Lawrence E. Adler

Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics

Diminished gating of the P50 auditory evoked response to repeated stimuli is a psychophysiological feature of schizophrenia, that is also present in many relatives of patients. Animal models of auditory sensory gating indicate that nicotinic cholinergic neurotransmission is a critical neuronal substrate. The aim of this experiment was to determine if the deficit in sensory gating could be reversed by nicotine administration. Nonsmoking relatives of schizophrenics with abnormal sensory gating were selected as subjects for this initial double-blind trial, to avoid effects of psychotropic medications that might complicate trials in schizophrenic patients themselves. Nicotine-containing gum increased P50 sensory gating to near normal levels within 30 min of administration. The effect was transient; the gating of P50 returned to baseline levels within 1 hr. There was no change observed after placebo administration. In one of the subjects, the anticholinesterase inhibitor physostigmine similarly normalized P50 gating. The results are consistent with the hypothesis that nicotinic cholinergic neurotransmission may mediate a familial psychophysiological deficit in schizophrenia.

Neurophysiological studies of sensory gating in rats: effects of amphetamine, phencyclidine, and haloperidol.

Central mechanisms of sensory gating were assessed in Sprague-Dawley rats by an evoked potential technique similar to one that we have previously used to show diminished sensory gating in psychotic patients. Middle latency (15-50 msec) auditory evoked potential responses were recorded at the skull in unanesthetized freely moving animals. Gating mechanisms were assessed in a conditioning-testing paradigm by measuring the suppression of response to a 74 dB click test stimulus following an earlier identical conditioning stimulus at 0.5-sec intervals. The rats demonstrated significant suppression of the N50 response to the second auditory stimulus. Amphetamine treatment significantly interfered with the suppression of the response to the second stimulus; haloperidol, injected after the amphetamine, returned the conditioning-testing ratio toward normal values. Phencyclidine caused a similar decrease in suppression and was similarly antagonized by haloperidol. During some periods of hyperarousal, animals showed spontaneous loss of suppression; this condition could be reversed by haloperidol treatment. These results with psychotomimetic drugs in an animal model parallel abnormalities in sensory gating previously observed in psychotic human subjects.

Auditory sensory gating in hippocampal neurons: A model system in the rat

Diminished evoked response to repeated auditory stimuli, an example of sensory gating normally present in human subjects, is often absent in schizophrenics. To examine the mechanism of the normal response and to delineate possible sites of its abnormality in psychosis, it would be desirable to reproduce the phenomenon in laboratory animals. In this study, we show that the pattern of diminished response to the second of paired auditory stimuli is found in activity recorded from the CA3 region of the hippocampus of anesthetized rats. The evoked potential recorded from this area is predominantly an N40 wave, at identical latency to the prominent negative wave recorded from the skull surface of unanesthetized rats. Similar responses were not found in other areas, including the auditory neocortex and the medial geniculate nucleus. Amphetamine, which diminished sensory gating in both animals and humans, diminished the gating of the evoked potential recorded in the hippocampus. The effect of amphetamine was reversed by haloperidol. The rat hippocampus may therefore contain neurons that can be used to study the neurobiology of sensory gating.

Neurophysiologic studies of sensory gating in schizophrenia: Comparison of auditory and visual responses

Gating of visual and auditory evoked responses was assessed in chronic schizophrenic patients treated with neuroleptic drugs. Middle latency components of the visual evoked response (N90-P130) were recorded at the occiput after flash stimulus. Possible inhibitory mechanisms of sensory gating were assessed in a conditioning-testing paradigm by measuring the change in amplitude of response to a second stimulus, relative to the response to the first stimulus. Simultaneous electrooculograms were recorded to detect contamination of recordings by eye movement. Neither schizophrenic patients nor normal control subjects demonstrated significant suppression of visual evoked responses in the conditioning-testing paradigm. These results differed markedly from similar measurements of a middle latency component of the auditory evoked response (P50) recorded using the same conditioning-testing paradigm in these subjects. Normal controls showed significant decrements of the P50 response to the second auditory stimulus (mean decrement over 80%), whereas schizophrenic patients failed to show a significant decrement (mean less than 40%). This finding for auditory evoked responses replicated previous studies of normal and schizophrenic subjects. Multiple conditioning stimuli were substituted for the single conditioning stimulus used previously in an attempt to enhance gating of auditory responses, but suppression of the P50 test response did not increase in either normal or schizophrenics.

Familial transmission of two independent saccadic abnormalities in schizophrenia

Difficulties with inhibiting inappropriate responses, i.e. disinhibition, and problems with spatial memory are both presumed to be a part of the phenotypic expression of the genetic risk for schizophrenia. Schizophrenic probands are impaired on saccadic eye movement tasks which require (a) response inhibition to prepotent stimuli and (b) generation of an accurate response to a remembered or calculated spatial location, but it is unknown how these deficits are inherited. Sixteen schizophrenic probands, their 32 parents, and two normal control groups completed a delayed oculomotor response and an antisaccade task. The parents with a positive ancestral family history for chronic psychosis (n = 8) were presumed to be more likely than their family history-negative spouses to be genetic carriers for schizophrenia. Probands and their positive family history parents had more failures of response inhibition than did normal control groups. However, it was the probands and their negative family history spouses who demonstrated impaired accuracy of the remembered- or antisaccades. Disinhibition may be closely tied to a specific genetic risk for schizophrenia. However, a second familial factor related to the maintenance or manipulation of spatial information may also contribute to the genetic risk of the full clinical disorder.

Defects in auditory sensory gating and their apparent compensation in relatives of schizophrenics.

Auditory sensory processing is defective at several stages in schizophrenics, as revealed by electrophysiological recordings. The purpose of this study was to assess the relationship between two of these defects in schizophrenics and their relatives. One defect is illustrated by the failure to gate the P50 wave of the auditory evoked potential in the conditioning-testing paradigm. In this paradigm, paired clicks are presented to the subject. Normals suppress or gate the P50 response to the second or test click. Schizophrenics fail to suppress the test response. This defect has been related to schizophrenics inability to filter out noise in their environment. A second defect is illustrated by schizophrenics lower than normal N100 wave, which has been related to failure to attend to particular features of interest in the stimulus. The question addressed in this study was whether these two defects inevitably occur together. While they do occur together in schizophrenics, even in very good prognosis, mildly ill subjects, they do not occur together in the relatives of schizophrenics. The defect in the gating of P50 occurs in half these relatives, but N100 amplitudes are not diminished. Instead, relatives with abnormal P50 gating have N100 amplitudes which are larger than normal. One interpretation of the data is that the relatives with the sensory gating defect can compensate for that defect at a subsequent stage of information processing, as demonstrated by their large amplitude N100 wave, whereas schizophrenic patients cannot.

Phencyclidine and auditory sensory gating in the hippocampus of the rat

The psychotomimetic drug 1-(1-phenylcyclohexyl) piperidine (PCP, phencyclidine) was found to cause a deficit in the gating of the response of the hippocampal neuron to repeated auditory stimuli, which is similar to a particular physiological feature observed in human psychosis. Other drugs, with sigma agonist and/or N-methyl-D-aspartate (NMDA) antagonist effects, were administered and their ability to cause a loss of auditory gating was compared to that of PCP. The rank order of effectiveness was levoxodrol > PCP and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) > N-allylnormetazocine (SKF 10047) > dexoxodrol > 3-(+/-)2-carboxypiperazine-4-yl) propyl-1-phosphonate (CPP). Further studies of two of the drugs, PCP and MK-801, showed that selective lesioning of the noradrenergic input with the neurotoxin DSP4, as well as less selective depletion of monoamines with reserpine, blocked the loss of gating. Phencyclidine, and other drugs with the same spectrum of action, most likely disrupt gating by increasing noradrenergic activity through a sigma mechanism.

The P50 auditory event–evoked potential in adult attention-deficit disorder: comparison with schizophrenia

BACKGROUNDnAttention-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.nnnMETHODSnThis 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnAdults 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.

Evidence for bilineal inheritance of physiological indicators of risk in childhood-onset schizophrenia

Childhood-onset schizophrenia is proposed to be associated with increased genetic loading compared with adult-onset schizophrenia because of its earlier age of onset and generally greater severity of symptoms. Diminished suppression of P50 auditory evoked responses to repeated stimuli and elevated anticipatory saccades during smooth pursuit eye movements are markers of genetic risk that are found in members of families with schizophrenia even in the absence of the full clinical disorder and appear to be transmitted in a single gene autosomal dominant fashion. Adult-onset schizophrenia is generally associated with one parent who demonstrates abnormal P50 sensory gating and elevated anticipatory saccades and one parent who is normal on the physiologic measures (i.e., unilineal inheritance). This study investigates whether childhood-onset schizophrenia is similarly unilineal or is associated with the inheritance of genetic risk factors from both parents (i.e., bilineal inheritance). Ten childhood-onset schizophrenic probands and their parents were studied. Their P50 sensory gating and anticipatory saccades were compared with adult-onset schizophrenic probands and their parents. Bilineality, measured as physiological impairment in both parents, occurred more frequently in childhood-onset probands than in adult-onset probands for both P50 sensory gating deficits (60% versus 13%) and elevated anticipatory saccades (60 versus 0%). Additionally, childhood-onset schizophrenic probands performed more poorly than adult-onset probands on the anticipatory saccade measure. This physiological evidence suggests that childhood-onset schizophrenia may be associated with increased genetic loading because of contributions of genetic risk from both parents.

The effects of age on a smooth pursuit tracking task in adults with schizophrenia and normal subjects

BACKGROUNDnPerformance during a smooth pursuit eye movement (SPEM) task has been proposed as a marker of genetic risk for schizophrenia, although the precise component of SPEM tracking most associated with genetic risk remains undetermined. Normal adult aging is associated with deterioration on SPEM tasks; it remains unclear whether investigations of SPEM abnormalities will allow inclusion of older subjects in genetic studies. This study examines 1) the effect of normal aging on several components of SPEM performance; and 2) whether schizophrenic-normal differences found in young adults continue over a broad adult age span.nnnMETHODSnSPEM was recorded during a 16.7 degrees per sec constant velocity task in 64 normal adults, ages 18 to 79 years, and 58 schizophrenic subjects, ages 18 to 70 years.nnnRESULTSnSmooth pursuit gain, the percent of total eye movements due to catch-up saccades, the frequency of large anticipatory saccades, and the frequency of leading saccades all deteriorate with increasing age. After correction for age, schizophrenic to control differences persist on most eye movement variables with the largest effect sizes for leading saccades (1.56) and smooth pursuit gain (1.17).nnnCONCLUSIONSnThe tendency to use saccades to anticipate target motion, even in small steps (leading saccades), deserves further attention as a potential marker useful in genetic analyses.