Avi Peled

Touch feel illusion in schizophrenic patients

BACKGROUND The rubber hand illusion is a tactile sensation referred to as an alien limb. The illusion has been explained by a spurious reconciliation of visual and tactile inputs reflecting functional connectivity in the brain and was used to explore alterations of functional connectivity in schizophrenia. METHODS The rubber hand illusion was achieved when two paintbrushes simultaneously stroke the hand of the subject hidden from vision by a screen, as well as an artificial hand placed in view of the subject. The rubber hand illusion was assessed with a questionnaire affirming or denying the occurrence of the illusion. RESULTS Schizophrenic subjects felt the illusion stronger and faster then did normal control subjects. Some rubber hand illusion effects correlated with positive symptoms of schizophrenia but not with negative symptoms. CONCLUSIONS Altered functional integration of environmental inputs could constitute the basis for erroneous interpretations of reality, such as delusions and hallucinations.

Somatosensory evoked potentials during a rubber-hand illusion in schizophrenia

The rubber-hand illusion (RHI), an illusion in which tactile sensations are referred to a synthetic alien limb, is enhanced in schizophrenia patients. Somatosensory evoked responses of the illusion were compared between schizophrenia patients and normal control subjects. Schizophrenia patients had significant alterations in long latency evoked responses during the illusion. These findings support the hypothesis of alterations in associative higher-level neuronal activity in schizophrenia. The findings support previous results pointing to alterations in associative brain regions in schizophrenia.

Multiple constraint organization in the brain: a theory for schizophrenia.

Schizophrenia may be reconceptualized as disturbances in the multiple constraint organization between and within neurological subsystems in the brain. In disorganized schizophrenia the disturbances of multiple constraint organization encompass most if not all brain systems. In reality-distortion schizophrenia, auditory unimodal and their connections with heteromodal networks are primarily affected. Delusions are related to disturbances of constraints among higher transmodal systems that involve conceptual processes of ideas. Poverty symptoms of schizophrenia presumably emerge from disturbances in constraint satisfaction of the networks located at the highest levels of the hierarchy; these are the networks that connect sensation with action. The reconceptualizations proposed in this work could generate testable predictions relevant to brain research in schizophrenia and may prove useful for devising a more etiologically oriented diagnostic system for the disorder.

Fluvoxamine Augmentation of Olanzapine in Chronic Schizophrenia: Pharmacokinetic Interactions and Clinical Effects

Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metab-olite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% (p < 0.01) increase of olanzapine from 31 ± SD 15 ng/mL (week 0) to 56 ± 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed (p > 0.05). Fluvoxamine concentrations were 48 ± 26 ng/mL on week 1 and 83 ± 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications.

Functional Connectivity and Working Memory in Schizophrenia: An Eeg Study

A leading hypothesis suggests that schizophrenic patients suffer from a disconnection syndrome. A failure in functional connectivity curtails the cortical integration and network activation needed to perform working memory tasks. Simulations with neural network models also indicate that connectivity is crucial for simulation of working memory asks. Multichannel EEG correlation-coefficient estimations are considered as a reliable measurement of connectivity patterns among cortical regions. in this study EEG samples are obtained selectively at the delay epochs of a delayed response working memory task. Results of correlation-coefficient estimations indicate a lack of statistically significant changes between non-task and task conditions in frontal, certain parietal, temporal and central channels. These findings propose that schizophrenics probably “fail” to activate the neural networks of the fronto-temporal regions. These are the networks involved in computation of the working memory task. Interestingly also good performers schizophrenics failed to activate these networks suggesting that the connectivity function is more relevant to the disorder than to task performance. If distinct deficits in cortical network activations would correlate with mental disorders it would be relevant to diagnosis and treatment of psychiatric disorders.

Functional connectivity abnormalities during contextual processing in schizophrenia and in Parkinson's disease

Functional connectivity was evaluated in patients with schizophrenia (SC) and in patients with Parkinsons disease (PD) during the performance of a local contextual processing paradigm, to investigate the proposition that functional disconnection is involved with contextual processing deficits in these populations. To this end, we utilized event-related EEG signals, synchronization likelihood and graph theoretical analysis. Local context was defined as the occurrence of a predictive sequence of stimuli before the presentation of a target event. In the SC patients, we observed a decrease in path length (L) in the beta band, for the predictive sequence and for predicted and random targets, compared with controls. These abnormalities were associated with weaker frontal-temporal-parietal connections. In the PD patients we found longer L (theta band) for predicted targets, and higher cluster coefficients for both the predictive sequence (theta band) and predicted targets (alpha and theta bands), compared with controls. Detection of predicted targets was associated with weaker frontal-parietal connections in PD. No group differences were found for randomized standard stimuli in both SC and PD patients. These findings provide evidence of task-specific functional connectivity abnormalities within frontal networks during local contextual processing.

Neural correlates of local contextual processing deficits in schizophrenic patients

Deficits in processing contextual information are one of the main features of cognitive dysfunction in schizophrenia, but the neurophysiologic substrate underlying this dysfunction is poorly understood. We used ERPs to investigate local contextual processing in schizophrenic patients. Local context was defined as the occurrence of a short predictive series of stimuli occurring before delivery of a target event. Response times of predicted targets were faster in controls compared to patients. Schizophrenia patients failed to generate the P3b latency shift between predicted and random targets that was observed in controls and demonstrated a prominent reduction of the peak of an early latency context dependent positivity. The current study provides evidence of contextual processing deficits in schizophrenia patients by demonstrating alteration in the behavioral and neural correlates of local contextual processing.

Optogenetic neuronal control in schizophrenia

Schizophrenia is a serious mental disorder characterized by a heterogeneous spectrum of clinical manifestations. Schizophrenia is basically incurable. The discovery of antipsychotic medications in the late 1940s has helped control some of the symptoms but has not reversed the course of the disorder and has had limited effect on the debilitating symptoms of the illness. In recent years brain stimulation technologies have emerged in the bio-scientific scenery. Deep brain stimulation now plays an important role in the treatment of many neurological disorders, and seems promising in treating depression. Optogenetics is a new technology that offers control over neuronal activity by turning on and off distinct neuronal populations. It has a great advantage over previous brain stimulation technologies in that it is accurate and specific to the neurons intended for activation and control. There is no evidence that brain stimulation has been investigated in schizophrenia patients. This possibility was discussed in a single commentary that proposed the hippocampus and nucleus accumbence as targets for DBS in schizophrenia, however it was emphasized that the neurophysiology and neuroanatomy of schizophrenia have not been elucidated to the extent that brain stimulation can be planned. In light of new optogenetic technology time is ripe to seriously consider optional targets of intervention in the brain of schizophrenia patients. Any such target should involve neuronal circuits (1) known to be relevant for schizophrenia, (2) involved in cognitive and brain functions that are disturbed in schizophrenia, and (3) relevant to alleged neuronal network mechanisms that are presumably damaged or malfunctioning in schizophrenia. This paper reviews the relevant literature and proposes that optogenetic interventions in schizophrenia should begin in the prefrontal cortex and the Globus-Pallidus Subthalamic nuclei systems. In the protocol for the prefrontal cortex, wide-arbore and chandelier inhibitory interneurons should be targets for optogenetic intervention and in the Globus-Pallidus Subthalamic nuclei the fast spiking neurons should be targets for optogenetic intervention. These subsystems are critical modulators of neural complexity which is directly relevant to connectivity organization in the brain. Schizophrenia is described as a disturbance of connectivity organization in the brain treatable by the relevant optogenetic interventions promoted in this paper.

Transcranial Magnetic Stimulation in a Finger-tapping Task Separates Motor from Timing Mechanisms and Induces Frequency Doubling

We study the interplay between motor programs and their timing in the brain by using precise pulses of transcranial magnetic stimulation (TMS) applied to the primary motor cortex. The movement of the finger performing a tapping task is periodically perturbed in synchronization with a metronome. TMS perturbation can profoundly affect both the finger trajectory and its kinematics, but the tapping accuracy itself is surprisingly not affected. The motion of the finger during the TMS perturbation can be categorized into two abnormal behaviors that subjects were unaware of: a doubling of the frequency of the tap and a stalling of the finger for half the period. More stalls occurred as the tapping frequency increased. In addition, an enhancement of the velocity of the finger on its way up was observed. We conclude that the timing process involved in controlling the tapping movement is separate from the motor processes in charge of execution of the motor commands. We speculate that the TMS is causing a release of the motor plan ahead of time into activation mode. The observed doubles and stalls are then the result of an indirect interaction in the brain, making use of an existing motor plan to correct the preactivation and obtain the temporal goal of keeping the beat.

Simulation of cognitive disturbances by a dynamic threshold semantic neural network

A neural network model with dynamic thresholds, asymmetric connections, and clustered memories simulates spread activation that is hypothesized for semantic networks in the brain. By altering the parameters of the dynamic threshold a large range of disturbances can be generated in the model. These disturbances show metaphorical resemblance to certain general clinical descriptions of mental disturbances found in psychiatric patients engaged in various cognitive tasks. Even though the model is highly theoretical and metaphoric, it may help to gain certain insights into the relation between alterations of certain neural parameters, for example, thresholds and connectivity, and clinical symptoms in patients.