Neurobehavioral probes for physiologic neuroimaging studies.

The potential of physiologic neuroimaging for contributing to the understanding of behavior and the psychopathologic condition is being enhanced by increased application of "neurobehavioral probes," tasks performed during measurement. Thus far, little attention has been paid to the psychometric properties of such tasks as reliability, difficulty, and construct validity. We propose steps for applying such probes, considering issues in defining the behavior and task selection. Few available neuropsychometric tasks meet criteria for optimal use in neuroimaging studies, and a procedure is outlined for developing new probes. Highlighted are issues encountered during the phases of conceptualization, assembly and screening of items, task construction, and the psychometric validation. A set of language tasks illustrates the process. The procedure may enhance efficiency of acquiring knowledge in this area where the magnitude of potential may be matched by the costs and complexity of research.

Midlatency auditory evoked responses in schizophrenia.

The auditory evoked component P50 has been reported as having an abnormal recovery cycle in patients with schizophrenia. Recent studies examining the effects of stimulus rate on the midlatency response (MLR) component P1, found P1 recovery cycles in normals similar to P50. This study examined the P1 recovery cycle in patients using a rate protocol and MLR recording procedures. MLRs were recorded from 13 controls and 13 patients with schizophrenia in response to binaurally presented clicks presented at three stimulus rates: 0.9/sec, 5.1/sec, and 9.9/sec. The P1 (50-70 msec latency) in patients did not decrease as much in amplitude as in controls at the 9.9/sec stimulus rate. This lack of recovery was correlated with clinical ratings of symptomatology. Since evidence from both the human and the cat model suggests that the P1 is generated in thalamus, these findings are consistent with reports of thalamic dysfunction in schizophrenia.

Course of treatment response in first-episode and chronic schizophrenia.

OBJECTIVE: The timing and clinical correlates of symptom change following antipsychotic treatment were examined in first-episode and chronic schizophrenia. METHOD: The subjects were 36 first-episode schizophrenic patients who had received minimal or no neuroleptics and 34 patients with chronic illness whose neuroleptics had been withdrawn. They were followed for 2 years and assessed with the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. Treatment decisions during follow-up were made clinically by the treating physicians. RESULTS: At 6-month follow-up, both the neuroleptic-naive and previously treated patients showed significant improvement in positive symptoms (52% and 44% reductions from baseline, respectively). The previously treated but not the neuroleptic-naive patients also showed a significant reduction in negative symptoms (19% from baseline). A longer duration of illness before baseline assessment and inconsistent treatment during follow-up were independently associated with poorer treatment outcome in terms of positive symptoms in both groups. There were no significant changes on the outcome measures in either group after the 6-month follow-up. CONCLUSIONS: The results suggest that maximum symptomatic improvement occurs within the first 6 months of treatment and that disease progression may blunt treatment efficacy in both first-episode and chronic schizophrenia.

Effects of medication history on midlatency auditory evoked responses in schizophrenia.

The recovery cycle of the P1 component of the auditory evoked potential (50-70 ms latency) has been reported as abnormal in both unmedicated and medicated patients with schizophrenia when a paired stimuli protocol is used to examine recovery. However, findings have been mixed when a stimulus train protocol is used. This study examined the effects of medication history on P1 abnormalities in schizophrenia assessed by a stimulus train protocol. Auditory evoked potentials were recorded from 14 normal controls, 14 neuroleptic naive patients with schizophrenia and 14 previously medicated patients in response to binaural clicks presented at three stimulus rates: 1/s, 5/s and 10/s. Neuroleptic naive patients showed a smaller P1 at the baseline rate (1/s) and greater recovery (less amplitude suppression) at faster rates than did normal controls or previously medicated patients. Additional analyses suggested that this latter effect was not due to smaller baseline P1 amplitudes. Greater recovery in neuroleptic naive patients was not associated with clinical symptomatology contrary to previous findings of the authors for a mixed sample of neuroleptic naive and previously medicated patients. Medication status appears to account for some of the variability in P1 abnormalities in schizophrenia although identification of the underlying mechanism responsible requires further study.

P50 abnormalities in schizophrenia: relationship to clinical and neuropsychological indices of attention.

While the P50 component (50-60-ms latency) of the auditory evoked potential has been reported as abnormal in schizophrenia, few studies have examined the relationship between this abnormality and clinical or neuropsychological measures. To examine these possible relationships, mid-latency auditory evoked potentials were recorded at the CZ recording site of 47 patients with schizophrenia in response to binaural clicks presented at three stimulus rates: 1, 5 and 10/sec. A sub-sample of patients were then divided into high- (n = 15) and low-P50 abnormality (n = 16) groups based on a median split of the P50 amplitude at a rate of 10/sec (a greater amplitude at this rate suggests a greater abnormality in recovery) of the entire sample. Only those patients with complete neuropsychological and clinical data and who were reasonably matched on demographic dimensions were included. A multivariate analysis of variance of 11 neuropsychological function profile scores showed a significant group x global score interaction (Hotelling t = 3.97, p < 0.005). The high-abnormality group had relatively greater deficits for attention profile scores than for the remaining neuropsychological measures. An analysis of global subscores for SAPS and SANS clinical measures revealed a significant difference only for the SANS attention subscale (p < 0.05). The high-abnormality group was rated as more severe on the attention measure. These convergent findings across both phenomenological and neuropsychological measures suggest that abnormalities in P50 recovery may be linked to deficits in attention processes in schizophrenia.

Facial emotion discrimination: I. Task construction and behavioral findings in normal subjects.

Facial discrimination tasks (age, happy-neutral, and sad-neutral) were developed to address the need for activation tasks that engage emotional processing and can be used during physiologic neuroimaging ("neurobehavioral probes"). The stimuli pictured professional actors and actresses who had been screened for asymmetric features. In experiment I, same-sex stimuli were used to examine the performance of normal subjects (24 men, 15 women) on the three tasks. Performance was better during the emotion-discrimination tasks than during the age-discrimination task, and males had higher sensitivity scores for the detection of sad emotion. However, experiment II showed that the sex of the stimulus interacts with the sex of the subject. Compared with female subjects, male subjects (n = 10) were selectively less sensitive to sad emotion in female faces. Female subjects (n = 10) were more sensitive overall to emotional expression in male faces than in female faces. Thus, men and women differed in performance depending on the sex of the facial stimulus.

Facial emotion discrimination: III. Behavioral findings in schizophrenia.

Emotional discrimination was studied in patients with schizophrenia (n = 20) and matched controls. Performance of the emotion-discrimination tasks in the schizophrenic patients was impaired, relative to their performance of an age-discrimination task. Performance patterns in the patient group could also be reliably distinguished from those of normal controls. The impairment was associated with the severity of both emotional and nonemotional symptoms specific to schizophrenia, but not with the severity of nonspecific symptoms. The deficit associated with schizophrenia is more marked than that reported for depression (Gur et al., 1992), particularly for the emotion-discrimination tasks, and showed no difference between "happy" discrimination and "sad" discrimination. The main difficulty in patients with schizophrenia is the assignment of emotional valence to neutral faces. The magnitude of the deficit underscores the salience of emotional impairment in schizophrenia, and its relation to cognitive dysfunction in this disorder merits further scrutiny.

Facial emotion discrimination: II. Behavioral findings in depression.

The facial discrimination tasks described in part I (Erwin et al., 1992) were administered to a sample of 14 patients with depression and 14 normal controls matched for sex (12 women, 2 men) and balanced for age and sociodemographic characteristics. Patients performed more poorly on measures of sensitivity for happy discrimination and specificity for sad discrimination, and had a higher negative bias across tasks. Severity of negative affect was correlated with poorer performance for patients. The results suggest that depression is associated with an impaired ability to recognize facial displays of emotion.

Event-related potential indices of ambiguous sentence processing.

An event-related potential (ERP) probe was used to examine various models of ambiguous sentence processing. ERPs to light flashes were recorded during and immediately after auditorily presented ambiguous and unambiguous target sentences. Each target sentence was preceded by either a relevant or a neutral context sentence. Principal component analyses of the ERPs indicated that although certain components varied as a function of ambiguity, none of the components varied as a function of preceding context. These findings provided some support for a postdecision model of ambiguity processing which suggests that both meanings of an ambiguity are always processed, even when prior disambiguating context is available.

Influence of language structure on brain-behavior development.

Lack of exposure to specific sensory patterns during critical periods of development can result in a lack of responsiveness to those stimuli in adulthood. The present study extends these observations to native speakers of Japanese, a language which does not contain the contrastive /r/ and /l/ sounds present in English. Both electrophysiological (P3 event-related evoked potential) and behavioral results indicate deficient or absent discrimination of /r/ versus /l/ sounds in Japanese adults compared to native speakers of English. Thus, language structure appears to provide a subtle yet measurable effect on specific aspects of brain development and function.

Relation of angiographically defined coronary artery disease to serum lipoprotein levels.

The relationship of coronary artery disease to plasma lipoproteins was examined in 43 men admitted to our unit with suspected ischemic heart disease. Coronary arteriography was performed, and a score reflecting the severity of disease was assigned to the angiogram. Plasma, obtained after a 12-h overnight fast, was assayed for triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, and HDL-3 cholesterol. HDL-2 cholesterol was found by subtraction. The cholesterol contents of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) were quantitated by the Freidwald equation. Men with high coronary scores tended to be older, and subjects with moderate coronary disease had significantly higher total and LDL cholesterol values than those with minimal disease. Age was the only factor to be significantly associated with coronary score and there was no significant association between coronary score and total LDL and HDL cholesterol or its subfractions when the age factor was taken into account.

The effect of food and water deprivation and satiation on recognition.

Food and water deprived and satiated subjects, as well as control subjects, were shown words presented tachistoscopically for .01 sec until word recognition. Five food-relevant, five water-relevant, and five neutral (animal) words of high string frequency were matched for letter confusability and letter predictability. Analyses of the data, in terms of number of presentations until recognition as well as number of words recognized at selected presentations, revealed that the amount but not the type of deprivation significantly altered word recognition. Moreover, the effect of motivation was significant already on the first slide presentation, while the effects of word characteristics (word category and generated value) occurred only after a number of presentations.

Midlatency auditory evoked responses: differential recovery cycle characteristics.

Middle latency responses (MLRs), in the 10-100 msec latency range evoked by click stimuli, were examined in two sets of 7 adult subjects utilizing 5 randomly ordered rates of stimulus presentation: 0.5/sec, 1/sec, 5/sec, 8/sec and 10/sec. Evoked potentials were collected in 250 trial averages for each rate, and a replication across rates yielded 500 trial averages. Peak-to-peak measurements for Pa-Nb and P1-Nb components revealed that the P1 component was reduced in amplitude or absent at the faster rates, while the amplitude of the Pa component remained unchanged across rates. In addition, the latency of Pa was significantly longer for the faster rates of stimulation. These findings were similar across both mastoid and sternovertebral references. Taken together with previous work, these data suggest that the human Pa and P1 potentials reflect different generator systems. Moreover, the physiological similarities between the human P1 potential and the cat wave A suggest that in the human, as in the cat, this potential may be generated within the ascending reticular activating system, whereas the physiological similarities between the human Pa and the cat wave 7, as well as previous clinical data, suggest an auditory cortex origin of this component.

Midlatency auditory evoked responses in the human and the cat model.

Findings from the experiments summarized above indicate that the MRL components, Pa and P1, are differentially affected by several functional and parametric variables, suggesting that each of these components reflects a separate and distinct generator system. Moreover, the similarities between the human Pa and the cat wave 7 suggest an auditory cortex origin of this component. The similarities between the human P1 and the cat wave A suggest that in the human, as in the cat, this potential may be generated by a component of the ascending reticular activating system.

The effect of focal interictal spikes on perception and reaction time. I. General considerations.

The effect of focal interictal spikes on visual perception and reaction time (RT) was studied in 3 subjects, by means of a computerized system of spike detection, presentation of visual stimuli, and timing of a button press. A total of 8646 such trials were analyzed, comparing spike-locked and control performances within the same subject. For stimuli locked to spikes involving visual cortex, both the rate of non-responses (non-perceptions) and the RTs of responses were increased (P less than 0.0001) in all 3 subjects. The magnitude of this effect was roughly proportional to the amplitude and breadth of field of the spike. Focal spikes in cortical areas uninvolved in the visual motor task did not impair performance. These findings indicate that single focal interictal spikes transiently disrupt aspects of cortical functioning, at least in the few subjects studied so far. This may have developmental and therapeutic implications for patients with very frequent interictal spikes, even thought they may not have seizures or their seizures may be well controlled.

The effect of focal interictal spikes on perception and reaction time. II. Neuroanatomic specificity.

By means of a computerized system of spike detection, presentation of visual stimuli, and timing of a button press, we showed previously that single posterior interictal spikes resulted in transient prolongation of reaction time and increased non-response rate in 3 subjects. By varying the response hand and the visual field of stimulus, conditions with maximum spike effect were defined more precisely, in relationship to the location of the spike. In general, spike-induced dysfunction was most pronounced when either response hand or visual field of stimulus was contralateral to the spike. This not only was true across all 3 subjects, but held even for independent right and left occipital spikes within the same subject. Also, perceptual versus motor aspects were differentially affected by the anterior-posterior location of the spike. These findings indicate that focal interictal spikes may transiently disrupt aspects of cortical functioning corresponding to their neuroanatomical location.

Transient impairment of visual perception induced by single interictal occipital spikes.

We have previously reported that focal occipital interictal epileptiform discharges (spikes) cause transiently prolonged reaction time (RT) and increased nonperception of stimuli, especially in the visual field contralateral to the spike. One subject with very frequent spikes was capable of carrying out a visual recognition task along with the RT task. During central fixation, computer-generated random digits were flashed for 150 ms at random locations on a screen. Some stimuli were delivered during spikes, by means of an amplitude-threshold trigger, whereas control stimuli were delivered at random times between spikes. Following each stimulus, the subject had to press a button for RT and then report the digit perceived. There was a statistically significant increase in nonresponse rate (nonperception) during spikes compared to controls, and this effect was maximal contralateral to the spike. Moreover, among the responses, perceptual accuracy (correct vs incorrect) was significantly impaired during spikes, again predominantly in the visual field contralateral to the spike. Thus, not all focal interictal spikes are necessarily "subclinical;" at least some induce a transient cortical dysfunction of the same kind as produced more enduringly from a structural lesion in the same location. These findings may have clinical relevance in patients, especially children, with very frequent epileptiform discharges and higher cortical dysfunction.

Focal spike-induced cerebral dysfunction is related to the after-coming slow wave.

By means of a computerized system of spike detection, presentation of visual stimuli, and registration of reaction times (RTs), we have shown previously that focal posterior interictal spikes cause transiently prolonged RT and increased nonperception and misperception of stimuli, especially contralateral to the spike. We report here the temporal profile of this phenomenon, ascertained by systematically increasing a delay between spike and stimulus-flash, until the latter was well beyond the limits of the entire spike-wave complex. In each of two subjects, the spike effect began just before the spike and ended with the termination of the after-coming slow wave. For stimuli with identical delays following spikes, RTs were significantly prolonged if the end of the slow wave overlapped the stimulus, and not otherwise. In one subject, who had an amplitude dissociation between spikes and after-coming slow waves, the prolongation of RT was associated with the larger waves, regardless of spike amplitude. These findings suggest that the after-coming slow wave (surround hyperpolarization) transiently disrupts aspects of cortical functioning, in addition to whatever effect the spike itself may have. Focal spike-wave-induced cortical dysfunction may be relevant to a variety of interictal cognitive disorders.

Midlatency auditory evoked responses: differential abnormality of P1 in Alzheimer's disease.

The human 'P1' middle latency evoked potential is postulated to be generated in the thalamus by a cholinergic component of the ascending reticular activating system. To test the hypothesis that P1 and its generator substrate are abnormal in Alzheimer's disease (AD), a disorder of marked cholinergic deficiency, recordings of middle latency responses to click stimuli were carried out. Comparisons between the AD and age-matched control groups indicated normal auditory brain-stem and Pa responses but a significant decrease in P1 amplitude. This P1 abnormality suggests that the midbrain cholinergic cells in AD may be dysfunctional.