Nashaat N. Boutros

Neuronal substrates of sensory gating within the human brain

BACKGROUND For the human brain, habituation to irrelevant sensory input is an important function whose failure is associated with behavioral disturbances. Sensory gating can be studied by recording the brains electrical responses to repeated clicks: the P50 potential is normally reduced to the second of two paired clicks but not in schizophrenia patients. To identify its neural correlates, we recorded electrical traces of sensory gating directly from the human hippocampus and neocortex. METHODS Intracranial evoked potentials were recorded using hippocampal depth electrodes and subdural strip and grid electrodes in 32 epilepsy patients undergoing invasive presurgical evaluation. RESULTS We found evidence of sensory gating only in the hippocampus, the temporo-parietal region (Brodmanns areas 22 and 2), and the prefrontal cortex (Brodmanns areas 6 and 24); however, whereas neocortical habituating responses to paired clicks were peaking around 50 msec, responses within the hippocampus proper had a latency of about 250 msec. CONCLUSIONS Consistent with data from animal studies, our findings show that the hippocampus proper contributes to sensory gating, albeit during a time window following neocortical habituation processes. Thus, sensory gating may be a multistep process, with an early phase subserved by the temporo-parietal and prefrontal cortex and a later phase mediated by the hippocampus.

Transcranial magnetic stimulation and auditory hallucinations in schizophrenia

12 patients with schizophrenia and auditory hallucinations received 1 Hz transcranial magnetic stimulation of left temporoparietial cortex. In a double-blind crossover trial, active stimulation significantly reduced hallucinations relative to sham stimulation.

A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression

BACKGROUND Multiple groups have reported on the use of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant major depression. The purpose of this study is to assess the efficacy of rTMS in unmedicated, treatment-resistant patients who meet criteria for major depression. METHODS Depressed subjects, who had failed to respond to a median of four treatment trials, were assigned in a randomized double-blind manner to receive either active (n = 10; 20 2-sec trains of 20 Hz stimulation with 58-sec intervals; delivered at 80% motor threshold with the figure-of-eight coil positioned over the left dorsolateral prefrontal cortex) or sham (n = 10; similar conditions with the coil elevated and angled 45 degrees tangentially to the scalp) rTMS. These sequences were applied during 10 consecutive weekdays. Continuous electroencephalogram sampling and daily motor threshold determinations were also obtained. RESULTS The group mean 25-item Hamilton Depression Rating Scale (HDRS) score was 37.2 (+/- 2.0 SEM) points. Adjusted mean decreases in HDRS scores were 14.0 (+/- 3.7) and 0.2 (+/- 4.1) points for the active and control groups, respectively (p <.05). One of 10 subjects receiving active treatment demonstrated a robust response (i.e., HDRS decreased from 47 to 7 points); three other patients demonstrated 40-45% decreases in HDRS scores. No patients receiving sham treatment demonstrated partial or full responses. CONCLUSIONS A 2-week course of active rTMS resulted in statistically significant but clinically modest reductions of depressive symptoms, as compared to sham rTMS in a population characterized by treatment resistance.

Sensory gating deficits during the mid-latency phase of information processing in medicated schizophrenia patients

Sensory gating during preattentive phases of information processing has been extensively examined. Sensory gating processes that occur during subsequent phases of information processing have not been fully examined. The relationship between P50 sensory gating and schizophrenia symptoms remains underspecified and the clinical correlates of N100 and P200 gating are yet to be examined. Sensory gating indices derived from the mid-latency auditory evoked responses during preattentive (P50) and attentive (N100, P200) phases of information processing were collected from schizophrenia patients who were stable and mainly being treated with atypical antipsychotic medications (n=23) and age- and gender-matched healthy control subjects (n=23). Schizophrenia patients had demonstrable habituation or sensory gating difficulties throughout the mid-latency range of information processing. Moreover, we found no correlations between P50-derived sensory gating indices and the amplitude or latency of the more attention-related P300 evoked response. A number of N100 and P200 gating measures correlated with P300 variables. Finally, we found no correlations between sensory gating indices and schizophrenia symptoms clusters. These results suggest that sensory gating is a pervasive abnormality in schizophrenia patients that is not limited to the preattentive phase of information processing. Furthermore, the data suggest that N100 and P200 gating indices may influence subsequent information processing.

Comparison of four components of sensory gating in schizophrenia and normal subjects: a preliminary report.

Dysfunction of sensory gating has been implicated in the pathophysiology of schizophrenia. The goal of this study was to provide evidence that sensory gating dysfunction in schizophrenia patients is a compounded problem with difficulty in filtering out irrelevant input and filtering in relevant input at both an early-preattentive stage and a later, early-attentive stage of information processing. Four components of sensory gating were examined in 12 medicated, stable schizophrenia patients and 12 age- and sex-matched normal control subjects. Evoked potential paradigms designed to examine the effects of stimulus repetition and stimulus change were utilized. Attenuation of the amplitude of the P50 and the N100 evoked potentials with stimulus repetition was significantly decreased in schizophrenia patients as compared to normal control subjects. The presentation of deviant stimuli caused the degree of attenuation to decrease in normal subjects. This effect was much decreased (and at times reversed) in schizophrenia subjects. These data suggest that schizophrenia patients have difficulty inhibiting incoming, irrelevant stimuli and responding to incoming, significant input as measured by preattentive EPs (P50). The data also suggest that similar abnormalities can be demonstrated at a slightly later phase of information processing (i.e. early-attentive phase) using the N100 EP.

Midlatency evoked potentials attenuation and augmentation reflect different aspects of sensory gating

A broad definition of sensory gating refers to the ability of the brain to modulate its sensitivity to incoming sensory stimuli. This definition allows the concept of gating to include both the capacities to minimize or stop responding to incoming irrelevant stimuli (gating out) and to respond when a novel stimulus is presented or a change occurs in ongoing stimuli (gating in). In order to further characterize the function of sensory gating, we examined the attenuation (decreased responding) and augmentation (increased responding) of the P50 EP amplitudes in 22 normal volunteers. Three EP paradigms, each including a number of conditions, designed to examine both EP habituation (inhibition) and dishabituation (excitation) were administered to each subject. In conditions designed to examine habituation (identical pairs of clicks or trains of repetitive identical clicks), the P50 behaved, as expected, with decrease of the amplitude with repetition. In conditions designed to examine dishabituation the amplitude of the P50, EP did not decrease as much (and frequently increased) with stimulus change. The results suggest that the P50 EP is sensitive to the effects of stimulus repetition and stimulus change and can be used to study the different aspects of sensory gating.

Phase synchronization of the ongoing EEG and auditory EP generation

OBJECTIVE We investigated the role of phase synchronization of the spontaneous electroencephalogram (EEG) in auditory evoked potential (EP) generation in a sample of healthy individuals. METHODS Auditory responses were obtained from 20 healthy subjects following a double stimulus paradigm, using two identical tone bursts (S1 and S2) separated by 0.5s. Single-trial auditory evoked potentials were decomposed into sinusoidal, exponentially decaying/increasing components using the piecewise Prony method (PPM). Pre- and post-stimulus phase histograms were compared to determine the degree of phase synchronization produced by auditory stimulation. RESULTS Analysis of single responses revealed that the S1 stimuli produced phase synchronization in the 2-8Hz frequency range, with little or no concomitant amplitude increase. A significantly reduced phase effect was seen in response to S2 stimuli. CONCLUSIONS Stimulus-induced phase synchronization of the ongoing EEG is a major mechanism for the generation of auditory EP components with a latency in the 50-250ms range. SIGNIFICANCE The fact that the EP components accessed here are generated through phase synchronization implies that the ensemble-averaged EP will not resemble the single trial response, and it would certainly be misleading to consider the single trial response as an amplitude-scaled version of the ensemble average.

Generators of the intracranial P50 response in auditory sensory gating.

Clarification of the cortical mechanisms underlying auditory sensory gating may advance our understanding of brain dysfunctions associated with schizophrenia. To this end, data from nine epilepsy patients who participated in an auditory paired-click paradigm during pre-surgical evaluation and had grids of electrodes covering temporal and frontal lobe were analyzed. A distributed source localization approach was applied to the intracranial P50 response and the Gating Difference Wave obtained by subtracting the response to the second stimuli from the response to the first stimuli. Source reconstruction of the P50 showed that the main generators of the response were localized in the temporal lobes. The analysis also suggested that the maximum neuronal activity contributing to the amplitude reduction in the P50 time range (phenomenon of auditory sensory gating) is localized at the frontal lobe. Present findings suggest that while the temporal lobe is the main generator of the P50 component, the frontal lobe seems to be a substantial contributor to the process of sensory gating as observed from scalp recordings.

Auditory verbal hallucinations and dysfunction of the neural substrates of speech

OBJECTIVE to evaluate the neural substrate of auditory verbal hallucinations (AVH), the correlation between AVH and subvocal speech (hereafter SVS), and the relationship between speech and AVH. METHOD we reviewed the papers found by an electronic literature search on hallucinations and speech. The review was extended to the papers cited in these publications and to classical works. RESULTS there is no conclusive evidence of structural abnormality of the speech perception area in hallucinating schizophrenic patients. However there is evidence of electrophysiological abnormalities of the auditory and speech perception cortices. Functional imaging data are inconsistent, yet point to the left superior temporal gyrus as one of the neural substrates for AVH. There is also evidence that SVS could accompany the experience of AVH. CONCLUSION there is evidence that dysfunction of brain areas responsible for speech generation is a fundamental mechanism for generating AVH in schizophrenia. It results in a secondary activation of Wernickes area (speech perception) and Brocas area (speech expression). The first leading to the experience of hallucinations, and the second, eventually, gives rise to a variable degree of vocal muscle activity detectable by EMG, and/or faint vocalizations detectable by sensitive microphones placed at proximity of the larynx. Direct stimulation or disease of Wernickes area produces AVH without SVS.

Test-retest reliability of the P50 mid-latency auditory evoked response

Attenuation in mid-latency auditory evoked responses (MLAERs) can be used to study sensory gating. If paired-click stimuli (S1 and S2) are used, lower amplitude in response to S2 vs. S1 (attenuation) is considered evidence for intact sensory gating. However, the need for reliable measurements of MLAER amplitude and attenuation is a recognized problem. Ten normal volunteers were studied six times each. An S1 amplitude test-retest reliability coefficient (r) of 0.585 was obtained when means of two recordings were used vs. reliability coefficients as high as 0.809 for means of six recordings. Averaging a higher number of runs (120 vs. 60) resulted in a reliability coefficient of 0.677/recording. Similar values were obtained for S1 and S2 latencies. Reliability coefficients for S2 attenuation (S2/S1) were not nearly as high (a value of 0.138 when means of all six recordings were used). The S1 amplitude as measured in this study (with 120 averages) appears to be a reliable psychophysiologic measurement, but the S2/S1 attenuation measure is more variable, perhaps reflecting a greater sensitivity of the S2/S1 to uncontrolled variables in this study. Further research to identify such variables is necessary.