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.     

Cognitive outcomes after deep brain stimulation for Parkinson's disease: a review of initial studies and recommendations for future research

Modern ablative surgery for movement disorders probably results in less frequent and severe cognitive morbidity than seen in early surgical series. Nonetheless, recent studies indicate that neurobehavioral functions commonly compromised in Parkinson's disease (PD) (e.g., executive functions, verbal fluency, and memory) are negatively impacted in some patients by lesion placement. The potential reversibility of cognitive dysfunction after chronic electrical deep brain stimulation (DBS) for PD has lead some to favor this treatment modality over ablation. This paper reviews the initial studies of the cognitive effects of thalamic, pallidal, and subthalamic DBS. These studies suggest that DBS is relatively safe from a cognitive standpoint and that the benefits of motor improvements probably outweigh the cost of minimal cognitive morbidity. This conclusion must be offered with caution, however, given the small numbers of studies to date and their methodological limitations. Neurobehavioral research has yet to adequately address (1) outcome relative to appropriate control groups; (2) effects of electrode placement versus stimulation; (3) laterality- and site-specific effects of DBS; (4) long-term effects of DBS; (5) effects of stimulation parameters; (6) risk factors for cognitive dysfunction with DBS; (7) whether cognitive dysfunction associated with DBS is reversible; and (8) comparative neurobehavioral outcome after DBS and ablation. DBS affords an exciting opportunity to clarify the neurobehavioral role of the basal ganglia.     

Should DBS for Psychiatric Disorders be Considered a Form of Psychosurgery? Ethical and Legal Considerations

Deep brain stimulation (DBS), a surgical procedure involving the implantation of electrodes in the brain, has rekindled the medical community’s interest in psychosurgery. Whereas many researchers argue DBS is substantially different from psychosurgery, we argue psychiatric DBS—though a much more precise and refined treatment than its predecessors—is nevertheless a form of psychosurgery, which raises both old and new ethical and legal concerns that have not been given proper attention. Learning from the ethical and regulatory failures of older forms of psychosurgery can help shed light on how to address the regulatory gaps that exist currently in DBS research. To show why it is important to address the current regulatory gaps within psychiatric DBS, we draw on the motivations underlying the regulation of earlier forms of psychosurgery in the US. We begin by providing a brief history of psychosurgery and electrical brain stimulation in the US. Against this backdrop, we introduce psychiatric DBS, exploring current research and ongoing clinical trials. We then draw out the ethical and regulatory similarities between earlier forms of psychosurgery and psychiatric DBS. As we will show, the factors that motivated strict regulation of earlier psychosurgical procedures mirror concerns with psychiatric DBS today. We offer three recommendations for psychiatric DBS regulation, which echo earlier motivations for regulating psychosurgery, along with new considerations that reflect the novel technologies used in DBS.     

Lessons learned in deep brain stimulation for movement and neuropsychiatric disorders

The introduction of deep brain stimulation (DBS) as a treatment for medication-refractory essential tremor in the late 1980s revealed, for the first time, that "chronically" implanted brain hardware had the potential to modulate neurologic function with surprisingly low morbidity. Over time, the therapeutic promise of DBS has become evident in Parkinson's disease and dystonia. In some experienced centers, complex tremor disorders, such as posttraumatic Holmes tremor and the tremor of multiple sclerosis, are being increasingly targeted. More recently, other indications, including obsessive-compulsive disorder, Tourette's syndrome, major depression, and chronic pain, have been proposed. As the field has expanded, our knowledge about potential cognitive side effects of DBS has also expanded. This article reviews the current knowledge regarding the impact of stimulation of the subthalamic nucleus, globus pallidus internus, and ventralis intermedius nucleus of the thalamus on symptoms in essential tremor, Parkinson's disease, and dystonia. Also discussed are the emerging targets, what is known about the cognitive sequelae of DBS, and what has been learned about the complications and therapeutic failures.     

Neuropsychological outcome of GPi pallidotomy and GPi or STN deep brain stimulation in Parkinson's disease

This paper highlights the neuropsychological sequelae of posteroventral pallidotomy (PVP) and deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) at 3/6 months postoperatively. Results are based on our extensive experience with PVP and our preliminary observations with DBS. Patients with borderline cognitive or psychiatric functioning risk postoperative decompensation. Nonlateralizing attentional and hemisphere-specific impairments of frontostriatal cognitive functions followed unilateral PVP. "Frontal" behavioral dyscontrol was observed in approximately 25% of patients. Three cases of staged bilateral PVP suggest that premorbid factors may predict outcome, although lesion size and location are also critical. Older patients are at risk for significant cognitive and behavioral decline after bilateral STN DBS, while GPi DBS may be safer.     

Brain stimulation techniques in the treatment of obsessive-compulsive disorder: current and future directions

Recent studies on the epidemiology of obsessive-compulsive disorder (OCD) estimate 50 million patients suffer from OCD worldwide, thus making it a global problem. The treatment of OCD has changed substantially over the last 2 decades following the introduction of selective serotonin reuptake inhibitors, which provide symptom improvement in approximately 60% of patients. However, some patients remain resistant to the standard pharmacologic and behavioral treatments. Although some treatment-resistant patients respond to pharmacologic augmentations, others do not, and there is evidence that some of the most severe cases benefit from treatment with neurosurgical interventions. Besides pharmacologic, behavioral, and neurosurgical approaches, different brain stimulation methods-transcranial magnetic stimulation, deep brain stimulation, and electroconvulsive therapy-have been investigated in treatment-resistant patients with OCD. However, available data about the use of these techniques in OCD treatment are quite limited in terms of sample size and study design, given the difficulty in conducting standard blinded trials for these procedures. In addition, none of the mentioned treatments have received Food and Drug Administration approval for the treatment of OCD. Nevertheless, promising findings regarding efficacy, tolerability, and non-invasiveness and/or reversibility of these techniques have increased interest in investigating their use in treatment-resistant OCD.     

The behavioral complications of pallidal stimulation: a case report

We report a case of recurrent manic episodes associated with chronic deep brain stimulation (DBS) targeting globus pallidus (GP) in the treatment of Parkinson's disease (PD). Cardinal PD symptoms and dyskinesia improved with DBS, and neuropsychological testing found improvements in visuospatial measures associated with left DBS and in verbal memory with right DBS when compared to the patient's preoperative baseline. Under conditions of right, left, and bilateral DBS, the patient experienced bouts of mania and hypomania lasting several days at a time. Positron emission tomography (PET) with (15)O-labeled water was performed after his first manic episode under four conditions: no stimulation, right DBS, left DBS, and bilateral DBS. Although no manic switch occurred during the course of the PET study, all three DBS conditions were associated with decreases in regional flow in the left parahippocampus and hippocampus and right mid-cingulate gyrus. Increases in flow in left inferior frontal area, bilateral insula, dorsolateral prefrontal cortex, and cuneus were common to all DBS conditions. GP stimulation in PD may be associated with behavioral and cognitive effects. Distributed blood flow changes observed with pallidal DBS support a role for the pallidum in cognition and affective regulation.     

Putative common pathways in therapeutic brain stimulation for affective disorders

Brain stimulation methods in the treatment of affective disorder are electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). Clinically, ECT is considered the strongest remedy in the treatment of severe depression, especially depression with psychotic features, and in the elderly. TMS, despite positive reports, is somewhat more controversial. VNS has, so far, only been used in treatment-resistant depression with limited results. DBS may be of potential use in rare cases of treatment-resistant cases of affective disorder. This article highlights the similarities and differences between the four stimulation methods. The main difference is the seizures necessary in ECT. A stronger involvement of the hippocampus following experimental seizures compared with effects in that region induced by TMS and VNS might explain the consistent findings of the superiority of ECT in the most severe cases of affective disorder.     

Neuropsychological Sequelae of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Critical Review

Neuropsychologists are increasingly involved in surgical candidacy evaluations and postoperative neurobehavioral assessments of patients with movement disorders, most notably those with disease (PD). We review here the initial studies regarding neuropsychological outcomes of deep brain stimulation (DBS) within the subthalamic nucleus (STN) for treatment of PD. Overall, these initial investigations provide preliminary support for the cognitive and neurobehavioral safety of STN DBS. Improvements in self-reported symptoms of depression and diminished verbal fluency were the most common findings, whereas changes in global cognitive abilities, memory, attention, and frontal/executive functions were inconsistent and most often described as nominal and/or transient. The generalizability of this literature is hindered by several methodological limitations, including small samples and the absence of appropriate control participants. The clinical and theoretical implications of these initial studies are highlighted and recommendations are offered to guide future research.     

Gruppenpsychotherapie

Group therapy treatments represent a most suited treatment option for a broad spectrum of psychological disturbances in the field of psychosomatic, psychiatric and somatic diseases. For some distortions and problems group therapy is the preferential treatment: personality disorders, substance abuses, eating disorders, psychiatric and chronic somatic diseases. The broad indicational options of the group setting are widely unknown, but they certainly need careful preparations and indicational decisions.     

Epilepsy, consciousness and neurostimulation

Consciousness is often disrupted in epilepsy. This may involve altered responsiveness or changes in awareness of self and subjective experiences. Subcortical arousal systems and paralimbic fronto-parietal association cortices are thought to underpin current concepts of consciousness. The Network Inhibition Hypothesis proposes a common neuroanatomical substrate for impaired consciousness during absence, complex partial and tonic-clonic seizures. Neurostimulation in epilepsy remains in its infancy with vagal nerve stimulation (VNS) as the only firmly established technique and a series of other methods under investigation including deep brain stimulation (DBS), intracranial cortical stimulation and repetitive transcranial magnetic stimulation (rTMS). Many of these systems impact on the neural systems thought to be involved in consciousness as a continuous duty cycle although some adaptive (seizure triggered) techniques have been developed. Theoretically, fixed duty cycle neurostimulation could have profound effects on responsiveness, awareness of self and subjective experience. Animal studies suggest vagal nerve stimulation positively influences hippocampal long term potentiation. In humans, a chronic effect of increased alertness in VNS implanted subjects and acute effect on memory consolidation have been reported but convincing data on either improvements or deterioration in attention and memory is lacking. Thalamic deep brain stimulation (DBS) is perhaps the most interesting neurostimulation technique in the context of consciousness. Neither bilateral anterior or centromedian thalamic nucleus DBS seem to affect cognition. Unilateral globus pallidus internus DBS caused transient wakefulness in an anaesthetised individual. As intracranial neurostimulation, particularly thalamic DBS, becomes more established as a clinical intervention, the effects on consciousness and cognition with variations in stimulus parameters will need to be studied to understand whether these secondary effects of neurostimulation make a significant positive (or adverse) contribution to quality of life.     

Application of pharmacological fMRI to developmental psychiatric disorders

Functional magnetic resonance imaging of neural activity induced by pharmacological stimulation (phMRI) is a promising technique for revealing pathophysiology and etiology of developmental psychiatric disorders. Recent investigations of the dopaminergic system have made possible the use of phMRI as a non‐invasive assay for neurotransmitter function. This paper explores applications of phMRI for identification of neurophysiological trait‐dependent and clinical state‐dependent mechanisms that can define biologically valid diagnostic criteria for developmental psychiatric disorders. Further, applications of phMRI for investigations of neurochemical changes induced by long‐term drug exposure, alternative therapies and normal brain maturation are discussed. The paper ends by highlighting methodological challenges posed by experimental control of pharmacological stimulation that is essential for valid interpretation of phMRI results.     

Surgery for psychiatric disorders

The modern therapeutic approach to most psychiatric diseases involves a combination of well-supervised psychotherapy, pharmacotherapy, and electroconvulsive therapy. Patients who fail to adequately respond to these modern treatment methods and remain severely disabled may be considered for surgical intervention. Cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy are the most common psychosurgical procedures performed today, with response rates in the 35% to 65% range. Modern stereotactic techniques have reduced complication rates, but controversy remains regarding the optimal surgical procedure. The major psychiatric diagnostic categories that might respond to surgery include treatment-refractory major affective disorders, obsessive-compulsive disorder, and chronic anxiety states. Surgery should be considered as one part of an entire treatment plan and must be followed by an appropriate psychiatric rehabilitation program. It should only be carried out by an expert multidisciplinary team consisting of a neurologist a neurosurgeon, and a psychiatrist with experience in these disorders. Surgical intervention remains a reasonable therapeutic option for select patients with a disabling psychiatric disease and may be underutilized.     

Essentialist Biases Toward Psychiatric Disorders: Brain Disorders Are Presumed Innate

A large campaign has sought to destigmatize psychiatric disorders by disseminating the view that they are in fact brain disorders. But when psychiatric disorders are associated with neurobiological correlates, laypeople's attitudes toward patients are harsher, and the prognoses seem poorer. Here, we ask whether these misconceptions could result from the essentialist presumption that brain disorders are innate. To this end, we invited laypeople to reason about psychiatric disorders that are diagnosed by either a brain or a behavioral test that were strictly matched for their informative value. Participants viewed disorders as more likely to be innate and immutable when the diagnosis was supported by a brain test as compared to a behavioral test. These results show for the first time that people spontaneously essentialize psychiatric conditions that are linked to the brain, even when the brain probe offers no additional diagnostic or genetic information. This bias suggests that people consider the biological essence of living things as materially embodied.     

Centrally elicited aggressive behavior: A model system for the study of episodic neurobehavioral pathologies?

Studies in which the predatory-like attack of a cat upon a rat has been elicited by electrical brain stimulation have been briefly reviewed with an emphasis on the question of where within the central nervous system such brain stimulation is producing its behaviorally meaningful effects. Two opposing but by no means mutually exclusive views are considered. The first is that brain stimulation elicits this behavior pattern primarily because it affects a specific motivated behavior system that is organized discretely in the midbrain and pons. The second is that forebrain neural activity is modulated in behaviorally significant ways by brainstem stimulation, which elicits predatory-like aggressive behavior in the cat. The possibility that further research on the altered state of central nervous system activity, induced by brain stimulation which elicits aggressive behavior in the cat, may lead to a further understanding of the altered states of central nervous system activity that underlie the aggressive dyscontrol syndrome and other episodic state disorders is discussed.     

Psychiatric symptoms associated with brain tumors: a clinical enigma

Patients in psychiatric settings may present with medical conditions, such as brain tumors, which may or may not be associated with neurological symptoms. In some cases, patients may only have psychiatric symptoms, such as mood changes (depression or mania), psychotic symptoms, panic attacks, changes in personality, or memory difficulties. Brain tumors may be detected in patients at their first presentation to mental health services or sometimes in patients with well-established psychiatric diagnoses. This article presents the case of a 29-year-old woman who was treated for >4 years for posttraumatic stress disorder and borderline personality traits, who developed depressive symptoms and memory difficulties. However, she did not develop any major neurological signs or symptoms. Brain imaging showed the presence of a left thalamic tumor, later confirmed as glioblastoma multiforme. She underwent surgical treatment and radiation therapy. With this we show that in some cases, brain tumors can be neurologically silent and only present atypical psychiatric symptoms. We emphasize the need for neuroimaging studies in a patient with atypical changes in mental status, even without neurological signs or symptoms.     

Electrical Stimulation, Endorphins, and the Practice of Clinical Psychology

Recent studies have demonstrated an alternative to drug treatment for patients presenting with anxiety disorders. This new technique involves electrical stimulation of the peripheral nervous system to induce chemical changes in the brain that can support and promote healing. This method was developed in part from studies of ancient Chinese acupuncture, but it is noninvasive and does not require needles, and it does not depend on prescientific rituals or metaphysical theories. Endorphins, natural neuropeptides active in basal brain structures, act upon anxiolytic receptors. Solid evidence from fMRI and neurochemical studies show that a simple office procedure involving electrical stimulation can stimulate the expression of endorphins in the brain. Patients have demonstrated symptom relief from this simple adjunctive treatment with a concomitant reduction in dependency on psychotropic medications.     

Modulation of tremor amplitude during deep brain stimulation at different frequencies

Rest tremor was quantified in the index finger tip of 16 patients with Parkinson's disease (PD) receiving deep brain stimulation (DBS) of the ventro-intermediate nucleus (Vim) of the thalamus, the subthalamic nucleus (STN), or the internal part of the globus pallidus (GPi) while being off L-dopa for 12h. Clinically, without DBS, tremor amplitude varied from absent to high. Tremor was recorded continuously for about 5 min under three conditions of DBS repeated twice, namely, effective frequency (E), ineffective frequency (I), and no DBS (O). No changes in tremor were observed across conditions in subjects with little or no tremor. However, in subjects with moderate to large amplitude tremor, DBS decreased tremor amplitude to near normal values within a few seconds. Generally, transitions were progressive and occurred with a varying time delay. Occasionally, tremor escaped from control regardless of the stimulation condition considered. In some cases tremor amplitude in one condition appeared to depend on the preceding condition. Finally, the results were reproducible on two consecutive days. We conclude that tremor control with DBS follows specific dynamical rules, which must be compatible with the hypotheses proposed regarding the underlying mechanisms of DBS.     

Effekte regionaler Psychosomatiktherapiemodule

Psychosomatics from the perspective of medicine assumes that somatic, psychological, and social aspects must always be taken into consideration. By combining psychosomatic and psychiatric care in community psychiatric/psychosomatic networks, existing structures can be used and costs decreased due to synergies (best point of treatment). Using a 1?year pre-/postcatamnesis comparison of 106 patients, it was possible to determine the cost of the 3?week psychosomatic treatment with respect to the medical, sociotherapeutic, and psychotherapeutic treatment effects and how long it helped. Based on the results, inpatient intensive therapy of psychosomatic illnesses in regional psychiatric departments of general hospitals can be recommended as a future treatment option – taking into account that patient-related factors can predict treatment success.     

不同感觉功能对抑郁的影响及其神经机制

大脑通过视觉、听觉、嗅觉、味觉和触觉等感官通道接收来自外界的信息。不同感觉功能受损涉及抑郁发生的中枢机制,而基于不同感官通道进行适当刺激以及多感官联合干预也可能发挥显著的抑郁治疗作用。笔者以症状-脑区-机制-治疗为逻辑主线,首次系统梳理了五种主要感觉障碍人群的抑郁临床症状、抑郁神经机制以及基于感觉刺激的抗抑郁治疗。结果表明,不同感觉功能障碍对抑郁相关神经机制的影响可能表征了不同的抑郁病理,涉及神经元电活动(某些神经元放电和神经环路激活等)和神经生化改变(神经可塑性和神经发生、炎症免疫和HPA轴、神经激素和神经递质等),且主要发生在边缘系统及其附近脑区,涉及岛叶、颞叶、额叶等。因此,未来研究可聚焦于机体对不同感觉信息的提取,这将为人类抑郁的病因和治疗提供新的研究视角。