Brian F. O'Donnell

Troublesome and disruptive behaviors in dementia. Relationships to diagnosis and disease severity

Patients with dementia often manifest troublesome and disruptive behaviors in addition to intellectual impairments. This study evaluated behavioral disturbances in 126 demented patients examined sequentially, using questionnaires administered to primary caregivers to quantify the types and severity of behavioral disturbances. Eighty‐three percent of the patients exhibited one or more of the targeted behaviors. The most common troublesome and disruptive behaviors clustered into three categories: aggressive, ideational, and vegetative. The prevalence and severity of the behaviors increased with global severity of dementia, but did not differ in either frequency or type when patients with three diagnoses were compared: Alzheimers disease (AD), multi‐infarct dementia (MID), and mixed AD and MID (MIX). The occurrence and severity of the target behaviors correlated modestly with the severity of dementia. Impairments of mental status correlated weakly with only a single troublesome and disruptive behavior—assaultiveness.

Incontinence and Troublesome Behaviors Predict Institutionalization in Dementia

Factors predicting the early institutionalization of demented patients were studied in 143 outpatients using univariate and multivariate life-table methods. Four types of factors were evaluated for prognostic value: severity of functional impairment, behavioral disorders, individual patient characteristics, and type of caregiver. After follow-up of 19 ± 12 months, 51 patients had been institutionalized. Increased global severity of dementia, the presence of troublesome and disruptive behaviors, and incontinence increased the likelihood of institutionalization. The best predictors of institutionalization were paranoia, aggressive behavior, and incontinence. Neither individual patient characteristics (age, education, and gender) nor caregiver relationship to the patient (male spouse, female spouse, and male or female child) influenced institutionalization. Since troublesome behavioral disorders are potentially treatable aspects of dementia leading to institutionalization, their management should be a major focus of therapy in dementia. (J Geriatr Psychiatry Neurol 1992;5:45–52).

Haloperidol Impairs Learning and Error-related Negativity in Humans

Humans are able to monitor their actions for behavioral conflicts and performance errors. Growing evidence suggests that the error-related negativity (ERN) of the event-related cortical brain potential (ERP) may index the functioning of this response monitoring system and that the ERN may depend on dopaminergic mechanisms. We examined the role of dopamine in ERN and behavioral indices of learning by administering either 3 mg of the dopamine antagonist (DA) haloperidol (n = 17); 25 mg of diphenhydramine (n = 16), which has a similar CNS profile but without DA properties; or placebo (n = 18) in a randomized, double-blind manner to healthy volunteers. Three hours after drug administration, participants performed a go/no-go Continuous Performance Task, the Eriksen Flanker Task, and a learning-dependent Time Estimation Task. Haloperidol significantly attenuated ERN amplitudes recorded during the flanker task, impaired learning of time intervals, and tended to cause more errors of commission, compared to placebo, which did not significantly differ from diphenhydramine. Drugs had no significant effects on the stimulus-locked P1 and N2 ERPs or on behavioral response latencies, but tended to affect post-error reaction time (RT) latencies in opposite ways (haloperidol decreased and diphenhydramine increased RTs). These findings support the hypothesis that the DA system is involved in learning and the generation of the ERN.

The auditory N2 component in schizophrenia: Relationship to MRI temporal lobe gray matter and to other ERP abnormalities

The N2 component of the auditory event-related potential (ERP) indexes cognitive processes involved in the categorization of deviant stimuli. Although N2 amplitude and latency abnormalities have been reported in schizophrenia, their relationship to MRI structural changes, clinical status, and P3 abnormalities has not been defined. We therefore studied the auditory N2 and P3 components elicited by an oddball paradigm in 15 right-handed male subjects with schizophrenia and 14 control subjects who had quantitative MRI measures of temporal lobe gray-matter structures. To provide a methodological comparison, we measured the auditory N2 from both the target ERP (N2t) and the target-minus-frequent ERP difference (N2d) waveforms. Both N2t and N2d amplitude were bilaterally reduced in schizophrenics, with N2d showing a more pronounced reduction. Within the schizophrenic group, N2 amplitude reduction was associated with reduction in gray-matter volume of the left superior temporal gyrus (STG) and of medial temporal lobe structures bilaterally, and clinically, with greater chronicity. P3 amplitude, in contrast, correlated only with left posterior STG volume, and was more prominently associated with delusions and thought disorder. These findings suggest that the N2 and P3 components, though occurring sequentially in the ERP, tap separable anatomic and behavioral abnormalities in schizophrenia.

Prefrontal cortex, negative symptoms, and schizophrenia: an MRI study

The present study measured prefrontal cortical gray and white matter volume in chronic, male schizophrenic subjects who were characterized by a higher proportion of mixed or negative symptoms than previous patients that we have evaluated. Seventeen chronic male schizophrenic subjects and 17 male control subjects were matched on age and handedness. Regions of interest (ROI) were measured using high-resolution magnetic resonance (MR) acquisitions consisting of contiguous 1.5-mm slices of the entire brain. No significant differences were found between schizophrenic and control subjects in mean values for prefrontal gray matter volume in either hemisphere. However, right prefrontal white matter was significantly reduced in the schizophrenic group. In addition, right prefrontal gray matter volume was significantly correlated with right hippocampal volume in the schizophrenic, but not in the control group. Furthermore, an analysis in which the current data were combined with those from a previous study showed that schizophrenic subjects with high negative symptom scores had significantly smaller bilateral white matter volumes than those with low negative symptom scores. White matter was significantly reduced in the right hemisphere in this group of schizophrenic subjects. Prefrontal volumes were also associated with negative symptom severity and with volumes of medial-temporal lobe regions - two results that were also found previously in schizophrenic subjects with mostly positive symptoms. These results underscore the importance of temporal-prefrontal pathways in the symptomatology of schizophrenia, and they suggest an association between prefrontal abnormalities and negative symptoms.

Steady State Responses: Electrophysiological Assessment of Sensory Function in Schizophrenia

Persons with schizophrenia experience subjective sensory anomalies and objective deficits on assessment of sensory function. Such deficits could be produced by abnormal signaling in the sensory pathways and sensory cortex or later stage disturbances in cognitive processing of such inputs. Steady state responses (SSRs) provide a noninvasive method to test the integrity of sensory pathways and oscillatory responses in schizophrenia with minimal task demands. SSRs are electrophysiological responses entrained to the frequency and phase of a periodic stimulus. Patients with schizophrenia exhibit pronounced auditory SSR deficits within the gamma frequency range (35-50 Hz) in response to click trains and amplitude-modulated tones. Visual SSR deficits are also observed, most prominently in the alpha and beta frequency ranges (7-30 Hz) in response to high-contrast, high-luminance stimuli. Visual SSR studies that have used the psychophysical properties of a stimulus to target specific visual pathways predominantly report magnocellular-based deficits in those with schizophrenia. Disruption of both auditory and visual SSRs in schizophrenia are consistent with neuropathological and magnetic resonance imaging evidence of anatomic abnormalities affecting the auditory and visual cortices. Computational models suggest that auditory SSR abnormalities at gamma frequencies could be secondary to gamma-aminobutyric acid-mediated or N-methyl-D-aspartic acid dysregulation. The pathophysiological process in schizophrenia encompasses sensory processing that probably contributes to alterations in subsequent encoding and cognitive processing. The developmental evolution of these abnormalities remains to be characterized.

Personality traits in schizophrenia and related personality disorders

We investigated whether schizophrenia spectrum disorders share common personality characteristics or traits. Participants with a diagnosis of schizophrenia or schizoaffective disorder (SZ) or with a schizophrenia spectrum personality disorder (schizophrenia spectrum PD: schizoid, paranoid, and schizotypal personality disorder) were compared with non-psychiatric control subjects on the five-factor model of personality and the psychosis-proneness scales. On the five-factor personality scales, SZ subjects showed higher levels of neuroticism, and lower levels of openness, agreeableness, extraversion, and conscientiousness than control subjects. Higher scores on openness and lower scores on neuroticism distinguished schizophrenia spectrum PD from SZ. On the psychosis-proneness scales, both PD and SZ participants scored high relative to non-psychiatric control participants on magical ideation and perceptual aberration, while PD participants scored intermediate between non-psychiatric control participants and SZ on social anhedonia. Discriminant analysis indicated that schizophrenia spectrum patients could be distinguished from PDs by more severe social withdrawal and maladjustment, while subjects with PDs could be best distinguished from control subjects on the basis of odd or novel ideation and decreased conscientiousness.

ERP assessment of visual and auditory language processing in schizophrenia

Language disturbance in schizophrenia has been recently attributed to disturbed priming mechanisms. In the present study, event-related potentials (ERPs), were recorded to final words in sentences presented to 13 chronic patients with schizophrenia and 12 normal controls. Half of the final words fit a sentence context and another half did not. The N400 (the ERP sensitive to language) latency was prolonged, and its amplitude was more negative to both correct and incorrect sentence endings in the group with schizophrenia relative to the group of normal controls. The early ERP components, N100 and P200, were similar in both groups. These results suggest that language abnormalities in schizophrenia are related to a dysfunction in the language system and not to a general cognitive dysfunction, and may be related to poor use of context in patients with schizophrenia.

A Roadmap for the Development and Validation of Event-Related Potential Biomarkers in Schizophrenia Research

New efforts to develop treatments for cognitive dysfunction in mental illnesses would benefit enormously from biomarkers that provide sensitive and reliable measures of the neural events underlying cognition. Here, we evaluate the promise of event-related potentials (ERPs) as biomarkers of cognitive dysfunction in schizophrenia. We conclude that ERPs have several desirable properties: (1) they provide a direct measure of electrical activity during neurotransmission; (2) their high temporal resolutions make it possible to measure neural synchrony and oscillations; (3) they are relatively inexpensive and convenient to record; (4) animal models are readily available for several ERP components; (5) decades of research has established the sensitivity and reliability of ERP measures in psychiatric illnesses; and 6) feasibility of large N (>500) multisite studies has been demonstrated for key measures. Consequently, ERPs may be useful for identifying endophenotypes and defining treatment targets, for evaluating new compounds in animals and in humans, and for identifying individuals who are good candidates for early interventions or for specific treatments. However, several challenges must be overcome before ERPs gain widespread use as biomarkers in schizophrenia research, and we make several recommendations for the research that is necessary to develop and validate ERP-based biomarkers that can have a real impact on treatment development.

Temporal processing dysfunction in schizophrenia

Schizophrenia may be associated with a fundamental disturbance in the temporal coordination of information processing in the brain, leading to classic symptoms of schizophrenia such as thought disorder and disorganized and contextually inappropriate behavior. Despite the growing interest and centrality of time-dependent conceptualizations of the pathophysiology of schizophrenia, there remains a paucity of research directly examining overt timing performance in the disorder. Accordingly, the present study investigated timing in schizophrenia using a well-established task of time perception. Twenty-three individuals with schizophrenia and 22 non-psychiatric control participants completed a temporal bisection task, which required participants to make temporal judgments about auditory and visually presented durations ranging from 300 to 600 ms. Both schizophrenia and control groups displayed greater visual compared to auditory timing variability, with no difference between groups in the visual modality. However, individuals with schizophrenia exhibited less temporal precision than controls in the perception of auditory durations. These findings correlated with parameter estimates obtained from a quantitative model of time estimation, and provide evidence of a fundamental deficit in temporal auditory precision in schizophrenia.