RESUMEN
Cocaine addiction, as with other stimulant abuse, produces psychotic symptoms. Although often moderate to mild in severity, these symptoms are, nevertheless, associated with poorer over-all outcome. Recent studies suggest diminished nicotinic cholinergic neurotransmission as a mechanism of a physiological deficit found in schizophrenia, failure of auditory sensory inhibition. Diminished inhibitory sensory gating also occurs in cocaine addicts, probably because of their increased catecholaminergic neurotransmission, which blocks the inhibition. In the present study, 11 cocaine addicts in the first week of detoxification were recorded electrophysiologically, after which the effects of 6 mg of nicotine gum, were assessed in a double-blind placebo-controlled crossover design. The test was repeated 10 days later. Treatment with nicotine, but not placebo, briefly reversed the inhibitory abnormality on both test days. Although nicotine itself may not be a desirable therapeutic agent, because desensitization of nicotinic receptors limits the time course of its effect, the study identifies a previously unexploited therapeutic target for new drug development for the neuropsychiatric sequelae of cocaine addiction.
Asunto(s)
Acetilcolina/metabolismo , Encéfalo/efectos de los fármacos , Trastornos Relacionados con Cocaína/complicaciones , Trastornos de la Audición/etiología , Inhibición Neural/fisiología , Nicotina/administración & dosificación , Receptores Nicotínicos/efectos de los fármacos , Adulto , Percepción Auditiva/efectos de los fármacos , Percepción Auditiva/fisiología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Cocaína/efectos adversos , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Trastornos Relacionados con Cocaína/fisiopatología , Estudios Cruzados , Potenciales Evocados Auditivos/efectos de los fármacos , Potenciales Evocados Auditivos/fisiología , Femenino , Alucinaciones/inducido químicamente , Alucinaciones/tratamiento farmacológico , Alucinaciones/fisiopatología , Trastornos de la Audición/tratamiento farmacológico , Trastornos de la Audición/fisiopatología , Humanos , Masculino , Inhibición Neural/efectos de los fármacos , Pruebas Neuropsicológicas , Nicotina/efectos adversos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/etiología , Trastornos Psicóticos/fisiopatología , Receptores Nicotínicos/metabolismoRESUMEN
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and schizophrenia are both conceptualized as disorders of attention. Failure to inhibit the P50 auditory event-evoked response, extensively studied in schizophrenia, could also occur in ADHD patients, if these two illnesses have common underlying neurobiological substrates. METHODS: This study examined the inhibition of the P50 auditory event-evoked potential in 16 unmedicated adults with ADHD, 16 schizophrenic outpatients, and 16 normal control subjects. Auditory stimuli were presented in a paired stimulus, conditioning-testing paradigm. RESULTS: The amplitude of initial or conditioning P50 response did not differ between the three groups; however, significant effects of psychiatric diagnosis on the amplitude of the test response and the ratio of the test to the conditioning response amplitudes were observed. Schizophrenic patients' P50 ratios and test amplitudes were higher than both the ADHD and normal groups. CONCLUSIONS: Adults with ADHD do not have the inhibitory deficit seen in patients with schizophrenia, suggesting that the mechanism of attentional disturbance in the two illnesses may be fundamentally different.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Potenciales Evocados Auditivos , Esquizofrenia/fisiopatología , Adulto , Atención , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Inhibición Neural , Nicotina/farmacologíaRESUMEN
Traumatic brain injury (TBI) can produce persistent attention and memory impairment that may in part be produced by impaired auditory sensory gating. The P50 evoked waveform response to paired auditory stimuli appears to be a useful measure of auditory gating. The first controlled measurement of the P50 ratio in TBI patients is described: when 20 patients with persistently symptomatic TBI were compared with 20 control subjects, the P50 ratio was significantly greater in the TBI group. The potential neurophysiologic and therapeutic implications of this finding in TBI patients who report symptoms consistent with impaired auditory gating are discussed.
Asunto(s)
Atención/fisiología , Lesión Encefálica Crónica/fisiopatología , Potenciales Evocados Auditivos/fisiología , Adulto , Lesión Encefálica Crónica/diagnóstico , Corteza Cerebral/fisiopatología , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Reacción/fisiología , Valores de Referencia , Procesamiento de Señales Asistido por ComputadorRESUMEN
Traumatic brain injury (TBI) is a common occurrence, with a rate of nearly 400,000 new injuries per year. Cognitive and emotional disturbances may become persistent and disabling for many injured persons, and frequently involve symptomatic impairment in attention and memory. Impairments in attention and memory have been well characterized in TBI, and are likely related to disruption of cholinergic functioning in the hippocampus. Additionally, disturbances in this neurotransmitter system may also account for disturbances in sensory gating and discriminative attention in this population. The electroencephalographic P50 waveform of the evoked response to paired auditory stimuli may provide a physiologic market of impaired sensory gating among TBI survivors. The first application of this recording assessment to the TBI population is reported. Preliminary findings in three cases are presented, and the interpretation of impaired sensory gating in this population is discussed. Given the impact of TBI on cholinergic systems, the effects of cholinergic augmentation on attention and memory impairment, and the availability of an electrophysiologic marker of cholinergic dysfunction responsive to cholinergic agents, a testable cholinergic hypothesis for investigation and treatment of these patients is proposed.
Asunto(s)
Atención/fisiología , Lesiones Encefálicas/fisiopatología , Fibras Colinérgicas/fisiología , Trastornos del Conocimiento/fisiopatología , Trastornos de la Memoria/fisiopatología , Umbral Sensorial/fisiología , Acetilcolina/farmacología , Acetilcolina/uso terapéutico , Adulto , Atención/efectos de los fármacos , Biomarcadores , Lesiones Encefálicas/complicaciones , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Discriminación en Psicología/fisiología , Emociones/fisiología , Potenciales Evocados Auditivos/fisiología , Femenino , Hipocampo/fisiopatología , Humanos , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Receptores Colinérgicos/fisiología , Volición/fisiologíaRESUMEN
Schizophrenic patients have decreased inhibition of the P50 auditory evoked potential response to the second of two paired click stimuli delivered 500 ms apart. This deficit in inhibitory gating does not change during treatment with typical neuroleptics. We recently reported that neuroleptic-resistant schizophrenics had enhanced P50 gating after 1 month of clozapine treatment, if they responded with decreased clinical symptoms. This study reports the outcome of more prolonged treatment. Ten treatment-refractory schizophrenic patients were studied at baseline, after 1 month on clozapine, and again after 15 +/- 6.1 (SD) months of clozapine treatment. Eight subjects reached a clinically stable improved state, at which time they had significantly improved P50 auditory gating. One patient had a return of impaired gating after stopping clozapine, as did another during a clinical relapse. Decreasing plasma 3-methoxy-4-hydroxyphenylglycol levels with clozapine treatment were correlated with improved P50 gating and improved Brief Bsychiatric Rating Scale-positive scores. This study provides further evidence that improved P50 gating in schizophrenic patients treated with clozapine coincides with clinical improvement and that this improvement can be sustained for at least 1 year.
Asunto(s)
Antipsicóticos/uso terapéutico , Clozapina/uso terapéutico , Potenciales Evocados Auditivos/fisiología , Metoxihidroxifenilglicol/sangre , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Adulto , Electroencefalografía/efectos de los fármacos , Femenino , Ácido Homovanílico/sangre , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Psicología del EsquizofrénicoRESUMEN
BACKGROUND: Altered sensory response is a prominent feature of schizophrenia. Inhibitory gatting mechanisms, shown by diminished P50 evoked responses to repeated auditory stimuli, seem to be deficient in schizophrenic persons. These inhibitory mechanisms usually are studied by averaging the electroencephalographic responses to many presentations of pairs of stimuli. Although averaging increases signal-to-noise ratio, it may obscure trial-to-trial differences. We compared differences between schizophrenic and normal persons in single trials and averages of P50 response. METHODS: Recordings from 10 schizophrenic patients and 10 normal subjects were analyzed using conventional averaging and single-trial measurements. A computer simulation of both methods examined their ability to extract evoked responses from background activity. Related single-neuron activity in the hippocampus in an animal model also was studied, because neuronal action potentials can be reliably identified in single trials. RESULTS: Averaged evoked potentials showed significant suppression of the P50 response to the second stimulus of the pair in normal patients, but not in schizophrenic patients. Single-trial analysis did not detect a response above background activity. Computer simulations gave similar results, suggesting that failure to detect suppression in single trials comes from inadequate differentiation of signal from noise. Recordings in animals confirmed almost complete suppression of the response of hippocampal pyramidal neurons to the second stimulus. CONCLUSIONS: The normal inhibition of response to repeated auditory stimuli seems to be compromised in schizophrenia. This loss of inhibitory gating could reflect a physiological deficit of hippocampal interneurons that is consonant with other evidence for interneuron pathologic defects in schizophrenia.
Asunto(s)
Electroencefalografía , Potenciales Evocados Auditivos , Inhibición Neural , Esquizofrenia/diagnóstico , Estimulación Acústica , Potenciales de Acción , Adulto , Animales , Simulación por Computador , Condicionamiento Psicológico/fisiología , Femenino , Hipocampo/fisiología , Humanos , Masculino , Persona de Mediana Edad , Inhibición Neural/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción , Esquizofrenia/fisiopatologíaRESUMEN
Schizophrenia may result from the concerted action of several pathophysiological factors. This pilot study compared the distribution of measurements of three such putative factors in 11 schizophrenics and their siblings: a neurophysiological deficit in auditory sensory gating, diminished hippocampal volume, and increased catecholamine metabolism. Abnormal auditory sensory gating was found in all schizophrenics in the 11 families studied and in 8 of their 20 siblings. Compared with the schizophrenics, the clinically unaffected siblings with abnormal auditory gating had larger hippocampal volume. There was no similar difference for the siblings with normal gating. The siblings with abnormal auditory gating also had lower homovanillic acid levels than the other siblings. The data suggest that a familial neuronal deficit, identified by diminished sensory gating, may be a necessary, but not sufficient factor in the pathogenesis of schizophrenia. Individuals with this deficit are generally clinically unaffected, except for schizophrenics, who also have other abnormalities, such as diminished hippocampal volume and increased catecholamine metabolism.
Asunto(s)
Nivel de Alerta/fisiología , Atención/fisiología , Catecolaminas/sangre , Potenciales Evocados Auditivos/fisiología , Habituación Psicofisiológica/fisiología , Hipocampo/fisiopatología , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Estimulación Acústica , Adulto , Amígdala del Cerebelo/patología , Amígdala del Cerebelo/fisiopatología , Nivel de Alerta/genética , Enfermedad Crónica , Dopamina/fisiología , Potenciales Evocados Auditivos/genética , Femenino , Habituación Psicofisiológica/genética , Hipocampo/patología , Ácido Homovanílico/sangre , Humanos , Imagen por Resonancia Magnética , Masculino , Metoxihidroxifenilglicol/sangre , Inhibición Neural/genética , Inhibición Neural/fisiología , Escalas de Valoración Psiquiátrica , Esquizofrenia/genética , Ácido Vanilmandélico/sangreRESUMEN
Because the clinical diagnosis of schizophrenia has not generally been an adequate phenotypic marker to detect the genes that convey risk for schizophrenia, efforts have been directed toward the identification of more elementary neuronal dysfunctions in schizophrenic patients and their families. Psychophysiological studies of sensory gating and selective attention suggest that defects in these brain functions are present in schizophrenic patients and some of their relatives. This study examines one of these defects in sensory gating, failure to suppress the P50 evoked response to repeated auditory stimuli. Six pedigrees, chosen because of the presence of large sibships containing several cases of schizophrenia, were studied. A mathematical model was developed to assess the familial association of the P50 defect with schizophrenia. The model preserves the quantitative nature of the data and is suitable for use in a sample with small numbers of pedigrees comprising many individuals. It is thus suitable for the evaluation of putative phenotypes in families to be studied by linkage analysis with polymorphic genetic markers. The results suggest that the P50 defect is familially associated with schizophrenia.
Asunto(s)
Nivel de Alerta/genética , Atención , Potenciales Evocados Auditivos/genética , Esquizofrenia/genética , Psicología del Esquizofrénico , Adulto , Humanos , Linaje , Fenotipo , Escalas de Valoración Psiquiátrica , Esquizofrenia/diagnósticoRESUMEN
The differences between schizophrenic patients with positive and negative symptoms have been the subject of extensive investigations. Psychophysiologists have proposed that there are elementary auditory sensory processing deficits in schizophrenia, but their prevalence in particular positive or negative subtypes has not been described. Our previous studies have shown that schizophrenics have impaired auditory sensory gating relative to normal controls, as demonstrated by the P50 auditory evoked potential conditioning-testing paradigm. In this paradigm, schizophrenics fail to show the normally expected diminished response to the second or 'test' stimulus. In the present study we assessed the possible relationship of this defect to negative symptoms in 20 schizophrenic patients treated with neuroleptics. Nine patients met the Andreasen criteria for predominantly 'negative schizophrenia'. 12 normal controls with no family history of schizophrenia were also studied electrophysiologically. Negative schizophrenics showed greater impairment than patients without such symptoms on the Trails B test of organic impairment, but there were no differences between groups on electrophysiological measurements of auditory sensory gating. Both schizophrenic groups showed impaired P50 auditory gating compared to normal controls. Both groups of schizophrenics also had a significantly diminished amplitude of the N100 waveform in the conditioning response, compared to normal controls. Auditory sensory processing defects in schizophrenia appear to be independent of negative symptoms.