在0～100ms内的右侧颞上回、岛叶、尾状核头部、额中下回激活增强,100～200ms内的右侧额中回、尾状核体,200～300ms内右额下回激活增强。此外还比较一致的发现抑郁组在楔前叶、后扣带回等顶叶脑区激活降低。结论：抑郁个体起注意调节功能的顶叶脑区如楔前叶功能不足,对视觉皮质向前部脑区情绪信息颞叶底部传递通路抑制不足,腹侧前额皮质、岛叶过度的激活,可能是抑郁症的一个发病基础。     

基于功能连接的复发缓解型多发性硬化患者默认网络静息态功能磁共振成像

目的 采用静息态功能磁共振成像(rs-fMRI)基于种子点相关性分析技术对复发缓解型多发性硬化(RRMS)患者默认网络的功能连接改变进行研究.方法 使用3.0T磁共振采集RRMS组和健康对照组(各27例)rs-fMRI数据.数据经预处理后,选择后扣带回(-5,-49,40)为种子点,采用基于种子点相关性分析技术进行功能连接分析,分别在默认网络内和默认网络外脑区比较两组功能连接的差异.分析差异脑区与临床参数如临床扩展残疾量表、同步听觉连续加法测验评分(PASAT)、脑实质分数、T2可见病灶数和病程的相关性.结果 基于种子点相关性分析技术构建的RRMS患者默认网络包含脑区主要有前额叶皮质腹侧、双侧顶下叶、后扣带回及楔前叶等脑区.在默认网络内比较,RRMS患者较健康对照组右侧额上回功能连接下降;右侧小脑后叶、右侧小脑脚、右侧颞中回、右侧额中回、左侧楔前叶及扣带回、右侧角回、右侧扣带回功能连接增高.RRMS患者组默认网络内差异脑区中,右侧颞中回功能连接系数(0.387±0.216)与PASAT呈负相关(r=-0.590,P =0.001);患者右侧额上回功能连接系数(0.039±0.293)与病程之间呈负相关(r=-0.390,P=0.041).在默认网络外比较,RRMS组后扣带回功能连接下降脑区有右侧额上回、左侧枕中回、左侧中央前回;功能连接增高脑区有右侧小脑前叶(含齿状核)、右侧额叶白质区.RRMS组后扣带回与左侧中央前回、右侧小脑前叶功能连接系数(-0.924±0.253和0.217±0.208)分别与病程之间存在正相关(r =0.650,P=0.000;r =0.436,P=0.023).结论 RRMS患者默认网络内和默认网络外均出现后扣带回静息态功能连接的异常改变,表明患者存在功能下降和代偿的复杂过程.RRMS患者存在有限功能重构或重组,以维持默认网络的功能稳定.     

早发性抑郁障碍患者静息态磁共振局部一致性研究

目的:探讨早发性抑郁障碍患者静息态下特征性脑功能改变与疾病严重程度的关系。方法:应用静息态功能磁共振(fMRI)中局部一致性数据分析法,选择20例早发抑郁障碍患者和性别、年龄、受教育年限相匹配的20名健康对照,分别给予fMRI扫描,应用双样本t检验对比病例组与对照组的ReHo图像,将存在差异性脑区的ReHo均值与汉密尔顿抑郁量表(HAMD-17)总分做相关性分析,观察其临床严重程度与差异性脑区活动的特征。结果:病例组左侧枕中回、左侧额中回、左侧额上回、右侧楔前叶、右侧扣带回的ReHo值随HAMD-17评分增加而逐渐增强;左侧距状裂、右侧缘上回、左侧中央前回区域随HAMD-17评分增加而逐渐减弱,相关有统计学意义(P均0.05)。结论:早发性抑郁障碍患者在前额叶、扣带回、边缘系统及部分枕、顶叶脑区自发活动的改变可能与抑郁障碍严重程度密切相关。     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.     

Treatment Considerations in Anticonvulsant Monotherapy

Summary: The long-standing practice of polypharmacy in treating epilepsy is giving way to use of monotherapy. Monotherapy can improve seizure control as well as reduce the risk of serious idiosyncratic reactions, dose-related side effects, and complex drug interactions. Monotherapy also offers improved compliance and cost-effectiveness. The basis of monotherapy is accurate diagnosis and assessment of the patient's seizure type(s), followed by selection of a single appropriate anticonvulsant drug. Many patients currently treated with multiple anticonvulsants can be successfully converted to monotherapy with a carefully monitored program in which troublesome and redundant drugs are gradually withdrawn from the therapeutic regimen.     

Anticonvulsant Drugs and Cognitive Function: A Review of the Literature

Summary: Alterations of cognitive function are separate from disturbances of behavior seen in association with epilepsy. The nature of the cognitive disability may to a certain extent depend on the seizure type. Partial seizures, mainly derived from a temporal lobe focus, impair memory tasks, while generalized seizures seem to have more effect on attentional abilities. A number of studies, reviewed in this paper, suggest that anticonvulsant drugs further impair cognitive function. Maximal impairments are seen in patients receiving polytherapy: rationalization of polytherapy improves cognitive abilities. Studies in children and adults have allowed differentiation of the effects of various commonly used antiepileptic agents. Maximal cognitive deficits are seen with. phenytoin, while phenobarbital and sodium valproate induce moderate disturbances, and carbamazepine seems relatively free from such toxicity. Further research is needed on the interrelationship between types of seizure disorders, types of anticonvulsant medications, and cognitive function.     

Dextromethorphan: Cellular Effects Reducing Neuronal Hyperactivity

Summary: Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and an-tiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N -methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.     

Effects of NMD A- and AMPA-Receptor Antagonists on Different Forms of Epileptiform Activity in Rat Temporal Cortex Slices

Summary: Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizurelike events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to. /V-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ket-amine, and 2-aminophosphonovalerate (2APV); as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 μM m. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.     

Pediatric Epilepsy Surgery

Summary: The use of implantable arrays of epidural electrodes has made it possible to carry out extraoperative electrocorticography (ECoG) and functional localization in the awake child. This has permitted cortical excisions that are determined by criteria similar to those obtained during surgical procedures performed under local anesthesia in adults. In addition, the method also permits simultaneous ECoG and video monitoring during the child's symptomatic seizures, providing additional important localizing information that is impractical to obtain in operations under local anesthesia. We report our experience with 75 children, ages 5 months to 15 years, whom we have managed with epidural electrode arrays. The method of extraoperative ECoG is described and illustrative cases are presented to demonstrate its feasibility and utility in children. In addition, we call attention to gliomas as a common cause of chronic focal seizures in children. Of 49 children undergoing resection and followed for from 1 to 14 years (mean of 5.8 years), 32 (65%) are either seizure free or have had a significant reduction in seizure frequency that has unambiguously improved their quality of life. The results are analyzed further by relating the surgical outcome to each of the pathologic entities that caused the seizures. This analysis reveals the variety of neurological conditions that commonly cause intractable focal seizure disorder in children and distinguishes those pathologic entities in which the seizure disorder is apt to respond to surgical intervention from those that will not.