Mechanisms and the current state of deep brain stimulation in neuropsychiatry

Deep brain stimulation (DBS) is established as a therapy for movement disorders, and it is an investigational treatment in other neurologic conditions. DBS precisely targets neuroanatomical targets deep within the brain that are proposed to be centrally involved in the pathophysiology of some neuropsychiatric illnesses. DBS is nonablative, offering the advantages of reversibility and adjustability. This might permit therapeutic effectiveness to be enhanced or side effects to be minimized. Preclinical and clinical studies have shown effects of DBS locally, at the stimulation target, and at a distance, via actions on fibers of passage or across synapses. Although its mechanisms of action are not fully elucidated, several effects have been proposed to underlie the therapeutic effects of DBS in movement disorders, and potentially in other conditions as well. The mechanisms of action of DBS are the focus of active investigation in a number of clinical and preclinical laboratories. As in severe movement disorders, DBS may offer a degree of hope for patients with intractable neuropsychiatric illness. It is already clear that research intended to realize this potential will require a very considerable commitment of resources, energy, and time across disciplines including psychiatry, neurosurgery neurology, neuropsychology, bioengineering, and bioethics. These investigations should proceed cautiously.     

Foraging for brain stimulation: toward a neurobiology of computation

The self-stimulating rat performs foraging tasks mediated by simple computations that use interreward intervals and subjective reward magnitudes to determine stay durations. This is a simplified preparation in which to study the neurobiology of the elementary computational operations that make cognition possible, because the neural signal specifying the value of a computationally relevant variable is produced by direct electrical stimulation of a neural pathway. Newly developed measurement methods yield functions relating the subjective reward magnitude to the parameters of the neural signal. These measurements also show that the decision process that governs foraging behavior divides the subjective reward magnitude by the most recent interreward interval to determine the preferability of an option (a foraging patch). The decision process sets the parameters that determine stay durations (durations of visits to foraging patches) so that the ratios of the stay durations match the ratios of the preferabilities.     

Brain plasticity and behavior

Although the brain was once seen as a rather static organ, it is now clear that the organization of brain circuitry is constantly changing as a function of experience. These changes are referred to as brain plasticity, and they are associated with functional changes that include phenomena such as memory, addiction, and recovery of function. Recent research has shown that brain plasticity and behavior can be influenced by a myriad of factors, including both pre- and postnatal experience, drugs, hormones, maturation, aging, diet, disease, and stress. Understanding how these factors influence brain organization and function is important not only for understanding both normal and abnormal behavior, but also for designing treatments for behavioral and psychological disorders ranging from addiction to stroke.     

Family-centered intensive case management: A step toward understanding individualized care

New York State's initial attempt at individualizing services occurred within the context of an experiment. We randomly assigned children 5–12 years old who were referred for out-of-home placement in treatment foster care to either treatment foster care, Family-Based Treatment (n=15), or to Family-Centered Intensive Case Management (FCICM) (n=27). FCICM used teams of case managers and parent advocates to provide in-home services. Flexible service dollars, respite care, and behavior management skills training were available to assist teams in individualizing care. Preliminary outcomes indicate that children in FCICM are doing as well or better than children assigned to FBT in their functioning and symptom reduction. Parents of children in FCICM have made gains, although not at a statistically significant level, in behavior management skills and family strengths that allow them to provide care for their children at home.     

Culture and education: new frontiers in brain plasticity

Cognitive neuroscience has started to probe cross-cultural differences in the neuronal mechanisms underlying cognitive, perceptual and social domains. Moreover, brain imaging has revealed how education changes the brain. Such research opens up a new frontier in brain plasticity research, breaking down the boundaries between neuroscience and other traditionally non-biological disciplines, resulting in many conceptual and practical implications.     

Brain development, plasticity, and behavior

Damage to the infant brain is associated with a complex array of behavioral and anatomical effects. Recent research is leading to a new understanding of the nature of, and mechanisms underlying, recovery from brain damage.     

Brain stimulation and conscious experience

Libet discovered that a substantial duration (> 0.5-1.0 s) of direct electrical stimulation of the surface of the somatosensory cortex at threshold currents is required before human subjects can report that a conscious somatosensory experience had occurred. Using a reaction time method we confirm that a similarly long stimulation duration at threshold currents is required for activation of elementary visual experiences (phosphenes) in human subjects following stimulation of the surface of the striate cortex. However, the reaction times for the subject to respond to the cessation of the visual experience after the end of electrical stimulation could be as brief as 225-242 ms. We also carried out extensive studies in cats under a variety of anesthetic conditions using the same electrodes and parameters of stimulation employed in the human studies to study the patterns of neuronal activity beneath the stimulating surface electrode. Whereas sufficiently strong currents can activate neurons within milliseconds, stimulating currents close to threshold activate sustained neural activity only after at least 350-500 ms. When currents are close to threshold, some neurons are inhibited for several hundreds of millisecond before the balance between inhibition and excitation shifts towards excitation. These results suggest that the prolonged latencies, i.e., latencies beyond 200-250 ms, for the emergence of conscious experience following direct cortical stimulation result from a delay in the sustained activation of underlying cortical neurons at threshold currents rather than being due to any unusually long duration in central processing time. Intracellular records from cortical neurological cells during repetitive electrical stimulation of the surface of the feline striate cortex demonstrate that such stimulation induces a profound depolarizing shift in membrane potential that may persist after each stimulus train. Such a depolarization is evidence that extracellular K+ concentrations have increased during electrical stimulation. Such an increase in extracellular K+ progressively increases cortical excitability until the threshold for sustained activation of cortical neurons is reached and then exceeded. Consequently, the long latency for threshold activation of cortical neurons depends upon a dynamically increasing cortical facilatory process that begins hundreds of milliseconds before there is sustained activation of such neurons. In some cases, this facilatory process must overcome an initial stimulus-induced inhibition before neuronal firing commences.     

Brain plasticity,learning, and developmental disabilities

This is a time of significant gains in methodological development for examining the developing human brain. New efforts are underway to unify the understanding of the development of brain anatomy with physiological, cellular and molecular processes that influence behavioral development. This special issue provides animal models of behavior and brain development, applications of noninvasive imaging and genetic methods to human brain development and behavior, and select reviews of how these models and methods have been applied to the examination of developmental disabilities. This issue reflects a sampling of current approaches to the study of brain plasticity, development and learning in typically and atypically developing humans and animals.     

第二语言学习与脑可塑性

脑可塑性指人脑会因为环境刺激、认知需求和行为经验而产生功能或结构改变。近10年来的单双语者对比和语言训练研究结果表明, 不论儿童、青年或老年人, 第二语言学习和使用都能改变其脑运行模式并带来相应结构变化, 包括灰质(GM)体积和白质(WM)密度增加, 且长期持续的双语经验还能形成认知优势, 帮助抵制由老化导致的负面认知影响。基于脑可塑性概念及其研究证据, 从双语经验与语言训练两方面, 对比分析了长期和短期第二语言学习引起脑功能或结构变化及其内在机制, 并对未来相关研究进行了展望。     

Rehabilitation of brain damage: brain plasticity and principles of guided recovery.

Rehabilitation of the damaged brain can foster reconnection of damaged neural circuits; Hebbian learning mechanisms play an important part in this. The authors propose a triage of post-lesion states, depending on the loss of connectivity in particular circuits. A small loss of connectivity will tend to lead to autonomous recovery, whereas a major loss of connectivity will lead to permanent loss of function; for such individuals, a compensatory approach to recovery is required. The third group have potentially rescuable lesioned circuits, but guided recovery depends on providing precisely targeted bottom-up and top-down inputs, maintaining adequate levels of arousal, and avoiding activation of competitor circuits that may suppress activity in target circuits. Empirical data are implemented in a neural network model, and clinical recommendations for the practice of rehabilitation following brain damage are made.     

A review of the treatment for refractory obsessive-compulsive disorder: from medicine to deep brain stimulation

This article provides an overview of the etiology, epidemiology, and first-line treatment options for obsessive-compulsive disorder (OCD). The subject of treatment-resistant and treatment-refractory OCD is then discussed, including a definition of these often-debated terms, and the latest treatment options delineated. This includes a review of the latest research concerning the pharmacological agents that have been studied as monotherapy or augmenting agents for the treatment of OCD, the use of experimental medications and procedures, treatment with reversible, minimally invasive procedures, such as vagal nerve stimulation and transcranial magnetic stimulation, invasive but the potentially reversible deep brain stimulation, and irreversible lesioning with ablative psychosurgery. A discussion of the role of psychotherapy in the treatment of OCD is also included.     

Brain stimulation as a reinforcer: intermittent schedules

Rats with chronically implanted, bipolar electrodes in the septal and medial forebrain bundle areas, in addition to the region of the mammillary bodies of the posterior hypothalamus, were trained to press a permanently mounted lever in order to produce a second, retractable lever. Rewarding brain stimulation was programmed on the retractable lever; following completion of the programmed number of CRF response-stimulations, that lever was retracted from the box. Responding on the permanent lever could reintroduce the retractable lever. Fixed interval, fixed ratio, DRL, and variable interval schedules were programmed on the permanent lever in the range of schedule parameters often used with conventional reinforcers. Typical effects are described, and it is concluded that there are no striking differences between brain-stimulation reinforcement and the conventional reinforcers.     

The elderly and high technology medicine: A case for individualized,autonomous allocation

The issues involved in decision making about the aggressiveness of future medical care for older persons are explored. They are related to population trends, the heterogeneity of older persons and a variety of factors involved in individual preferences. Case studies are presented to illustrate these points, as well as a review of pertinent literature. The argument is offered that, considering these many factors, a system of flexible, individualized care by informed patient preference, is more rational than the rationing of technological services by age.     

Making good choices: toward a theory of well-being in medicine

The principle of beneficence directs healthcare practitioners to promote patients’ well-being, ensuring that the patients’ best interests guide treatment decisions. Because there are a number of distinct theories of well-being that could lead to different conclusions about the patient’s good, a careful consideration of which account is best suited for use in the medical context is needed. While there has been some discussion of the differences between subjective and objective theories of well-being within the bioethics literature, less attention has been given to the questions of what work a theory of well-being needs to do in bioethics and which standards of success ought to be used in selecting a theory of well-being for use in medicine. In this article, I argue that traditional theories of well-being developed in philosophy are not well suited to meet the needs of the medical context. For the principle of beneficence to be most useful, the underlying account of well-being should satisfy two conditions: first, it needs to lead to a concrete, action-guiding determination of the patient’s good; and, second, any recommendations it offers need to be justifiable to patients. Standard accounts of well-being have difficulty satisfying both conditions. Exploring the limitations of these theories when applied to treatment dilemmas helps point the way toward the development of an account of well-being better suited to healthcare.     

Affective style, psychopathology, and resilience: brain mechanisms and plasticity

The brain circuitry underlying emotion includes several territories of the prefrontal cortex (PFC), the amygdala, hippocampus, anterior cingulate, and related structures. In general, the PFC represents emotion in the absence of immediately present incentives and thus plays a crucial role in the anticipation of the future affective consequences of action, as well as in the persistence of emotion following the offset of an elicitor. The functions of the other structures in this circuit are also considered. Individual differences in this circuitry are reviewed, with an emphasis on asymmetries within the PFC and activation of the amygdala as 2 key components of affective style. These individual differences are related to both behavioral and biological variables associated with affective style and emotion regulation. Plasticity in this circuitry and its implications for transforming emotion and cultivating positive affect and resilience are considered.     

Vagus nerve stimulation: a new form of therapeutic brain stimulation

Although the vagus nerve has traditionally been considered to perform efferent functions, in reality it performs significant afferent functions as well, carrying information from the body, head, and neck to the brain. Preliminary studies examining this afferent activity led to the theory that vagus nerve stimulation (VNS) could successfully control seizure activity in persons who are refractory to antiepileptic medications. Unlike other forms of brain stimulation, VNS is unable to directly stimulate multiple discrete areas of the brain; however, through several pathways, it is able to relay sensory information to higher brain regions. An implantable VNS device known as the VNSTM NeuroCybernetic Prosthesis (NCP) System has been used in approximately 9,000 epilepsy patients in Europe and the United States since 1994. The implant has reduced seizure frequency by an average of 25% to 30%, with minimal side effects. Studies underway are also showing some degree of success in the management of treatment-refractory depression. The future efficacy of the implantable system in other disorders may depend on whether the implant can be more precisely focused to affect different brain regions. Research in this area is underway.