Evolving Notions of Schizophrenia as a Developmental Neurocognitive Disorder.

We review the changing conceptions of schizophrenia over the past 50 years as it became understood as a disorder of brain function and structure in which neurocognitive dysfunction was identified at different illness phases. The centrality of neurocognition has been recognized, especially because neurocognitive deficits are strongly related to social and role functioning in the illness, and as a result neurocognitive measures are used routinely in clinical assessment of individuals with schizophrenia. From the original definitions of the syndrome of schizophrenia in the early 20th century, impaired cognition, especially attention, was considered to be important. Neurocognitive impairments are found in the vast majority of individuals with schizophrenia, and they vary from mild, relatively restricted deficits, to dementia-like syndromes, as early as the first psychotic episode. Neurocognitive deficits are found in the premorbid phase in a substantial minority of pre-teenage youth who later develop schizophrenia, and they apparently worsen by the prodromal, high-risk phase in a majority of those who develop the illness. While there is limited evidence for reversibility of impairments from pharmacological interventions in schizophrenia, promising results have emerged from cognitive remediation studies. Thus, we expect cognitive interventions to play a larger role in schizophrenia in the coming years. Moreover, because youth at risk for schizophrenia can be identified by an emergent high-risk syndrome, earlier interventions might be applied in a pre-emptive way to reduce disability and improve adaptation. The notion of schizophrenia as a developmental neurocognitive disorder with stages opens up a window of possibilities for earlier interventions. (JINS, 2017, 23, 881-892).

Pathophysiology of mental illness: a view from the fourth ventricle.

The concept of mental disorders as diseases of the brain is as old as the ancient Greek philosopher-physicians. However, for thousands of years, the majority of doctors, as well as laypersons, held strongly to the belief that epilepsy and "madness" (i.e., schizophrenia)--the major disorders discussed in this paper--were caused by demonic "possession." As always, the theory of causation led to apposite therapies: Cast out the devil by whatever means necessary. Later, more enlightened views of etiology led to less punitive "cures," which, to modern sensibilities, still seem barbaric. The 20th century saw the introduction of medications that provide symptomatic relief, if not cures, for seizure disorders and schizophrenia. In this paper, we consider the etiology of absence (petit mal) epilepsy and schizophrenia based on the pathophysiology underlying the shared symptom of impaired sustained attention. We emphasize the role of abnormal functioning of brainstem structures in the region of the fourth ventricle, whether caused by genetic or environmental factors or a combination thereof. Our theorizing relies on the findings of Lindsley, Magoun, and Moruzzi, who delineated the role of the brainstem reticular activating system in sleep, wakefulness, and consciousness. It also relies on the work of Penfield, Jasper, and Gloor, who sought to illuminate the role of brainstem-thalamus-cortical dysfunction in idiopathic generalized epilepsies. We consider evidence from recent studies that emphasize the phasic attentional functions supported by brainstem structures in the region of the fourth ventricle, and possible genetic links among disorders in which impaired attention is a prominent symptom.

Closed head injury-related information processing deficits: an event-related potential analysis.

Event-related potentials (ERPs) can elucidate aspects of sensory and cognitive processing that have been compromised due to closed head injury. We present the results of two investigations, one previously unreported, in which we used ERPs to evaluate information processing in head-injury survivors. In the first study, we used visual and auditory reaction time tasks differing in attentional demands to assess processing after head trauma. We found numerous changes in auditory processing in survivors: longer reaction times (but normal accuracy), longer N200 and P300 latencies, and reduced N100 and N200 amplitudes. In contrast, on visual tasks, only reduced N200 amplitude distinguished survivors and controls. To increase attentional demands, in a second study, we administered the continuous performance test (CPT). Survivors performed with lower accuracy than controls on visual and auditory tasks, and their ERPs were characterized by smaller visual and auditory N200s and P300s and smaller auditory N100s. We also present a synthesis, derived from a review of the literature, of closed head-injury effects on ERPs. Our own findings are in agreement with that synthesis. Namely, cognitive ERP components are more sensitive than sensory components to the effects of trauma. Specifically, in survivors, the amplitudes of N200 and P300 are often reduced, and their latencies prolonged. In general, as compared with visual ERPs, auditory ERPs may be more susceptible to the effects of closed head injury, suggesting that the auditory processing system is more vulnerable than the visual system. We conclude by discussing the potential use of ERPs to monitor clinical course and recovery in survivors of closed head injury.

Evaluation of traumatic brain injury: brain potentials in diagnosis, function, and prognosis.

The focus of this review is an analysis of the use of event-related brain potential (ERP) abnormalities as indices of functional pathophysiology in survivors of traumatic brain injury (TBI). TBI may be the most prevalent but least understood neurological disorder in both civilian and military populations. In the military, thousands of new brain injuries occur yearly; this lends considerable urgency to the use of highly sensitive ERP tools to illuminate brain changes and to address remediation issues. We review the processes thought to be indexed by the cognitive components of the ERP and outline the rationale for applying ERPs to evaluate deficits after TBI. Studies in which ERPs were used to clarify the nature of cognitive complaints of TBI survivors are reviewed, emphasizing impairment in attention, information processing, and cognitive control. Also highlighted is research on the application of ERPs to predict emergence from coma and eventual outcome. We describe primary blast injury, the leading cause of TBI for active duty military personnel in present day warfare. The review concludes with a description of an ongoing investigation of mild TBI, aimed at using indices of brain structure and function to predict the course of posttraumatic stress disorder. An additional goal of this ongoing investigation is to characterize the structural and functional sequelae of blast injury.

Assessment of the attention impairment in absence epilepsy: comparison of visual and auditory P300.

We report an investigation of P300 measures of information processing in patients with generalized epilepsy of the absence type and those with complex partial epilepsy. Studies have demonstrated that absence patients perform more poorly than complex partial patients on behavioral tests of sustained attention (the Continuous Performance Test, or CPT). Duncan [Duncan, C.C., 1988. Application of event-related brain potentials to the analysis of interictal attention in absence epilepsy. In: Myslobodsky, M.S., Mirsky, A.F. (Eds.), Elements of Petit Mal Epilepsy. Peter Lang, New York, pp. 341-364] reported that P300 was significantly reduced in a group of absence patients as compared with healthy controls. The present investigation was undertaken to compare the attention deficit in absence patients to that in complex partial seizure patients. Thus, ERPs were recorded while participants with absence seizure disorder, complex partial seizure disorder, and healthy controls performed auditory and visual versions of the CPT. A significant reduction in the amplitude of P300 on the visual CPT was observed in both groups of seizure patients as compared to controls. In contrast, P300 on the auditory CPT was reduced only in the group with absence seizures. These ERP data support and amplify previous behavioral findings of the impaired capacity of absence patients to mobilize and sustain attentional resources. Auditory sustained attention seems to be more affected by the pathophysiology of absence epilepsy than visual attention. Two possible factors may be involved: (a) There are separate visual and auditory attention systems in the brain, and the latter is more vulnerable than the former [Duncan, C.C., Kosmidis, M.H., Mirsky, A.F., 2005. Closed head injury-related information processing deficits: An event-related potential analysis. Int. J. Psychophysiol. 58, 133-157]; and (b) Auditory processing depends on intact mechanisms in the brainstem, which are dysfunctional in patients with absence seizures.

Event-related potential assessment of information processing after closed head injury.

We evaluated alterations in information processing after closed head injury as a function of task demands and stimulus modality. Visual and auditory discrimination tasks were administered to 11 survivors of a head injury and 16 matched healthy controls. In auditory tasks, compared with controls, the survivors had smaller N100s, smaller and later N200s, a more posterior scalp distribution of N200, and longer P300 and response latencies. Auditory N200 and P300 correlated highly with duration of unconsciousness. In contrast, in visual tasks, only a reduced N200 in the survivors differentiated the groups. Our results indicate that processing of auditory stimuli, including the perception and discrimination of stimulus features and the evaluation and categorization of stimuli, may be impaired after head trauma. Visual sensory processing may be spared, but higher-order visual processing involved in stimulus classification may be compromised.

Familial association of neuropsychological traits in patients with generalized and partial seizure disorders.

To investigate familial effects of neuropsychological deficits associated with seizure disorders, we studied 65 families, in which 1 member had epilepsy. The disorders included childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME) and temporal lobe epilepsy (TLE). Age-appropriate tests were administered to assess sustained attention, encoding and verbal memory, executive and focused attention and attentional flexibility/impulsivity. CAE probands attained lower scores than other probands in visual sustained attention and the ability to focus on and execute a visual-motor task. Scores of the unaffected relatives tended to fall between those of the probands and the controls. JME relatives had lower scores than other relatives in tests of visual and auditory sustained attention and attentional flexibility, and showed greater variability in response time. Behavioral information of this type may aid in the specification and differentiation of genetic linkages in affected families.