Deep brain stimulation as a new therapeutic approach in therapy-resistant mental disorders: ethical aspects of investigational treatment.

Deep brain stimulation (DBS) is an established treatment option for some movement disorders, in particular Parkinson's disease. Only recently, a number of promising studies with small samples of patients have been published in which impressive therapeutic outcomes achieved by DBS in otherwise treatment-resistant obsessive-compulsive disorder, major depression, and Tourette's syndrome were reported. It seems probable that the investigational approach to treat mental disorders by DBS will increase substantially. Neurosurgical interventions in psychiatric patients raise ethical considerations not only based on the disreputable experiences of the era of psychosurgery. Therefore, it is necessary to implement transparent and well-defined regulations for the protection of the patients as well as appropriate support for therapeutic research. The current article aims to provide a synopsis of the DBS approach in mental disorders and the hitherto existing criteria for research. It suggests some additional requirements for ethically justifiable therapeutic research employing DBS in psychiatric patients.

Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation.

BACKGROUND: Dementia represents one of the most challenging health problems. Despite intense research, available therapies have thus far only achieved modest results. Deep brain stimulation (DBS) is an effective treatment option for some movement disorders and is under study for psychiatric applications. Recently, diencephalic DBS revealed selective effects on memory functions, another facet of subcortical DBS. OBJECTIVE: To report a new DBS strategy for the modification of cognitive functions in a patient with severe Parkinson-dementia syndrome. DESIGN: Prospective study with double-blinded sham stimulation period. SETTING: Departments of Stereotaxy and Functional Neurosurgery and Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. PATIENT: A 71-year-old man with slowly progressive Parkinson-dementia syndrome. Intervention We inserted 2 electrodes into the nucleus basalis of Meynert in addition to electrodes in the subthalamic nucleus. Main Outcome Measure Improvement of cognitive functions. RESULTS: Turning on the subthalamic nucleus electrodes improved motor symptoms but left cognitive performance almost unchanged. Turning on electrical stimulation of the nucleus basalis of Meynert resulted in markedly improved cognitive functions. The improvement in attention, concentration, alertness, drive, and spontaneity resulted in the patient's renewed enjoyment of former interests and enhanced social communication. CONCLUSIONS: Such a broad effect on cognition is consistent with ample experimental evidence revealing that the nucleus basalis of Meynert provides cholinergic innervation to the cortical mantle, complemented by glutaminergic and gamma-aminobutyric acid-transmitting projections from the basal forebrain. These projections provide background tuning facilitating cortical operations. Furthermore, nucleus basalis of Meynert stimulation paired with sensory stimuli can accomplish persistent reorganization of specific processing modules. The improvements in cognitive and behavioral performance in our patient are likely to be related to the effects of stimulating residual cholinergic projections and cell bodies in the nucleus basalis of Meynert.

Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?

Chronic consumption of alcohol represents one of the greatest health and socioeconomic problems worldwide. We report on a 54-year-old patient with a severe anxiety disorder and secondary depressive disorder in whom bilateral deep brain stimulation (DBS) of the nucleus accumbens was carried out. Despite the absence of desired improvement in his primary disorder, we observed a remarkable although not primarily intended alleviation of the patient's comorbid alcohol dependency. Our case report demonstrates the extremely effective treatment of alcohol dependency by means of DBS of the nucleus accumbens and may reveal new prospects in overcoming therapy resistance in dependencies in general.

Disappearance of self-aggressive behavior in a brain-injured patient after deep brain stimulation of the hypothalamus: technical case report.

OBJECTIVE: Self-mutilation is a severe symptom of diseases with varying etiologies. It can be observed in the context of mental retardation and after traumatic brain injury. Pharmacological treatment approaches often prove ineffective. CLINICAL PRESENTATION: We report the case of a 22-year-old woman with repetitive self-mutilating behavior in the mouth area after severe traumatic brain injury. RESULTS: Bilateral deep brain stimulation of the posterior hypothalamus was conducted and resulted in the complete elimination of self-mutilation during a 4-month observation period. CONCLUSION: This technical case report indicates that deep brain stimulation of the posterior hypothalamus could be a promising approach in the treatment of severe self-mutilating behavior.

Sensory gating in schizophrenia: P50 and N100 gating in antipsychotic-free subjects at risk, first-episode, and chronic patients.

BACKGROUND: Abnormal sensory gating in schizophrenia has frequently been reported; however, only limited data on unmedicated patients and patients at risk to develop a psychosis have, as yet, been available. METHODS: P50 and N100 suppression were assessed with an auditory double-click paradigm in five groups: 18 at-risk subjects who did not develop a full psychosis within the follow-up period of 2 years, 21 truly prodromal subjects who developed frank psychosis within the follow-up period, 46 antipsychotic-naïve subjects with first-episode schizophrenia, 20 antipsychotic-free subjects with chronic schizophrenia, and 46 healthy control subjects. RESULTS: P50 and N100 suppression indices differed significantly between groups and were lowest in chronic schizophrenia patients. Compared with healthy control subjects, P50 suppression was significantly impaired in at-risk subjects, truly prodromal and first-episode patients (stimulus 2 [S2]/stimulus 1 [S1] P50 amplitude ratio), and chronic schizophrenia patients (difference and ratio), and N100 suppression was significantly reduced in truly prodromal and first-episode patients (S1-S2 difference) and in chronic schizophrenia patients (difference and ratio) but not at-risk subjects. At-risk subjects with and without conversion to psychosis did not significantly differ on any test parameter. CONCLUSIONS: Sensory gating is already impaired in early stages of schizophrenia, though this is most prominent in chronic stages. Future studies will have to clarify the type and impact of variables modifying sensory gating disturbances, such as illness progression and genetic load. Furthermore, the meaning and nature of differences between P50 and N100 suppression need further elucidation.

Sensory gating revisited: relation between brain oscillations and auditory evoked potentials in schizophrenia.

Disturbances of auditory information processing have repeatedly been shown in schizophrenia. To contribute to a better understanding of the neurophysiological underpinnings of habituation in auditory processing and its disturbance in schizophrenia we used three different approaches to analyze auditory evoked responses, namely phase-locking (PL) analyses, single trial amplitudes, and averaged event-related potentials (P50 and N100). Given that brain oscillations reflect the neuronal correlates of information processing we hypothesized that PL and amplitudes reflect even more essential parts of auditory processing than the averaged ERP responses. In 32 schizophrenia patients and 32 matched controls EEG was continuously recorded using an auditory paired click paradigm. PL of the lower frequency bands (alpha and theta) was significantly reduced in patients whereas no significant differences were present in higher frequencies (gamma and beta). Alpha and theta PL and amplitudes showed a marked increase after the first click and to a minor degree after the second one. This habituation was more prominent in controls whereas in schizophrenia patients the response to both clicks differed only slightly. N100 suppression was significantly reduced in schizophrenia patients whereas no group differences were present with respect to the P50. This corresponded to the finding that gamma mostly contributed to the prediction of the P50 response and theta mostly to the N100 response. Our data showed that analyzing phase and amplitude in single trials provides more information on auditory information processing and reflects differences between schizophrenia patients and controls better than analyzing the averaged ERP responses.

Transient Manic-like Episode Following Bilateral Deep Brain Stimulation of the Nucleus Accumbens and the Internal Capsule in a Patient With Tourette Syndrome.

Objective. Deep brain stimulation (DBS) increasingly attracts attention as a potential treatment of mental disorders. Beside depression and obsessive-compulsive disorders, DBS has already been shown to be beneficial for Tourette syndrome (TS). Clinical Presentation/Method. The authors report on the outcome of a patient with treatment-resistant TS who underwent bilateral DBS of the nucleus accumbens and the internal capsule. Results. Within the 10-month follow-up, a substantial reduction of tics has been observed. Yet, as a side-effect of DBS, the patient developed a transient manic-like episode when primarily stimulated by the most proximally contact in the internal capsule. Conclusions. This case supports the hypothesis that DBS of the nucleus accumbens and the internal capsule represents an effective therapeutic alternative for otherwise treatment-resistant TS. Yet, future controlled studies are needed to determine optimal stimulation parameters and to reduce negative side-effects such as transient hypomanic episodes.

Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?

Chronic consumption of alcohol represents one of the greatest health and socioeconomic problems worldwide. We report on a 54-year-old patient with a severe anxiety disorder and secondary depressive disorder in whom bilateral deep brain stimulation (DBS) of the nucleus accumbens was carried out. Despite the absence of desired improvement in his primary disorder, we observed a remarkable although not primarily intended alleviation of the patient's comorbid alcohol dependency. Our case report demonstrates the extremely effective treatment of alcohol dependency by means of DBS of the nucleus accumbens and may reveal new prospects in overcoming therapy resistance in dependencies in general.