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.     

Continuous opportunity for reinforcing brain stimulation

The performance of a rat provided with continuous opportunity to obtain reinforcing brain stimulation over a 20-day period is described in detail. The animal averaged 29.2 responses per min during the entire time. Testing session was terminated by experimenters, but a day-by-day analysis of behavior provided no evidence that the animal would have stopped responding.     

A multifunctional on-line brain stimulation system

A flexible on-line electrical brain stimulation system designed for brain stimulation reward (BSR) research is described. A Cromemco Z-2D microcomputer is interfaced with a constant-current stimulator and a standard operant chamber. The system programs, written substantially in BASIC, calculate BSR threshold by two rate-independent methods, measure rate of operant responding, and determine resistance of the brain. Other software programs are used for training rats on complex schedules of reinforcement, for system hardware calibration, and for sophisticated statistical data analyses.     

Electrical stimulation of the brain for psychiatric disorders

Despite advances in therapies, there remain psychiatric patients who are extremely ill and cannot be helped by classic psychiatric treatments, including psychotherapy and drug therapy. Certain of these patients may be helped by use of bilateral brain lesioning. The complication rate of standard stereotactic psychosurgery techniques is very low. The main rationale for the continued experimental use of deep brain stimulation (DBS) in neurosurgery for mental disorders is its reversibility. This reversibility is not an advantage in terms of the benefits obtained, but rather if side effects emerge. In addition, electrical stimulation may provide patients with some autonomy for their treatment. The first, very preliminary results of electrical stimulation for obsessive-compulsive disorder and for a small heterogeneous group of patients with other psychiatric disorders have been published. Electrical stimulation of the brain for psychiatric disorders may become a new treatment option for certain intractable psychiatric disorders. Nevertheless, the mechanism of action of DBS in psychiatric disorders is unknown, and the experience with this modality is extremely limited. The first results look promising, but this treatment option may prove unusable for some time because of a lack of knowledge of appropriate brain stimulation targets and technical problems such as the availability of sufficient current supply.     

On-line brain stimulation: Measurement of threshold of reinforcement

This program and interface for a small computer (PDP8/e) performs the following operations: generates and delivers constant current stimulation to the brain of an animal, monitors electrical resistance at the stimulating electrode, and calculates the threshold of reinforcement based upon the frequency of characteristic pauses in the animal’s responding.     

Detection by the guinea pig of acoustic stimulation and of electrical stimulation of the brain

A threshold procedure using operant behavioral techniques with positive reinforcement was developed after initial efforts with avoidance behavioral procedures proved unsatisfactory. In the first of three experiments the operant threshold procedure was tested by determining masked auditory thresholds for trains of clicks. In a second experiment, similar techniques were used to measure thresholds for electrical stimulation of the brain. The last experiment, again an auditory problem, involved a determination of the absolute thresholds for trains of short noise bursts as a function of the time between bursts. Middle ear malfunction proved to be a more severe problem than had been anticipated on the basis of reports in the literature. The threshold procedure, however, seems to be adequate for determination of absolute or masked thresholds with auditory or electrical stimuli.     

The role of brain stimulation priming effects in self-deprivation

Choice of brain stimulation reward (BSR) over biologically necessary substances in some self-stimulating animals is referred to as self-deprivation. In several recent papers, it has been argued that this phenomenon is produced by the rewarding aspects of the brain stimulation. This conclusion is partially based on data showing that self-deprivation and brain stimulation reward increase and decrease in a similar manner in response to changes in the brain stimulation parameters. However, the priming aspects of the brain stimulation also fluctuate with changes in stimulation parameters. Therefore, changes in the priming rather than the rewarding aspects of the brain stimulation could be responsible for self-deprivation. To determine whether the priming effects of brain stimulation play an important role in self-deprivation, rats with bipolar stimulating electrodes were given the choice between BSR and food. Time-outs were enforced within each BSR/food competition session. Since priming effects decay over time, increasing time-out length should have decreased self-deprivation due to decay of priming. It was found that time-out length did not affect the degree of self-deprivation. It was concluded that self-deprivation is not mediated by the priming aspects of brain stimulation.     

Neuroleptic-induced attenuation of brain stimulation reward in rats.

In 30-min free-operant tests, the dopamine receptor blockers pimozide (.125, .25, and .50 mg/kg) and (+)-butaclamol (.1, .2, and .4 mg/kg) attenuated lever pressing for lateral hypothalamic brain stimulation. When discrete self-stimulation trials were offered in a straight alleyway, pimozide increased start box latencies, slowed running speeds, and reduced lever-pressing rates. However, performance early in both lever-pressing and runway sessions was normal; performance deteriorated as testing progressed, following patterns that paralleled those seen when animals were tested with reductions in the amplitude of stimulating current. Spontaneous recovery was obtained in both situations; experimenter-imposed 10-min time-outs caused renewed lever pressing and running. In contrast, alpha-noradrenergic receptor blockade by phenoxybenzamine (5, 10, and 20 mg/kg) failed to produce extinction-like response patterns. These data support the view that central dopaminergic systems are important components of the neural mechanisms mediating reward.     

The importance of subject control in reinforcing brain stimulation

A comparison between the reinforcement strength of self-administered and externally imposed brain stimulation was undertaken. Rats performed on a chain schedule in order to receive brain stimulation, either selfadministered or imposed, during the second component of the chain. Response rates during the first component of the chain schedule indicated that self-stimulation was more reinforcing than imposed stimulation. In addition, contrast, both positive and negative, seemed to be present. It was concluded that reinforcement strength may be enhanced when the subject controls the presentation of reinforcement.     

State-dependency in brain stimulation studies of perception and cognition

We address the importance of understanding initial states of neuronal populations and of state-dependent responses in cognitive neuroscience experiments with special emphasis on brain stimulation studies of perception and cognition. The approach we present is based on evidence that behavioural and perceptual effects of transcranial magnetic stimulation (TMS) are determined by initial neural activation state; by systematically manipulating neural activation states before application of TMS, one can selectively target specific, even spatially overlapping neural populations within the affected region. This approach is potentially of great benefit to cognitive neuroscience and remediation programmes as it combines high spatial and functional resolution with the ability to assess causality.     

Polydipsia induced by a schedule of brain stimulation reinforcement

Rats pressed a lever for a signaled brain stimulation reinforcement on either fixed-interval or fixed-ratio schedules. Both schedules induced polydipsia, with a median water intake of 22.5 ml (about four times the control level) in 3-hr sessions. The stimulation did not directly elicit drinking or other behaviors. In a second experiment, two out of four rats became polydipsic during extinction following a continuous schedule of brain stimulation reinforcement. The results were compared with previous attempts to induce polydipsia with a schedule of brain stimulation reinforcement and were discussed in terms of polydipsia as a model of human “compulsive” behaviors.