Deep Brain Stimulation

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Application and Efficacy of Electrical Brain Stimulation for OCD

Deep brain stimulation (DBS) has, over the past decade, achieved widespread acceptance for the treatment of nonpsychiatric neurological diseases, namely, Parkinson disease (PD), pain, dystonia, and tremor. The application of DBS for psychiatric disease, while in its infancy, shows much promise as an effective and relatively safe therapeutic tool. Several recent studies and case reports show hope, in particular, for the treatment of severe, medically refractory OCD (Anderson and Ahmed, 2003 Nuttin et al., 2003a,b Aouizerate et al., 2004 Abelson et al., 2005 Greenberg et al., 2006).

Deep brain stimulation for the treatment of Parkinsons disease C Hamani J Neimat and A M Lozano

Approximately 30,000 patients have been treated throughout the world with deep brain stimulation for Parkinson's disease and other conditions. With accumulating experience, there has been an appreciation of the important benefits of this procedure, including the alleviation of disability and improvement in the quality of life. We have also become aware of some limitations of DBS surgery. Among the important issues that remain to be resolved are the timing of surgery, whether early or late in the course of the disease, and the best target for the individual patient, including a reassessment of the relative merits of globus pallidus versus subthalamic nucleus surgery. A better understanding of the symptoms that are resistant to both levodopa therapy and DBS surgery is also required. The introduction of deep brain stimulation (DBS) as a therapeutic alternative for the treatment of advanced Parkinson's disease (PD) has revolutionized the clinical management of this condition. In...

Deep brain stimulation in Parkinsons disease patients biochemical evidence

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen - PUT - and GPi) and in a thalamic relay nucleus, the antero-ventral thalamus (VA). It has been recently shown that subthalamic nucleus (STN) deep brain stimulation (DBS) increases cGMP in the internal pallidus (GPi) while it induces a motor improvement similar to l-dopa treatment, in Parkinson's disease (PD) patients (Stefani et al., 2005). In the central nervous system, extracellular cGMP levels are considered as a marker of excitatory activity, being enhanced either by increased glutamatergic or by reduced GABA transmission (Fedele and Raiteri, 1999 Pepicelli et al., 2004). Paradoxically therefore, the recent report (Stefani et al., 2005) suggests that STN-DBS...

Peripheral Cortical and Deep Brain Stimulation

Motor cortex and deep brain stimulation are techniques that have been explored to treat highly refractory neuropathic pain syndromes, including central pain, deafferentation syndromes, trigeminal neuralgia, and others (Figure 7.8).40 Deep brain stimulation has become a widely used technique for movement disorders, and much less so for painful indications, although there have been many case reports of utility in treating highly refractory central pain syndromes.41

Review of Other Technologies

The current practice for treating epilepsy includes AEDs, vagus nerve stimulation, the ketogenic diet, and resective surgery. There are currently no FDA-approved implantable direct brain stimulation devices available to treat epilepsy. In the research setting, direct brain stimulation for epilepsy has had mixed results. The vast majority of this work used noncontingent continuous or on-off cycling stimulation, also referred to as open-loop stimulation.

Electrode and Pulse Generator Considerations

FIGURE 6.5 Post-operative x-ray of the first patient ever implanted for chronic deep brain stimulation, showing silver wiring and electrode adapted to a radio-frequency coupled spinal cord receiver. (J. Neurosurg. 47 184-194, 1977.) FIGURE 6.5 Post-operative x-ray of the first patient ever implanted for chronic deep brain stimulation, showing silver wiring and electrode adapted to a radio-frequency coupled spinal cord receiver. (J. Neurosurg. 47 184-194, 1977.)

Indications and Patient Selection

Patients selected for deep brain implantation first should have chronic intractable pain, defined as unrelieved by the usual procedures directed toward the underlying etiology, that has been present for six months or longer, and which is located in an area not easily controlled by other surgical procedures, such as spinal cord stimulation. Patients with pain in the lower extremities and back may be treated by either spinal cord stimulation or deep brain stimulation, but spinal cord stimulation is a less demanding procedure, and therefore a better choice. The selection of deep brain stimulation for the treatment of pain that has not responded to other pain-relieving modalities, such as spinal cord stimulation or other techniques, is an invalid selection criteria. If a patient does not respond to one technique, it does not follow that deep brain stimulation will be effective the well, nothing else has been effective so we might as well try it approach is not appropriate to decision...

Demands on the Medical System

The advent of DBS (deep brain stimulation) and other FDA-approved neurotechnologies, which now includes tens of thousands of human recipients, is already stimulating growth in this area, and is bringing the experience of neurosurgeons, neurologists, and other health-care providers toward the development of NMPs. There will likely be a need for additional training programs, perhaps as subspecialty fellowships in neurotechnology, to meet the special multidisciplinary demands of these patients. Physicians will be required to track the function of these devices and adjust them when necessary such functions have already emerged for DBS and vagal nerve stimulators, as well as other stimulators and drug pumps. The unique integration of brain and machine in an NMP, coupled with the ongoing medical needs of patients with movement disorders, will require specially trained physicians and health-care workers. As assistive technology becomes more complex, it may be necessary to train a new...

Design Specifications for a Clinical ISMS System

Another consideration is the ability to image the ISMS implant in vivo, allowing us to determine changes in its position over time. Therefore, future ISMS designs should be composed of MRI-compat-ible, nonmagnetic materials such as platinum-iridium (e.g., Figure 19.11). The development of improved MRI techniques will result in increased image resolution and therefore more accurate measurements. This imaging technique could also significantly improve the surgical procedure if used intraoperatively for microwire implantation, similar to its use for the implantation of deep brain stimulation devices (Gibson et al., 2003 De Salles et al., 2004).

MCS and Trigeminal Neuropathic Pain

Trigeminal neuropathic facial pain is a syndrome of severe, constant facial pain related to disease of, or injury to, the trigeminal nerve or ganglion. Causes of trigeminal neuropathic pain can include injury from sinus or dental surgery, skull and or facial trauma, or intentional destruction for therapeutic reasons (deafferentation), as well as intrinsic pathology of any part of the trigeminal system (Burchiel, 2003). Despite extensive studies, no significant advances have occurred in its pharmacological treatment and it continues to be treated with anticonvulsant and antidepressant therapies. Many patients who fail surgical treatment for trigeminal neuralgia will develop trigeminal neuropathic pain (also called trigeminal deafferentation pain (Burchiel, 2003)), for which there are few, if any, effective treatments. Many treatments that are effective for trigeminal neuralgia can, in fact, worsen trigeminal neuropathic pain. Deep brain stimulation of well-defined targets in the...

Study Design

Once the precise epileptic focus was defined, the transitory electrodes were replaced by four contact depth brain stimulation electrodes (3789 DBS and IPG by Medtronic, Inc., Minneapolis, MN) (Figure 3.4) and connected to an independent internalized pulse generator system that was placed in a subcutaneous subclavicular pocket on each side. The target of the electrode contacts was the site of maximal interictal and ictal activities. All antiepileptic drugs were withdrawn to avoid any possible interference with the neuromodulation procedure (Velasco et al., 2000e) and were replaced with phenytoin.


The concept of aborting or preventing seizure activity by applying direct electrical, magnetic, or mechanical brain stimulation is not a new one. Approximately twenty centuries ago, Pelops from Alexandria was able to abort something that could be considered a simple partial seizure, by tying a ligature around the affected limb 20, 46 . Later, Brown-Sequard, Jackson, and Gowers, working independently, suggested that counter-irritation could be a mechanism for abating seizure activity 5, 21, 25, 26 . A large series of in vitro and in vivo studies have demonstrated that electrical stimulation effectively reduces and can control synchronized bursting in cortical neurons 4, 19, 31, 44, 51, 63 . Although the effects of electrical stimulation can be accurately predicted at the level of an individual neuron or nerve axon, this is not possible when dealing with highly complex real neuronal networks. The effect of electrical stimulation in a neuronal network is uncertain and its effects on...


Patients will often return saying they are not obtaining good pain relief from deep brain stimulation. The problems fall into two major categories. First, there are changes in the patient that obviate good stimulation pain relief, and second there is a failure of the device.


Despite the reported success with MCS for the treatment of trigeminal neuropathic pain, there have been no large, controlled, prospective, randomized trials of this modality. We face a situation similar to that experienced with deep brain stimulation (DBS) for pain in the 1970s and 1980s. The procedure was widely utilized with little strong evidence for efficacy until two prospective trials were eventually current status. Pain, 104(3) 431-435. Brown, J.A. and Pilitsis, J.G. (2005). Motor cortex stimulation for central and neuropathic facial pain a prospective study of 10 patients and observations of enhanced sensory and motor function during stimulation. Neurosurgery, 56(2) 290-297 discussion 290-297. Burchiel, K.J. (2001). Deep brain stimulation for chronic pain the results of two multi-center trials and Coffey, R.J. (2001). Deep brain stimulation for chronic pain results of two multicenter trials and a


Neurosurg., 100(3 Suppl.) 254-267. Coffey, R.J. (2001). Deep brain stimulation for chronic pain results of two multicenter trials and a mechanisms of deep brain stimulation. Thalamus & Relat. Syst., 1 269-277. Grill, W.M. and Mortimer, J.T. (1994). Electrical properties of implant encapsulation tissue. Ann. Biomed. Eng., 22 23-33. Gross, R.E. (2004). Deep brain stimulation in the treatment of neurological and psychiatric disease. Expert Rev. Neurother., 4, 465-78. Mclntyre, C.C., Grill, W.M., Sherman, D.L., and Thakor, N.V. (2004). Cellular effects of deep brain stimulation model-based analysis of activation and inhibition. J. Neurophysiol., 91 1457-1469.

Methods New Frontiers in Neuroscience

Our goal in creating the Methods & New Frontiers in Neuroscience series is to present the insights of experts on emerging experimental techniques and theoretical concepts that are or will be at the vanguard of the study of neuroscience. Books in the series cover topics ranging from methods to investigate apoptosis to modern techniques for neural ensemble recordings in behaving animals. The series also covers new and exciting multidisciplinary areas of brain research, such as computational neuroscience and neuroengineering, and describes breakthroughs in classical fields such as behavioral neuroscience. We want these to be the books every neuro-scientist will use in order to graduate students and postdoctoral fellows when they are looking for guidance to start a new line of research. We hope that as the volumes become available, the effort put in by us, by the publisher, by the book editors, and by the individual authors will contribute to the further development of brain research....

Methods and New Frontiers in Neuroscience

Our goal in creating the Methods and New Frontiers in Neuroscience Series is to present the insights of experts on emerging experimental techniques and theoretical concepts that are, or will be, at the vanguard of neuroscience. Books in the series will cover topics ranging from methods to investigate apoptosis to modern techniques for neural ensemble recordings in behaving animals. The series will also cover new and exciting multidisciplinary areas of brain research, such as computational neuroscience and neuroengineering, and will describe breakthroughs in classical fields like behavioral neuroscience. We want these to be the books every neuroscientist will use in order to get acquainted with new methodologies in brain research. These books can be given to graduate students and postdoctoral fellows when they are looking for guidance to start a new line of research. We are working with these goals in mind and hope that as the volumes become available the effort put in by us, the...

Heimer1 M Rivlin12 Z Israel3 and H Bergman12

Early physiological studies emphasized changes in the discharge rate of basal ganglia in the pathophysiology of Parkinson's disease (PD), whereas recent studies stressed the role of the abnormal oscillatory activity and neuronal synchronization of pallidal cells. However, human observations cast doubt on the synchronization hypothesis since increased synchronization may be an epi-phenomenon of the tremor or of independent oscillators with similar frequency. Here, we show that modern actor critic models of the basal ganglia predict the emergence of synchronized activity in PD and that significant non-oscillatory and oscillatory correlations are found in MPTP primates. We conclude that the normal fluctuation of basal ganglia dopamine levels combined with local cortico-striatal learning rules lead to non-correlated activity in the pallidum. Dopamine depletion, as in PD, results in correlated palli-dal activity, and reduced information capacity. We therefore suggest that future...

Summary and conclusions

By the end of the nineteenth century, 'internal mechanisms' predominated and the old lists of predisposing causes had become stereotyped and uninteresting. Nonetheless, medical doctors continued using efficient causes, particularly in the context of case-notes narrative. Interest in internal mechanisms favoured academic psychiatry and led to some progress in brain research.

Modeling to Test New Therapies

Alternative treatments for epilepsy also benefit from animal research. Vagus nerve stimulation (VNS), for instance, was first investigated with acute seizures in dogs and then with chronic epilepsy in monkeys before it was tried in humans (Schachter and Wheless, 2002). Animal research is also playing an important role in developing the techniques of deep brain stimulation as a treatment for epilepsy. Epilepsy surgery, gamma knife surgery, and the ketogenic diet (KD) have been used effectively in patients without preliminary studies in animals. However, animal research continues to be of value in our efforts to understand how these therapeutic interventions work, what might be done to improve them, and which patients are most likely to benefit from their use. Identifying appropriate animal models for testing therapeutic interventions is a prime concern. For example, because KD is principally used in children, understanding and improving KD-based approaches require comparable immature...

Chapter References

Super, H., Soriano, E., and Uylings, H.B.M. (1998). The functions of the preplate in development and evolution of the neocortex and hippocampus. Brain Research Reviews, 26, 40-64. 15. Berger-Sweeney, J. and Hohmann, C.F. (1997). Behavioral consequences of abnormal cortical development insights into developmental disabilities. Behavioural Brain Research, 86, 121-42.

Education Physical Activity and Brain Trauma and the Onset of Alzheimers

Epidemiological investigations would indicate that higher level of formal education and early brain stimulation would delay the onset of AD (Katzman, 1993 Terry & Katzman, 2001). Likewise, exercise and multisen-sory environmental stimulation appear to provide an increase resistance to the development of age-related cognitive problems (Briones, 2006). These observations have been confirmed by experimental evidence in AD-like transgenic

Correlation Across a Few Situations Is Limited Evidence

According to the definition above, an NCC is a system that correlates with consciousness across arbitrary cases of normal functioning, in any environment, with any unusual input or limited brain stimulation. In practice, though, evidence is far weaker than this. Typically one has a few cases, involving either a few subjects with different lesions, or a study in which subjects are given different stimuli and one notes an apparent correlation. This is to be expected, given the current technological and ethical constraints on experimental methods. But it does mean that the evidence which current methods give is quite weak. To truly demonstrate that a given system is an NCC, one would need to show correlation across a far wider range of cases than is currently feasible. Of course current methods may give good negative evidence about systems that fail to correlate and thus are not NCCs, but strong positive evidence is harder to find. Positive hypotheses based on current sorts of evidence...

Methodological Summary

We can use all this to sketch a general methodology for the NCC search. First, we need methods for determining the contents of conscious experience in a subject, presumably by indirect behavioral criteria or by first-person phenomenology. Second, we need methods to monitor neural states in a subject, and in particular to monitor neural representational contents. Then we need to perform experiments in a variety of situations to determine which neural systems correlate with conscious states and which do not. Experiments involving normal brain functioning with unusual inputs and limited brain stimulation are particularly crucial here. Direct conclusions cannot be drawn from systems with lesions, but such systems can sometimes serve as

Microvascular Endothelium Models the Blood Brain Barrier

Advances in brain research, especially in set-ups investigating problems of drug passage through the human BBB, have led to improved models which might be exploited also for fungal infection research in the future. For example, reconstitution of the natural micro-environment by co-culture of microvascular EC with astrocytes, astrocyte-conditioned medium or extraluminal C6-glia cells augmented the physiological properties of BBB models (Abbott, 2005 Abbott et al., 2006 Josserand et al., 2006 Megard et al., 2002 Neuhaus et al., 2006b). Also the addition of physiological flow was found to have positive effects on BBB integrity and permeability in vitro (Cucullo et al., 2002 Neuhaus et al., 2006b Santaguida et al., 2006). Up to now, these technical advances barely have been implemented in investigation of fungal pathogenesis.

Genetic Testing For Parkin Mutations

There are two reasons to look for PARKIN mutations. The first is to confirm a diagnosis. Given the frequency of dystonia in patients with PARKIN mutations, they may be difficult to distinguish from those with dopa-responsive dystonia. Correct diagnosis is also important for patients with juvenile onset, because it can affect prognosis and treatment patients with PARKIN mutations are, for example, good candidates for deep brain stimulation. PARKIN should also be tested in view of genetic counselling. The identification of PARKIN as the cause of their disease is reassuring for patients and their sibs, since it excludes the high risk recurrence in subsequent generations by autosomal dominant transmission. In situations where the spouses are related, testing should also be performed. If both are carriers, prenatal diagnosis can be envisaged.

Therapeutic Intervention

That cannot be visualized with conventional technique, such as deep brain stimulation, and procedures using as an effector an agent that cannot be employed within the usual confines of the operating room. A classic example of this latter category is stereotactic radiosurgery (also discussed in Chapter 11). Conventional neurosurgery in many instances was designed to address a structural target that, in many cases, had to be removed. A classic example is resection of an intracranial tumor. As these lesions can be seen by the naked eye once exposed, conventional surgery was performed with direct visualization and removal of the target. In the previous sections, examples of how this process can be made less invasive have been given. However, neurosurgery has now evolved to the point at which restoration of function, as opposed to removal of a lesion, is the target of many procedures. An example of this effort is deep brain stimulation for movement disorder. This technique, which has been...

F I Consequences of Demyelination

Figure 1 Ionic currents recorded from a rat sciatic demyelinated internode with a loose patch clamp pipette. The membrane potential was held 30 mV negative to the resting value and was depolarized by pulses of 40, 60, 70, 80, 90, and 110 mV This nerve was 3 days postinjection. (Reprinted from Brain Research Shrager, 1989 , copyright 1989, with permission from Elsevier.) Figure 1 Ionic currents recorded from a rat sciatic demyelinated internode with a loose patch clamp pipette. The membrane potential was held 30 mV negative to the resting value and was depolarized by pulses of 40, 60, 70, 80, 90, and 110 mV This nerve was 3 days postinjection. (Reprinted from Brain Research Shrager, 1989 , copyright 1989, with permission from Elsevier.)

Using Brain Structures To Guide The Search For Mental Operations

Cognitive research into memory operations yielded little direct empirical evidence about the operations involved in memory.19 In this section I will describe how recent research that is directed towards identifying the brain structures involved when people perform various memory tasks can play a heuristic role in identifying the mental operations involved. This is not to suggest that brain research supplants the need for cognitive research that attempts to decompose memory operations. If we are to understand memory mechanisms, it is necessary to characterize the information processing operations that figure in them. The focus, accordingly, is on how information about which neural structures are involved in particular tasks can help with the project of identifying key mental operations (and, less often so far, also help settle issues about the nature of the

The depressed state functional anatomy

In summary, much of the functional imaging work so far completed has been inconclusive. It has served to implicate frontal and limbic rather than posterior brain areas, but this has done little more than broadly confirm anatomical conclusions derived from observing the effects of lesions or brain stimulation. (19) It has failed to illuminate mechanisms underlying the depressed state either at the neuropsychological or neurochemical level. Progress requires that relevant neuropsychological and drug challenges are incorporated into imaging protocols. The likely neuropsychological candidates include the representation of facial emotion the choice of relevant drug challenges will be guided, as outlined below, by experience in neuroendocine challenge studies and the pharmacology of effective treatments. Finally, 'functional' abnormalities may importantly predict structural abnormality in depression.

Letter 33 To Th Huxley

I am really truly sorry to hear about your health . I entreat you to write down your own case,--symptoms, and habits of life,--and then consider your case as that of a stranger and I put it to you, whether common sense would not order you to take more regular exercise and work your brain less. (N.B. Take a cold bath and walk before breakfast.) I am certain in the long run you would not lose time. Till you have a thoroughly bad stomach, you will not know the really great evil of it, morally, physically, and every way. Do reflect and act resolutely. Remember your troubled heart-action formerly plainly told how your constitution was tried. But I will say no more excepting that a man is mad to risk health, on which everything, including his children's inherited health, depends. Do not hate me for this lecture. Really I am not surprised at your having some headache after Thursday evening, for it must have been no small exertion making an abstract of all that was said after dinner. Your...

Methodological Considerations

Although most studies examining the effects of adrenalectomy on the behavioral responses to drugs are consistent, some studies have not observed decreased drug effects following ablation of the adrenal glands. For example, as mentioned previously, adrenalectomy does not decrease sensitization to the locomotor effects of cocaine when it is performed after a sensitizing paradigm (18,19). In addition, adrenalectomy does not reduce cocaine facilitation of brain stimulation (46) or drug-induced reinstatement of seeking behavior (for review, see ref. 43). The nature of this discrepancy is unclear. However, it is important to point out that corticosterone levels at the time of adrenalectomy (i.e., circulating levels of corticosterone at the time when the adrenal glands are removed) could play a fundamental role in determining whether adrenalectomy will or not reduce drug effects. Thus, it has been shown (12,47) that adrenalectomy has no effects on the locomotor response to cocaine or on the...

Other electromagnetic stimulation magnetoconvulsive treatment MCT

The potential hazard of seizure induction during repetitive transcranial magnetic stimulation (rTMS) has recently been turned into a potential strength, by using a varying magnetic field to induce seizures during magnetoconvulsive therapy (MCT) (Lisanby et al., 2001). Without the vagaries of poor and variable electric conductivity that allows only a small proportion of the current applied during ECT to pass through the brain, MCT can focus and dose the brain stimulation more accurately and reliably, with the potential benefit of limiting stimulation to the brain structures essential for treatment response, and reducing side effects, such as memory impairment.

Specific Pain Syndromes In Pd

Deficiency for many patients, off' pain can represent a secondary consequence of increased rigidity and immobility. Pain caused by dystonia can be diagnosed when there is visible twisting, cramping, and posturing of the painful extremity or body part. Dystonia may be painful in the off' state, but medication-induced dystonia, occurring in the on state or during transitions between states, may be painful. Deep brain stimulation may induce painful, dystonic muscle spasms, sometimes attributed to spread of discharge to the corticospinal tract.

The set of procedures and techniques that guide the planning execution and analysis of a type of tasks

The field of memory research is equipped with its own special repertoire of methods. These are exemplified in classical conditioning, cue revaluation, delay task, fear conditioning, habituation, instrumental conditioning, LTP, maze, priming, real-life memory, sensitization, transfer, and working memory. But brain research in general is in a special situation. It is a truly multidisciplinary enterprise. The more it advances, the more it is quick to incorporate knowledge and methods from a great variety of other disciplines. These range from molecular, cellular, and developmental biology, via physiology and anatomy, clinical neurology and neuroimaging, psychology, and ethology, to computational science and information theory (Dudai 1989 Martin and Bateson 1993 Baddeley 1997 Manning and Dawkins 1998 Zigmond et al. 1999 Kandel et al. 2000). Not surprisingly, a recent textbook in the neurosciences is authored by no less than 150

Intracranial Self Stimulation

Has been reported to lower intracranial self-stimulation thresholds in rats, suggesting the activation of central hedonic systems (174,175). The opioid antagonist naloxone blocked the enhancing effects of THC on electrical intracranial self-stimulation reward, at doses of naloxone that themselves have no effect on brain reward, which reveals the involvement of the endogenous opioid system in the rewarding effects of THC (176). Interestingly, the facilitation of brain stimulation reward induced by most drugs of abuse is also reversed by naloxone administration (177).

Tt7 Candidates For The Ncc Iii Consciousness Iv Anesthesia And The Nmda Receptor Complex

Hans Flohr is the prototypical example of an active neuroscientist with a long-standing, deep, and serious interest in the philosophical issues related to mind-brain research. For a number of years he has been working on what he calls a realization theory of consciousness, a theory that will render the relations between brain events and states of consciousness intelligible. Such a theory would order the diverse empirical correlations and define which causes are relevant or proximal, and which are trivial. His approach also contains a philosophical element phenomenal content is the content of higher-order representations. Therefore, Flohr says, the search for the neural correlate of consciousness converges with the search for a computational mechanism generating the integrated, large-scale neural assemblies to which those higher-order representations will necessarily belong. Flohr's hypothesis states that in human cortex this function is implemented by the NMDA receptor complex....

Letter 119 To Th Huxley

I have just finished No. 1 of the Natural History Review, and must congratulate you, as chiefly concerned, on its excellence. The whole seems to me admirable,--so admirable that it is impossible that other numbers should be so good, but it would be foolish to expect it. I am rather a croaker, and I do rather fear that the merit of the articles will be above the run of common readers and subscribers. I have been much interested by your brain article. (119 2. The Brain article of Huxley bore the title On the Zoological Relations of Man with the Lower Animals, and appeared in No. 1, January 1861, page 67. It was Mr. Huxley's vindication of the unqualified contradiction given by him at the Oxford meeting of the British Association to Professor Owen's assertions as to the difference between the brains of man and the higher apes. The sentence omitted by Owen in his lecture before the University of Cambridge was a footnote on the close structural resemblance between Homo and Pithecus, which...

Infrastructure And Human Resources

Special mention has to be made of the demand for human resources and infrastructure in the case of patients in whom pharmacological manipulations fail to modify long-term motor complications and who are considered candidates for stereotactic surgery (both lesional or deep-brain stimulation). Although the percentage of patients requiring these procedures is still small, the demand will probably grow until better pharmacological options are available. The cost of these procedures is quite high and the need for specialized personnel, infrastructure, and equipment is significant.

A memory system in which new patterns are stored on top of previous ones

'Palimpsest' has been used as a metaphor for brain and mind by Romantic writers. 'What else than a natural and mighty palimpsest is the human brain Everlasting layers of ideas, images, feelings, have fallen upon your brain softly as light. Each succession has seemed to bury all that went before. And yet not one has been extinguished Yes, reader, countless are the mysterious hand-writing of grief or joy which have inscribed themselves successively upon the palimpsest of your brain' (De Quincey 1866). Postulated palimpsestic properties of biological memory systems were also contemplated by Freud (1925). Similarly, Gestalt psychologists have proposed that new memory records are inscribed on top of old ones (Koffka 1935).1 'Palimpsest' resurfaced in modern neurosciences with the introduction of models of artificial neural networks (Nadal et al. 1986 Amit 1989 Amit and Fusi 1994). In subclasses of such model networks, which keep a permanent capacity for learning, new patterns are stored on...

Clinical approach when the risk to fall is high and mobility is compromised

At the most advanced stages of PD when ''Offs'' are very frequent and very disabling with dyskinesias which can cause major disability, functional neurosurgery at the level of the basal ganglia should be considered (Giladi and Melamed, 2000). Pallidotomy and deep brain stimulation of the sub-thalamic nucleus (STN) or the internal globus palli-dum (GPi) have been very effective in avoiding motor response fluctuations with the elimination of ''Off'' periods and dyskinesias (Allert et al., 2001 Ferrarin et al., 2004).

Pathogenesis Of Voiding Dysfunction In Pd

It is interesting to note that stimulation of the red nucleus, the subthalamic nucleus, and the substantia nigra was more inhibitory than that of the thalamus. This may suggest that current deep brain stimulation procedures may be more effective in improving voiding dysfunction if STN rather than the thalamus is the target. Stereotaxic thalamotomy in parkinsonian patients, on the other hand, demonstrated an increase in detrusor activity.22,25

Functional Procedures

Originally epilepsy surgery was based on physiological as well as structural principles. Increasing knowledge of the underlying pathology and improved direct brain imaging have resulted in less attention being paid to functional operations, especially stereotactic lesion-ing. Currently, the available procedures for epilepsy are stereotactic lesioning, cutting various fiber tracts or other connections, including the various methods of callosotomy and multiple sub-pial transection, and, finally, brain stimulation either with intracranial electrodes or VNS.

Neurosurgery for Neuroacanthocytosis

2.2 Deep Brain Stimulation 3 Abstract Neuroacanthocytosis (NA) is a group of neurodegenerative diseases characterized by the presence of acanthocytes in peripheral blood and various types of involuntary movements which are often resistant to medical treatment. We report data concerning four NA patients who benefited from functional surgery two had pallidotomies and two had deep brain stimulation (DBS) of the internal pallidum (GPi). The clinical outcome of pallidotomy was partial in the first patient, but clearly improved involuntary movements in the second patient without inducing side effects. In the patients who underwent DBS, GPi 40 Hz stimulation gave the best clinical benefit, improving chorea without an effect upon hypotonia. Higher frequency stimulation (130 Hz) was effective for dystonia but increased chorea, worsened dysarthria and induced drooling. Low frequency (10 Hz) GPi stimulation was ineffective. Therefore, in this small series of NA patients, both pallidotomy and...

Along 12 years of STN stimulation in Parkinsons disease and of 17 years of stimulation of the thalamus

Ture was able to diminish the prolactine release of GH3 cells as well as the release of dopamine, epinephrine and norepinephrine in PC12 cells, suggesting that exhaustion of the neurotransmitter production could be part of the mechanism involved. This leads to a putative model of the mechanism of HFS encompassing the globality of these mechanisms, which might all of them play altogether a specific role leading to this very clinically efficient effect, acute and reversible as well as titrable, of deep brain stimulation.

What are the alternatives

Ardouin C, Pillon B, Peiffer E, Bejjani P, Limousin P, Damier P, Arnulf I, Benabid AL, Agid Y, Pollak P (1999) Bilateral subthalamic or pallidal stimulation for Parkinson's disease affects neither memory nor executive functions a consecutive series of 62 patients. Ann Neurol 46 217-223 Aziz TZ, Peggs D, Sambrook MA, Crossman AR (1991) Lesion of the subthalamic nucleus for the alleviation of (MPTP)-induced parkinsonism in the primate. Mov Disord 6 288-292 Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM, Dormont D, Cornu P, Pidoux B, Samson Y, Agid Y (1999) Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 340 1476-1480 Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J (1987) ''Combined (thalamotomy and stimulation) stereotactic surgery of the Vim thalamic nucleus for bilateral Parkinson disease.'' Appl Neurophysiol 50 344-346 Benabid AL, Wallace B, Mitrofanis J, Xia R, Piallat B, Chabardes S, Berger F (2005) ''A putative generalized...

Building a World Wide Database

The most important aspect, however, from a clinical point of view, is the gathering of detailed information about past treatments. Experiences with botulinum toxin injections were recently collected among the patients (via neuroacanthocytosis but this approach must be extended using a systematic protocol. Similarly, the effects of deep brain stimulation ought to be compared between the few patients who so far have undergone the procedure. Drug treatments such as sulpiride, tetrabenazine, tiapride, levetiracetam 21 or other substances should be documented, as should be approaches such as physiotherapy, dysphagia treatment, and psychotherapy. Accumulation of an extensive set of therapeutic experiences may then be followed by the design of observational treatment studies that in such uncommon medical conditions are only feasible if close international collaboration is achieved. Collectively, these activities effectively constitute a Virtual Neuroacanthocytosis Institute.

Memory for the circumstances in which one first learned of a surprising consequential or emotionally arousing event

In recent years, brain research has unveiled clues to the biological mechanisms that encode the memory of intensely emotional and consequential events. These candidate mechanisms deal with two levels of brain organization the circuit level and the cellular level. The circuit mechanisms are assumed to involve subcortical modulation of the cerebral cortex, which causes certain sensory events to be perceived as highly salient because of the concomitant activation (coincidence detection) of neuromodulatory systems such as the acetylcholine and the noradrenaline systems (Naor and Dudai 1996 McGaugh and Cahill 1997 Tang et al. 1997). This hypothesis is a neurobiological version of the 'unique acquisition' accounts mentioned above (Brown and Kulik 1977). The cellular explanations are based on the assumption that the consolidation of long-term memory is triggered by a certain configuration of transcription factors (CREB, immediate early genes, spaced training). This configuration acts as a...

Personality change due to a general medical condition JLC

Oreland, L. and Hallman, J.(1995). The correlation between platelet MAO activity and personality short review of findings and a discussion on possible mechanisms. In Progress on brain research, 106, Current neurochemical and pharmacological aspects of biogenic amines (ed. P.M. Yu, K.F. Tipton, and A.A. Boulton), pp. 77-84. Elsevier, Amsterdam.

Stimuli for activation of the sympathetic nervous system and adrenal medulla

For instance, the effects of the sympathetic nervous system on the circulatory system (heart and blood vessels) are brought into play by a fall in blood pressure. This may happen quite often. Think for a moment of the hydrostatic pressure of a column of blood about 2 metres high. Then contemplate the fact that when you get out of bed and stand up, the pressure of blood available to perfuse your brain is going to drop rapidly and dramatically. This is an immediate stimulus to the sympathetic nervous system to maintain blood pressure, which it does, as we shall see in more detail below, by effects both on the heart and the blood vessels. Most people are familiar with a feeling of faintness on standing up too quickly, particularly on a hot day when blood volume may be depleted by sweating. The brain receives the information that blood pressure is beginning to fall from receptors in the great vessels, collates this in the hypothalamus and causes the appropriate responses to be set in...

Autosomal Dominant Inheritance

Depression can be treated with classical antidepressants. Deep brain stimulation of the globus pallidus internus has been performed experimentally, and has been reported to provide temporary benefit in single cases, but it cannot stop neurodegeneration 59 . Multiple drug trials are currently being carried out in the hope of finding neuroprotective agents.

Nonpharmacological Approaches to the Treatment of Parkinsonism

Additional approaches to the treatment of Parkinson's disease include surgical procedures, brain stimulation, and transplantation of dopaminergic cells. In general, surgical procedures are reserved for patients who are refractive to levodopa or who have profound dyskine-sias or fluctuations in response to levodopa. Tremor can be abolished by ablation of the ventral intermediate nucleus of the thalamus. Dyskinesias can be effectively controlled by ablation of the posteroventral portion of the globus pallidus. Brain stimulation appears to be a promising technique. High-frequency electrical stimulation of the thalamus, subthalamic nucleus, or globus pal-lidus can improve various symptoms of parkinsonism and reduce levodopa dosage.

Placebo Effect And Reward Circuitry

Reward Circuitry Depression

Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, Bergamasco B, Lopiano L (2004) Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 7 587-588 de la Fuente-Fernandez R (2004) Uncovering the hidden placebo effect in deep-brain stimulation for Parkinson's disease. Parkinsonism Relat Disord 10 125-127

Animal Models Of Depression

In the chronic stress models developed initially by Katz25 and further refined in several studies12,13,26 an anhedonic state is induced by the repeated application of mild-to-moderate stressors over a prolonged time period. Rats were exposed to stressors like soiled cages, restricted food access, alterations of the light dark cycle, cage tilt, change of cage mate, and introduction of novel objects into the cage for up to 3 months. The model mirrors most of the findings seen in depressive episodes that can be examined in animals. Hedonic measures are the primary focus of the model and the effects of stress are assessed with repeated tests for preference for a palatable weak sucrose solution or saccharin solution. Chronic mild stress decreases preference for sweet solutions which is interpreted as a sign of anhedonia. Higher brain stimulation thresholds as well as decreased place preference conditioning also suggest decreased response to rewarding stimuli after chronic mild stress....

Human the only extant species of the primate family Hominidae

There used to be additional Homo (Wood and Collard 1999). At least with one of these, neanderthalen-sis, we shared this planet for a while. It is questionable whether we remember the experience, a sort of infantile sapiens amnesia, although it is still possible that some reminiscences do linger in the obscure legends of our collective memory. It is generally assumed that sapiens emerged 1-2 x 105 years ago, probably in Africa, and made the first massive out-of-Africa exodus 0.6-1 x 105 years ago (Quintana-Murci et al. 1999).1 Assuming 20 years per generation, it means that the distance between us and the first true human may be only 5000 generations, not an astronomic number (try to imagine several thousand individuals holding hands this is it). What was the brain power of the lost hominids species And which cognitive capabilities, memory included, enabled us to win over the Neanderthal, or at least to linger longer Attempts to unearth the answers combine prehistoric archaeology with...

A figure of speech in which one entity is described in terms of another

Brain research uses metaphors for both aforementioned reasons. To describe the mind and memory, multiple classes of metaphors have been generated, most of them antedating the scientific era (Abrams 1953 Roediger 1980). The vehicle and ground in these metaphors involve either space, written records, vision, or technology. Especially common are spatial metaphors, depicting memory as a physical repository, and retrieval as a search for the location of an item filed in storage (for classical examples see Plato, Theaetetus 197c-e Augustine 400 Locke 1690 engram, mnemonics). Written record metaphors (which could be regarded as a subset of the spatial ones) advanced from etched wax tablets (Plato, Theaetetus 193a-a95a) to more fancy writing pads (Freud 1925). In an influential model of working memory, we encounter a subsystem termed the 'visuospatial scratch pad' or 'sketchpad' (Baddley 1986).2 Working memory as such was also referred to as 'the blackboard of the mind' (Goldman-Rakic 1996).

Clinical Phenomenology

In addition to careful clinical observation of the signs described above, bedside examination of bradykinesia includes evaluation of speed, amplitude, and rhythm of sequential movements on each side of the body through finger taps, opening and closing fists, pronation-supination of the hands, and heel or toe tapping. In early disease, these tasks usually show mild slowing and decreased amplitude the longer the movements are performed. As the disease progresses, these movements become less coordinated, with frequent hesitation or arrests. Fortunately, bradykinesia responds well to dopaminergic medications and deep brain stimulation (DBS) surgery. Stimulation of both the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) seem to be equally effective for bradykinesia.1516

Dualism and Its Discontents

Bodies and guide their bodies, but that are not part of their bodies and are not subject to the same physical laws as their bodies. This idea has been widely accepted since the time of Descartes, and is often credited to him, but only because he stated it so clearly I think it is what anyone would come to believe if they did a few experiments. Suppose I ring a bell in your presence, and then play a recording of the 1812 Overture for you. You are supposed to raise your hand when you hear the sound of that bell. How do you know when you hear that sound Introspectively, it seems that, though you don't actually hear a bell ringing, you can summon a mental image of it that has the same tonal quality as the bell and compare it at the crucial moment to the sounds of the church bells near the end of the overture. (You can summon it earlier, too, if not as vividly, and note its absence from the music.) Now the question is, where do mental sounds (or visual images, or memories of smells) reside...

Imaging Of Dementia In Pd

The treatment of dementia occurring in the setting of PD represents a major unmet need for patients and an ongoing source of frustration for clinicians. PD patients with dementia experience more severe side effects from their medications than those without dementia, including drug-induced psychosis.23 176 In addition, patients with dementia often cannot tolerate adequate doses of medication to control their motor symptoms. Since the presence of dementia is considered a contraindication for surgical treatment of PD,177 these patients do not even have the option of considering emerging therapies such as deep brain stimulation (DBS) for their disease. As a result, demented PD patients have a worse prognosis and a higher mortality than their nondemented counterparts.178 One early controlled clinical trial attempted, unsuccessfully, to use phosphatidylserine to treat dementia in parkinsonian patients.179 Sano et al.180 used the nootropic (cognitive enhancer) piracetam to treat intellectual...

Pharmacotherapy Research in Posttraumatic Stress Disorder

Croatian Institute for Brain Research, Medical School, University of Zagreb, Croatia 1 Corresponding Author Neven Henigsberg, Head, Department of Psychopharmacology, Croatian Institute for Brain Research, Medical School, University of Zagreb, Salata 12, HR-10000, Zagreb, Croatia E-mail neven.henigsberg

Treatment Management And Cost

Functional surgery, both lesional or deep-brain stimulation, also plays an important role in the treatment of the complicated PD patient with drug-refractory disease, as this resource has become increasingly useful in the management of motor complications (motor fluctuations and dyskinesias) (20). Three different brain targets for surgery are presently used, depending on the characteristics of the patient.

Series Editors

Our goal in creating the Methods & New Frontiers in Neuroscience Series is to present the insights of experts on emerging experimental techniques and theoretical concepts that are, or will be, at the vanguard of Neuroscience. Books in the series cover topics ranging from methods to investigate apoptosis, to modern techniques for neural ensemble recordings in behaving animals. The series also covers new and exciting multidisciplinary areas of brain research, such as computational neuroscience and neuroengineering, and describes breakthroughs in classical fields like behavioral neuroscience. We want these books to be the books every neuroscientist will use in order to get acquainted with new methodologies in brain research. These books can be given to graduate students and postdoctoral fellows when they are looking for guidance to start a new line of research. We hope that as the volumes become available, the effort put in by us, by the publisher, by the book editors, and by...

Pattern changes

A third major change in the discharge patterns of basal ganglia neurons in parkinsonism is that dopamine loss enhances the tendency of neurons in the basal ganglia-thalamocortical circuitry to discharge in an oscillatory pattern (Soares et al., 2004 Bergman et al., 1994). These oscillatory changes are rapidly reversed by systemic treatment with dopaminergic agents (Levy et al., 2002), and are therefore likely to represent a direct effect of dopamine deficiency. Such oscillations are mostly confined to the extrastriatal basal ganglia, and characteristically occur in the alpha- and beta frequency bands. For instance, in parkinso-nian monkeys and patients, oscillatory bursting typically emerges in both the 3-8 Hz band, and a power spectral band around 10 Hz (Bergman et al., 1994 Levy et al., 2000). Local field potential (LFP) recordings through implanted deep brain stimulation (DBS) electrodes in GPi and STN of untreated parkinsonian patients have shown similar oscillatory activity in...

Overall Definition

The conditions C'' clause here represents the relevant range of cases, as discussed above. If the reasoning above is on the right track, then conditions C might be seen as conditions involving normal brain functioning, allowing unusual inputs and limited brain stimulation, but not lesions or other changes in architecture. Of course the precise nature of conditions C is still debatable. Perhaps one could make a case for including a limited range of lesion cases in the definition. In the other direction, perhaps one might make a case that the requirement of correlation across brain stimulation or unusual inputs is too strong, due to the abnormality of those scenarios. But I think the conditions C proposed here are at least a reasonable first pass, pending further investigation.

Key Speakers

Department of Psychopharmacology, Croatian Institute for Brain Research, Medical School, University of Zagreb, Salata 12, HR-10000, Zagreb, Croatia Tanja Jovanovic Croatian Institute for Brain Research, School of Medicine, Zagreb University Hospital Center Gojka Suska 12, HR-10000 Zagreb, Croatia Dragica Kozaric-Kovacic, MD, PhD

Surgical Therapies

The past decade has seen renewed interest in surgery for the treatment of PD.130 The limitations of drug treatment, a better understanding of disordered basal ganglia physiology, and the significant clinical benefits of surgery have made this option more attractive. Advances in neuroim-aging, stereotactic surgery, and better physiological localization with techniques such as microelectrode recording and macrostimulation have also made surgery more accurate and therefore safer.130 The two techniques employed are ablation and deep brain stimulation. The latter has become popular because of reversibility and the ability to


Finally, image guidance allows the use of novel therapeutic interventions, such as deep brain stimulation and radiation therapy, permitting the completely noninvasive amelioration of symptomatology or destruction of tissue, which would be impossible in the absence of image guidance.

The Protoself

The presumed relation between specific brain regions and a proposed function such as protoself should be qualified at this point. The non-conscious protoself is not produced in any of the single regions mentioned above. Such functions as protoself or the core self and autobiographical self, to be introduced later, are not located in one particular brain region, or in one set of regions, but are the product of the interaction of neural and chemical signals among a set of regions. Phrenological thinking, which consists of attributing complicated mental functions to simple brain regions on the basis of correlative evidence, is a natural tendency in mind and brain research. But there are no single centers responsible for the sort of complex functions that are part of mind processes.


Yet those are not the cognitive or neuronal virtues of the bee that have carried it to these pages. Clearly, many species do outperform the bee in behavioural complexity and brain power. The bee is of interest here because it is the subject of a systematic, multilevel, top-down research programme, that has successfully managed to link the phenomenology of ecological behaviour to the mechanistics of circuits and molecules. Furthermore, this programme attempts to explain concretely real-life learning in terms of alterations in identifiable internal representations. This critical step in bridging behaviour and brain is still a rather uncommon enterprise in the neurobiology of learning and memory.

Nervous Tissue

Nervous tissue contains cells that receive and transmit messages in the form of electrical impulses. These cells, called neurons (NOO-rahnz), are specialized to send and receive messages throughout the body. Nervous tissue makes up your brain, spinal cord, and nerves. It is also found in parts of sensory organs, such as the retina in your eye. Some nervous tissue senses changes in the internal and external environment. Other nervous tissue interprets the meaning of sensory information. Still other types of nervous tissue cause the body to move in response to sensory information. Coordination of voluntary and involuntary activities and regulation of some body processes are also accomplished by nervous tissue. Figure 45-1b, on the following page, shows an illustration of cells of nervous tissue.

Parkinsons Disease

The demise of dopaminergic neurons in the substantia nigra leads to a reduced innervation of the striatum, primarily the putamen, which is a major center for motor control (review in Dauer and Przedborski 2003). Symptoms occur when more than 60 of substantia nigra dopaminergic neurons and about 80 of putamenal dopamine have been lost. The discovery of dopamine deficiency was the basis for the development of symptomatic therapeutic strategies. Replacement of dopamine by its precursor L-dopa and administration of dopaminergic agonists can relieve the symptoms of PD, however, after several years of pharmacological treatment, most patients develop adverse effects, notably motor fluctuations and dyskinesias. Surgical interventions such as deep brain stimulation offers hope for patients whose motor complications can not adequately be controlled pharmacologically. Despite these advances, no strategies have yet been established to halt or delay the progression of the degenerating process.

Future Directions

The ultimate goal of the neuroprosthetic experiments in monkeys is the translation of the technique to the clinic i.e., the chronic implant of such devices in humans with motor disabilities. As discussed in this chapter, further primate studies have yet to address the fundamental question of whether current BMI technology and approaches may be applied successfully to human subjects.17,18,44 It is also important to identify which regions of the brain may provide an effective motor control signal for task prediction, and ultimately for neuroprosthetic control. In a recent report13 we showed how neuronal acute recordings from subcortical motor regions of the human brain, such as motor thalamus (ventralis oralis posterior VOP ) and subthalamic nucleus (STN), serve as predictors of motor function. During deep brain stimulation surgery, 11 Parkinsonian patients performed a motor task in the form of squeezing a sensorized ball to control the one-dimensional movement of a vertical bar in a...

The patient less so

The placebo effect can be encountered in a great variety of medical conditions, but is particularly prominent in pain, depression and Parkinson's disease. It has been shown that placebo responses play a part in the effect of any type of treatment for Parkinson's disease, including drug therapy, deep brain stimulation and dopa-mine tissue transplantation. Recent studies have demonstrated that the placebo effect in Parkinson's disease is related to the release of substantial amounts of endogenous dopamine in both the dorsal and ventral striatum. As the ventral striatum is involved in reward processing, these observations suggest that the placebo effect may be linked to reward mechanisms. In keeping with this placebo-reward model, most recent experiments have shown activation of the reward circuitry in association with placebo responses in other disorders. In addition, as dopamine is the major neurotransmitter in the reward circuitry, the model predicts that the release of...


Male birds sing to selected audiences. The male is a landlord and potential warrior, notifying other males that it is ready to defend its territory. It is also a charming troubadour attempting to convince females that it is the best in town. The song occupies such a cardinal role in the male's life that it may even dream about it (Dave and Margoliash 2000). Whereas we humans could enjoy the song repertoire regardless of gender, the male and the female of songbirds are probably each tuned to understand only that part of the song that speaks to their heart (Williams and Nottebohm 1985). The plasticity of birdsong has been well known to bird fanciers in the Orient since ancient times, and expert manipulations of song were exploited for aesthetic and commercial purposes (Konishi 1985). This neuronal and behavioural plasticity has also long attracted scientists' attention (Darwin 1871 Mertfessel 1935 Koehler 1951 Thorpe 1954). In addition to being a beautiful system to investigate ethology...


Specific surgical treatments for PD, such as ablative procedures and deep brain stimulation of the thalamus, globus pallidus, and subthalamic nucleus, are generally thought to produce insubstantial benefit on the voice. Bilateral procedures and unilateral gamma knife may result in worsening of voice loudness and speech production. Patients should be counseled appropriately before undergoing these procedures.17-20

Sensory Symptoms

Deep brain stimulation of the globus pallidus tends to improve sensory complaints half of the 16 patients operated on by Loher et al. had dysesthesias, and in each case the dysesthesia essentially disappeared postoperatively.34 The effect on sensory symptoms of subthalamic stimulation, now a more common intervention for PD, has not been systematically studied. High-frequency thalamic stimulation, sometimes used to alleviate parkinsonian tremor, in many patients will cause parasthesias at high settings. This iatrogenic sensory symptom is easily and instantly cured by reducing the stimulation. Alternatively, the stimulation can be delivered via adjacent lead contacts to reduce the field. In this way, side effects can be restricted without sacrificing tremor control. Parenthetically, thalamic (ventrocaudal) stimulation was found not to worsen somatosensory acuity.35

The Souls of Robots

Similarly, it's part of the concept of aesthetics that something is beautiful, or stirring, or funny because there is an emotional resonance between that something and you. The resonance must be understood as having real meaning, not the result of a short circuit somewhere. Supposedly (Kurzweil 1999) there is a region of the brain that when electrically stimulated makes everything seem hilarious. If this part of your brain were stimulated without your knowing it, you would think that some very funny stuff was happening around you. But if you find out it's due to brain stimulation, you'll decide that you're having a vivid hallucination. (You still might enjoy it, of course, but you wouldn't describe it the same way.) Nitrous oxide makes everything seem profound for a few seconds after it is inhaled. The feeling is impossible to shake while it is present. Nonetheless, a theory explaining how nitrous oxide works is not a theory of profundity.

Sleep fragmentation

Apomorphine is has been found to increase nocturnal sleep time and reduce nighttime movements in PD (Priano et al., 2003). Deep brain stimulation surgery has also been demonstrated to improve sleep quality and sleep fragementation (Iranzo et al., 2002). Paradoxically, despite observations that PD medications alleviate night time sleep fragmentation, some studies have shown that these drugs, particularly the direct dopamine agonists, cause increased nocturnal activity (van Hilten et al., 1994) as measured by polysomnography (Hogl et al., 2003) or acti-graphy (Comella et al., 2005).

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