Joachim Klosterkoetter

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.

Deep brain stimulation of the nucleus accumbens and the internal capsule in therapeutically refractory Tourette-syndrome

Sirs: Tourette Syndrome (TS) is a neuropsychiatric disorder with typical onset in childhood, characterized by the chronic occurrence of motor and vocal tics. High rates of comorbidity with other psychiatric disorders, such as obsessive compulsive disorders (OCD) are to be found. OCD symptoms, which almost always accompany TS, are even discussed as constituting an integral component of the phenomenology of the disorder. Pharmacological treatment of the tics of TS centres predominantly on the use of neuroleptics. Patients with comorbid OCD can additionally benefit from clomipramine and selective serotonin reuptake inhibitors. Despite maximum dosage and combination of all known therapeutic approaches, a number of seriously affected individuals fail to experience satisfactory treatment results. In light of initially successful experimental treatment of TS using deep brain stimulation (DBS) it is hoped that this approach may, in the future, provide an alternative therapeutic option for pharmacologically refractory individuals. We report on a 26 year old male patient suffering, from puberty onwards, from a serious TS. The disorder is characterized by a broad spectrum of high-frequency simple and complex motor and vocal tics. Massive impairment is especially induced by autoaggressive and automutilative tics, as well as repetitive spitting and coprolalia. The disorder is additionally complicated by a severe OCD. The case history of the patient documents the unsuccessful administration of maximum doses and combinations of established treatments. The gravity of the disorder is substantiated by the fact that the patient has found himself in continuous in-patient psychiatric treatment since puberty. Furthermore, the patient has for the most part of this treatment period been physically restrained in order to prevent self injury. On account of this history, we considered a therapeutic trial using DBS to be indicated. Based on our experiences and the beneficial results gained in a pilot series of patients with intractable OCD and anxiety disorders [15], we selected the region of the nucleus accumbens (NA) as primary target for DBS in our patient with TS and comorbid OCD. Access and electrode trajectories were determined by a computer-supported image fusion of MRI and intraoperative CT. 3-D coordinates for localisation of the target point were as follows: 2,5 mm rostral anterior border of AC, 6,5 mm lateral of midline, 4,5 mm ventral AC. Stereotactically guided implantation of quadripolar electrodes (Medtronic 3387; Medtronic, Inc., Minneapolis, MN) was carried out under general anaesthetic. The correct positioning of these was postoperatively confirmed by means of CT and conventional x-ray procedures (pole 0,1: fundus subventricularis medialis of the nucleus accumbens; pole 2,3: anterior limb of the internal capsule). A pulse generator (Kinetra, Medtronic, Inc., Minneapolis, MN) connected to the electrodes was implanted inferior to the clavicles. During a post-operative phase of adjustment lasting a few months, the following settings appeared most effective: ()0,)1,)2,)3 anode; + case cathode; pulse width 90 ls, 130 Hz, 7 V); although these parameter settings also resulted in an extremely high energy consumption. Under application of DBS with the aforementioned parameters, the patient showed a significant reduction in both the frequency and gravity of his tics over the course of a two and half year observation period. Remission rates of 41% and 50% were found based on measurements with the Yale Global Tic Severity Scale [12] and the Modified Rush Video Rating Scale [7] respectively (Figure 1). Tics involving self injury were especially reduced and symptoms of coprolalia disapJ. Kuhn, MD (&) Æ W. Huff, MD S.-H. Lee, MD Æ J. Klosterkoetter, MD Dept. of Psychiatry and Psychotherapy University of Cologne Kerpener Strasse 62 50924 Cologne, Germany Tel.: +49-221/478-4005 E-Mail: Jens.Kuhn@uk-koeln.de

Observations on Unaided Smoking Cessation after Deep Brain Stimulation of the Nucleus Accumbens

Aims: We explore whether clinical research on deep brain stimulation (DBS) of the nucleus accumbens (NAc) to treat addiction is justified besides theoretical speculation. Methods: Since 2004, 10 patients who were also smokers were treated at the University of Cologne for Tourette’s syndrome (TS), obsessive-compulsive disorders (OCD) or anxiety disorders (AD) by DBS of the NAc. We assessed their smoking behavior after DBS and (in retrospection) before by the Fagerström Test for Nicotine Dependence (FTND) and additional items. Results: Three male patients were able to quit smoking after DBS. They were less dependent and higher motivated compared to the rest of the sample. They are stimulated with a higher voltage. During 1-year, 2-year, and 30-month follow-ups, we found a higher rate of successful smoking cessation (20, 30 and 30%) compared to unaided smoking cessation in the general population (13, 19 and 8.7%). Conclusions: Albeit the results of the study are severely limited by the method of retrospective self-assessment of psychiatric patients, further research of DBS of the NAc to treat addiction seems justified. In addition to biological mediators, psychosocial factors should be assessed in further prospective studies.

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 patients 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.

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.

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.

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.

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).

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.

P03-156 Oxcarbazepine as an adjunct of antipsychotic therapy in acute schizophrenia: A double-blind, randomised placebo-controlled clinical trial

The outcome in treatment of schizophrenia is still not satisfactorily, and using the adjunctive administration of various anticonvulsant drugs adjunctive to antipsychotics has become widely distributed. This study determines the efficacy of oxcarbazepine combined to olanzapine in treatment of schizophrenia in a double-blind, randomized, placebo-controlled, parallel-group, add-on therapy, 7 week study in 54 patients suffering schizophreniform disorder or schizophrenia. Patients were randomized to oxcarbazepine or placebo and titrated up to 1800 mg/ day in week 1 and maintained at that dose for another 6 weeks. Treatment of olanzapine started at week 2 with 5 mg/day. According to weekly improvement in Brief Psychiatric Rating Scale (BPRS), olanzapine dose was maintained constant or escalated in regular steps of 2.5 mg. Main outcome measure was the cumulative olanzapine dose from beginning administration of oxcarbazepine/placebo for a period of 42 days. Comparing treatment of oxcarbazepine and olanzapine with placebo and olanzapine, there was no difference in cumulative olanzapine doses in both groups. In the oxcarbazepine group was not significantly more rescue medication given. A mixed regression model was used to assess time trends in BPRS over the treatment period: the differences in the rate of change of BPRS in the two treatment groups suggested that the scores sank more rapidly in the oxcarbazepine group (p=0.063). Mean post-treatment aggression score also showed no significant difference. Results from this study do not support the use of OXC as an adjunct to atypical antipsychotics in patients with schizophrenia.