Electroencephalographic photic driving in patients with schizophrenia and depression.
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Biomedical subjects
Publications and source records attributed to C A Sandman.
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Apparent insensitivity to pain, ritualistic patterns of behavior, and improvement in symptoms after administration of opiate receptor blockers implicated the endogenous opioid system in the initiation and maintenance of SIB. This study was designed to determine whether plasma levels of proopiomelanocortin (POMC)-derived peptides, beta-endorphin-like activity (beta E), ACTH, and adrenal cortisol immediately after an episode of SIB predicted subsequent response to an opiate blocker. Blood samples were collected from 10 patients with mental retardation within minutes of a self-injuring act and during an SIB-free control period. On another day, morning and afternoon samples were collected at least one week apart from the other samples. Effects on SIB of naltrexone hydrochloride (NTX) were examined in a double-blind, placebo-controlled crossover study. After an SIB episode, beta E, but not ACTH, was elevated compared with morning levels, p < .003. Patients with increased plasma levels of beta E after SIB had the most positive response to 2 mg/kg NTX, p < .03. Results suggest that changes in the hypothalamic-pituitary-adrenal axis after SIB may predict differences in individual patient response to opiate blockers.
Few studies of human fetal habituation have included dishabituation procedures (i.e., assessment of the reemergence of a habituated response) to determine if response decrements are the result of reevaluation of information (a brain process) or fatigue of peripheral receptors. The purpose of this study is to describe the ability of the human fetus to learn and recall information with procedures to assess the central nervous system. Fetal heart rate (FHR) of 84 fetuses between 30 and 32 weeks gestational age was examined in response to 3 series of vibroacoustic (VA) stimuli presented at pseudorandom intervals of 25-45 s over the head of the fetus. Responses to the first series of 15 stimuli (S1) were compared with an identical second series of 15 stimuli (S1) presented over the head of the fetus. Between the 2 series, a novel (dishabituating) VA stimulus (S2) was presented, differing from S1 in intensity and frequency. The third series of S1s was applied to the mother's thigh as a control for possible maternal responses to the stimulus. Prestimulus FHR was computed during a 5 s interval before each stimulus, and mean FHR was computed during the intertrial interval (average FHR). The response to S1 during the first series of trials (1-15) produced a sustained rise in both prestimulus and average FHR, r(83) = .90, p < .001. After the novel S2 (trial 16) the rate of change was attenuated for average FHR, r(83) = .12, ns, to S1 for trials 17-31 but not prestimulus FHR, r(83) = .50, p < .001. The decrease in FHR response was reestablished when stimulation was applied to mother's thigh, trials 32-41, r(83) = .92, p < .001. A significant habituation pattern across trials was observed for the first series of S1s when prestimulus HR was subtracted from each preceding average FHR value (delta FHR). After the single novel stimulus (S2), the FHR response to S1 reemerged. All combinations of beginning and ending series slopes were compared, and only the rate of change during the last 4 trials of the initial presentation of S1 and the first 4 trials after the novel stimulus was significant, F(1, 82) = 9.21, p < .003. Uterine contractions collected from the continuous record were not related to the presentation of the novel stimulus, chi 2(1, N = 84) = 0.59, p < .50, ns, or delta FHR slope after the novel stimulus, chi 2(9, N = 84) = 10.52, p < .50, ns. These results established that the 32 week human fetus is capable of detecting, habituating, and dishabituating to an external stimulus and support the premise that areas of the human fetal central nervous system critical for detecting and discriminating information and for learning and memory have developed by the early third trimester.
Central nervous system (CNS) inhibitory mechanisms hypothesized to "gate" repetitive sensory inputs have been implicated in the pathology of schizophrenia. The present study investigated gender differences in inhibitory gating of evoked brain responses to repeated stimuli in normal subjects (30 women and 30 men) using an auditory conditioning-testing paradigm. Pairs of click stimuli (S1 and S2) were presented with a 0.5 s intrapair and a 10 s interpair interval. The amplitudes and latencies of the P50, N100, P180 components of the auditory evoked response to the conditioning (S1) and test response (S2) were measured, and the gating ratios were computed (T/C ratio = S2/S1 * 100). The amplitudes to S1 were not significantly different between men and women at P50, N100, or P180. However, women had significantly higher amplitudes to S2 at P50 (p = 0.03) and N100 (p = 0.04). The T/C ratios for women were higher (i.e., less suppression of response to S2) for P50 (p = 0.08) and N100 (p = 0.04) compared to men. The results suggested that differences in auditory gating between men and women were not due to biological differences in the P50 and N100 generators but possibly to differential influence of inhibitory mechanisms acting on the generator substrates of these evoked responses.
OBJECTIVES: To determine whether diabetes is rare in Alzheimer disease (AD) relative to other types of dementia and whether diabetics with dementia have a low frequency of the Apolipoprotein-E E4 genotype. DESIGN: Observational survey study. SETTING: An Irvine, California, outpatient dementia assessment center. PARTICIPANTS: A total of 123 patients with AD, 51 with vascular dementia, 57 with "mixed" vascular dementia and AD, and 34 with "other" dementias (non-vascular non-AD). MEASUREMENTS: Demographic data; histories and evidence of diabetes, hypertension, heart disease, stroke; and Apolipoprotein-E genotype for 95 cases distributed across the groups. RESULTS: There were 15 diabetics in the sample (5.7%), all of whom had extensive vascular disease. Diabetes was rare in AD patients (0.8%) relative to vascular dementia (11.8%), mixed vascular/AD dementia (8.8%), and "other" dementia patients (8.8%). In addition, the E4 allele of apolipoprotein-E, associated with high risk for AD, was frequent in the AD group (71.4%), but in the diabetic group it was only as frequent as in the general population (38.5%). In the diabetics with E4, 60% (3/5) had mixed dementia. CONCLUSIONS: Diabetics with dementia rarely have AD except as a component of mixed dementia. Apo-E genotyping showed only average E4 allele frequency in diabetics compared with the high E4 frequency found in AD patients. However, mixed dementia in diabetics may be associated with the E4 allele, suggesting that close control of diabetes may be particularly important for those with E4 since they may be more likely than others to develop both diseases.
NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex. Levels of mRNA for the NR2C subunit were very low overall. By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate. Significant alterations in the schizophrenic cohort were confined to the prefrontal cortex. Here there was a shift in the relative proportions of mRNAs for the NR2 subunit family, with a 53% relative increase in expression of the NR2D subunit mRNA. No comparable changes were found in neuroleptic-treated or untreated controls. These findings indicate regional heterogeneity of NMDA receptor subunit expression in human cerebral and cerebellar cortex. In schizophrenics, the alterations in expression of NR2 subunit mRNA in prefrontal cortex are potential indicators of deficits in NMDA receptor-mediated neurotransmission accompanying functional hypoactivity of the frontal lobes.
In a prospective study, third trimester plasma levels of BE and ACTH were determined in 58 women who delivered vaginally. Peptide regulation was compared between subjects who used conduction anesthesia at delivery and subjects who did not. Third trimester levels of maternal BE and ACTH were significantly related; however, the relationship was significant only in subjects who did not receive conduction anesthesia (n = 24) at delivery. The normal co-release pattern between BE and ACTH in subjects receiving conduction anesthesia (n = 34) during birth was uncoupled. The use of conduction analgesia during vaginal delivery was significantly related to a disregulation index created to quantify the BE-ACTH release pattern. Uncoupled ACTH and BE patterns may result from modified control of pro-opiomelanocortin (POMC) expression during pregnancy or unique proteolytic processing of POMC, and may alter pain tolerance during delivery.
In a 19-channel EEG photic driving paradigm the steady-state evoked response was studied in schizophrenic patients and normal controls. Seventeen drug-free patients and 15 normal controls were compared. Schizophrenic patients had lower EEG photic driving in the alpha range, particularly in the high alpha frequency band (p = 0.08). Topographic analysis revealed that the group differences were primarily located in the mid-frontal, central and parietal areas (p < 0.05). Temporal and lateral frontal lobe alpha remained the same in the two groups. Separate analysis of eye movement (EM) showed an opposite effect on the alpha-frequency photic driving as compared to that on the resting alpha EEG. EM decreased the resting alpha EEG and increased the photic driving. This finding suggested that the lower EEG photic driving in the schizophrenic patients could not be explained by the eye movement artifact. We hypothesize that the 10 Hz range photic driving that reflects the intrinsic EEG spindle generation in the thalamus may play an important role in the psychophysiology of schizophrenia.
Three groups representing different phases of the developmental lifecycle--12 senior citizens, 67 young adults, and 14 healthy middle-aged normal adults--were assessed using a multidimensional control inventory. Senior citizens had a healthy over-all sense of control comparable to those of the other two groups and a significantly lower (healthier) negative sense of control. They also were significantly more likely to endorse acceptance as a way of addressing areas of concern and to complement self as a source of control with a sense of control coming from others (including God, belief in a higher power).
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Elevated blood levels of beta-endorphin have been associated with high-intensity exertion, but the stimulus for beta-endorphin release is unknown. Some studies of exercise have associated beta-endorphin release with increased exertion levels, but other evidence suggests that acidosis may stimulate the release of beta-endorphin. This study examines acidosis as a possible stimulus for beta-endorphin release by examining the effects of arterial blood gases, whole blood lactate, and respiratory changes on beta-endorphin levels and by examining the effects of buffering during exercise on these levels. Initially, seven healthy adult males were evaluated during incremental exercise. During incremental exertion, indicators of acidosis correlated with endorphin levels: pH (r = -0.94), PCO2 (r = -0.85), HCO3- (r = -0.88), base excess (r = -0.94), and lactate (r = 0.89). A multivariate model showed that beta-endorphin levels were predicted best by the change in base excess. A time course analysis showed that beta-endorphin responses peaked postexercise and paralleled blood acid levels. Subsequently, subjects were compared after alkali loading and placebo during constant-intensity exercise at 85% of maximal exertion to determine whether acidosis is necessary for endorphin release. Treatment with a buffer, which effectively maintained pH above 7.40, significantly suppressed endorphin release (F = 3.07; P < 0.0001). The results of this study indicate that acidosis rather than any other physiological change associated with high-intensity exertion is the primary stimulus for beta-endorphin release.
Epidemiological and anatomical studies support the theory that disturbances of brain development may play a contributory role in the etiology of schizophrenia. Anatomical findings suggest that the normal pattern of neuronal migration during development of the cerebral cortex may be affected in the brains of schizophrenics, with the implication that cortical connectivity and associative function will be disrupted. In the present investigation in matched schizophrenic and control brains, we examined a particular population of neurons found in the prefrontal cortex and underlying white matter and characterized by histochemical staining for the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase. In normal brains, these neurons are found in highest numbers in the white matter immediately deep to layer VI of the cortex where they remain from the subplate, an early formed, but transitory structure that plays a key role in cortical development and connection formation. The dorsolateral prefrontal area of schizophrenics showed a significant decline in nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in the superficial white matter and in the overlying cortex but a significant increase in these neurons in white matter deeper than 3 mm from the cortex. These findings are consistent with a disturbance of the subplate during development in which the normal pattern of programmed cell death is compromised and accompanied by a defect in the normal orderly migration of neurons toward the cortical plate. These are likely to have serious consequences for the establishment of a normal pattern of cortical connections leading to a potential breakdown of frontal lobe function in schizophrenics.
OBJECTIVE: The aim was to test a model of the influence of maternal prenatal psychosocial stress on birth outcomes after controlling for biomedical risk. STUDY DESIGN: In a prospective study a sociodemographically homogeneous sample of 90 women was assessed during the third trimester with standard, reliable questionnaires that measured episodic and chronic stress, strain (response to stress), and pregnancy-related anxiety. Birth outcomes included infant birth weight, gestational age at birth, and intrapartum complications. Parity and biomedical (antepartum) risk was also coded. Bivariate and multivariate analyses were performed after controlling for the effects of biomedical risk factors. RESULTS: Independent of biomedical risk, each unit increase of prenatal life event stress (from a possible sample range of 14.7 units) was associated with a 55.03 gm decrease in infant birth weight and with a significant increase in the likelihood of low birth weight (odds ratio 1.32), and each unit increase of prenatal pregnancy anxiety (from a possible sample range of 5 units) was associated with a 3-day decrease in gestational age at birth. CONCLUSION: Independent of biomedical risk, maternal prenatal stress factors are significantly associated with infant birth weight and with gestational age at birth.
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There are no reports of an association between the menstrual cycle and self-injurious behavior (SIB) in the mentally retarded population. However, the endogenous opiate system has been implicated in both menstrual cycling and SIB. Catamenial and behavioral records of 9 women with mental retardation who exhibited SIB were analyzed for 6 months to determine the association between phases of the menstrual cycle and rates of SIB. Menstrual cycles were divided into four phases: (a) menses and early follicular phase, (b) late follicular phase, (c) early luteal phase, and (d) late luteal or premenstrual phase. Analysis showed that the highest frequency of SIB occurred in the first two phases: 43.5% during early follicular phase and 47.3% in the late follicular phase. Pairwise t and binomial expansion tests confirmed that SIB was cyclic across the menstrual cycle with Phase 1 > Phase 3, Phase 1 > Phase 4, Phase 2 > Phase 3, and Phase 2 > Phase 4. Seven of the 9 women were cyclers and manifested identical phase/SIB relations. The cyclical character of SIB may relate to changing peripheral and central endorphin and pain threshold during the cycle.
Cardiovascular phase, especially diastole, influences attention and the event-related potential (ERP) of the right hemisphere of the brain. Depression and schizophrenia are characterized by attentional deficits, unique lateralization of brain function, and deviant phase relationships of biological oscillators. In the present study, the ERP was recorded during stimulation triggered by diastole and systole in control (n = 16), depressed (n = 16), and schizophrenic (n = 9) subjects. Fifty tones were presented and subjects were instructed to count them silently. Previous findings were supported of delayed latencies and increased amplitude in depressed patients and decreased amplitudes and delayed latencies in schizophrenics. An exaggerated effect of diastole on the ERP in the right hemisphere was observed in depressed patients, however, no cardiovascular effect on the ERP was apparent in schizophrenic patients. Results suggested that heart/brain networks are tightly coupled in normal controls, perhaps "overdriven" in depressed patients, and uncoupled in schizophrenics.
Precipitous decline (terminal decline) characterizes changes in the elderly just prior to death. The neurological and temporal parameters of terminal decline are not defined. The present study compared sensitive changes in the brain event-related potential (ERP) in 7 subjects who died within 1 year of evaluation with matched controls. Cross-correlation of annual ERPs revealed disorganization within and between subjects in response to memory dependent conditions but not in response to a novel stimulus (oddball). Motor reaction time to targets was not sensitive to decline. The changes associated with impending death were restricted to decline in reliability of the ERP within 1 year of death.