Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88) presented a critique of our recently published paper in Cell Reports entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ (Lam et al., Cell Reports, Vol. 21, 2017, 2597–2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229–237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from ‘inflation in the FDR [false discovery rate]’, as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88), and are not ‘more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence’.

Learning and memory were assessed in 24 monozygotic (MZ) pairs of individuals discordant for schizophrenia or delusional disorder and seven normal pairs of MZ twins. On declarative memory tasks, the affected group displayed a pattern that might best be characterized as dysmnesic in that they performed significantly worse than the discordant unaffected group on story recall, paired associated learning, and visual recall of designs, but they learned over time, had relatively preserved recognition memory, and did not show profoundly accelerated rates of forgetting. Effortful, volitional retrieval from the lexicon, measured by verbal fluency, was also compromised in the affected group. On the other hand, procedural learning of the motor skill in a pursuit rotor task was relatively intact in the affected group. Comparisons of the normal group and unaffected group indicated that the latter group had very mild impairments in some aspects of episodic memory, namely, immediate and delayed recall of stories and delayed recall of designs. It is highly unlikely that the impairments observed in the affected group can be attributed to differences in genome, family environment, socioeconomic circumstance, or educational opportunity, as all of these were controlled by the twin paradigm. Rather, the impairments appear to be related to the intercession of disease. The neuropsychological profile is consistent with frontal lobe and medial temporal lobe dysfunction, as noted in this sample as well as other samples of schizophrenic singletons. Significant correlations between many measures of memory and global level of social and vocational functioning within the discordant group were also found. Thus difficulties in rapidly acquiring new information and propitiously retrieving old information may burden patients with schizophrenia in many of the transactions of everyday life.

There has been increasing interest in the semantic cognitive system in schizophrenia. Recent findings suggest a possible breakdown of semantic information processing in this disorder. The current study attempts to further examine semantic organization in schizophrenia. Twenty-eight chronic, early-onset schizophrenic patients and 32 controls were matched for prcmorbid intelligence and compared in their ability to spontaneously cluster exemplars from a specific category during a fluency task. Using multidimensional scaling and clustering techniques, 11 exemplars occurring most frequently in both groups were chosen for examination of their relative “proximity” during word generation. Patients with schizophrenia showed a less stable two-dimensional organization of exemplars and were less likely to group exemplars into subordinate clusters than were normals. These results suggest that semantic networks arc disorganized in these patients. These findings may have some implications for the debate over the origin of “thought disorder” in schizophrenia. (JINS, 1996, 2, 267–273.)

Schizophrenia is being increasingly viewed as a neurodevelopmental disorder, that is, one in which early, fixed pathology becomes manifest clinically during the normal course of maturation of the brain. Evidence for this position comes first from neuroimaging research, such as (1) studies that demonstrate morphologic brain changes (such as ventriculomegaly on CT scans) even in first break patients; and (2) a lack of correlation between these morphologic changes and duration of illness. Another source of evidence is studies of normal brain development in rodents and primates, including research that shows (1) the prefrontal cortex is a late maturing part of the brain, and (2) lesions of the prefrontal cortex may be initially silent and show delayed onset of dysfunction as the brain matures. A neurodevelopmental approach to schizophrenia, in turn, has stimulated further work into the normal development of brain regions implicated in the illness, such as the frontal cortex. Thus, the fields of neuropsychiatry and neurodevelopment have been mutually stimulated during the course of this work. In addition, viewing schizophrenia in developmental terms may have implications for the understanding of changes in cognition and behavior during normal adolescence.

This is a critical review of the literature related to the neurodevelopmental hypothesis of schizophrenia which posits that the illness is related to abnormal brain development. The review focuses on data deriving from clinical studies, and it is organized according to the life phase from which the data were collected: conception and birth, infancy and childhood up to the onset of the illness, after illness onset, and postmortem. The neurodevelopmental hypothesis is supported by several pieces of evidence, including increased frequency of obstetric complications in patients with schizophrenia; the presence of minor physical anomalies; the presence of neurological, cognitive, and behavioral dysfunction long before illness onset; a course and outcome of the illness itself that is incompatible in most cases with a degenerative illness; the stability of brain structural measures over time; and the absence of postmortem evidence of neurodegeneration. A historical perspective on how this research accumulated and a section addressing important areas of future investigation are also provided. We conclude that schizophrenia is certainly not a degenerative brain disorder, and that it is likely that a brain insult in utero or at birth plays a role in its expression. Current evidence cannot completely exclude the role of environmental variables after birth. In addition, it is possible that other psychiatric disorders may also have a neurodevelopmental component.

The association of attentional, neuropsychological, and behavioural abnormalities with Tourette's syndrome (TS) suggests that the abnormal function of the disorder extends beyond the motor circuits of the basal ganglia. To explore this possibility we studied, with conventional 18-channel electroencephalography, monozygotic twins ranging from 8 to 26 years of age, where at least one member of the twin pair suffered from TS. In nine out of the 11 twin pairs that differed in clinical severity of the tic disorder, the twin with the more severe course of illness had a significantly more abnormal electroencephalogram (EEG) by qualitative visual analysis. Most of the differences were due to excessive frontocentral theta activity, suggesting dysfunction outside the basal ganglia. There was also a significant relationship between a lower global neuropsychological testing score and a worse overall EEG. In eight of nine twin sets with different global neuropsychological testing scores, the twin with the lower score had a worse EEG. A similar relationship was found between birth weight and overall EEG quality. In the nine sets that differed in birth weight, the twin with a lower birth weight had a worse EEG in seven of the sets. The EEG findings are unlikely to be a medication effect because the same result was seen in the six twin pairs who had been medication-free for at least six months before entry into the study. The origin of this slowing may relate to the interaction between environmental insults to the central nervous system and the genetic component of TS, an interaction producing damage to the cortex, thalamus, or both.

The issue of progressive cognitive decline in patients with schizophrenia has been debated. We performed a cross-sectional study of patients with chronic schizophrenia, aged from 18 to 69 years, in order to address this issue. The patients included in this study passed a rigorous screen for any comorbid condition with an adverse impact on central nervous system function. We assessed intellectual deterioration with a battery of neuropsychological tests known to be sensitive to cognitive impairment in progressive dementia. No evidence of accelerated intellectual decline was found. No significant differences were found between the five age-derived cohorts (18–29, 30–39, 40–49, 50–59, and 60–69 years of age) on the Mini-Mental State Examination, Dementia Rating Scale, or other tests sensitive to dementia. While performance on the Boston Naming Test significantly declined with age, this was mainly due to age rather than duration of illness. However, it is important to note that mean performances on the majority of the tests were abnormal across all cohorts studied. These results suggest that intellectual function does not markedly decline during the adulthood of patients with schizophrenia. The course of schizophrenia is more consistent with a static encephalopathy than a dementing disorder.

To test the hypothesis that depressed and schizophrenic patients have a common pathophysiological mechanism for hypofunction of the prefrontal cortex (‘hypofrontality’), we measured regional cortical blood flow (rCBF) in ten depressed patients, ten patients with schizophrenia, and 20 age- and sex-matched normal controls. Blood flow was measured during three different cognitive conditions: a resting state, a simple number-matching sensorimotor control task, and the Wisconsin Card Sorting test (WCS). The schizophrenic patients had lower prefrontal rCBF during the WCS. There were no differences in global or regional flow between the depressed patients and the normal subjects during any testing condition. Analysis of rCBF lateralisation showed that during the WCS normal subjects had relatively more left parietal blood flow than depressed patients, who had more right parietal blood flow. Since the testing condition that has most consistently revealed hypofrontality in schizophrenia (i.e. the WCS) was not associated with abnormal rCBF in the depressed patients, these data suggest that the pathophysiological mechanisms underlying prefrontal hypofunction in depression and schizophrenia are different.

Psychiatric symptoms and cognition were assessed in 13 patients with schizophrenia, one patient with schizoaffective disorder, and one patient with psychosis not otherwise specified while they received a conventional neuroleptic and again after an average of 15 months on clozapine. Despite improvements in psychiatric symptoms, attention, memory, and higher-level problem-solving were essentially unchanged. This suggests that certain cognitive deficits are relatively independent of psychotic symptoms in schizophrenia, and are probably central and enduring features of the disorder. Cognitive disability appeared to have been rate-limiting in the sample's rehabilitation, as patients' social and vocational adjustment remained marginal during the study. We also observed that treatment with clozapine was associated with a decline in some memory functions; the potent anticholinergic properties of the drug may have been responsible for this.

Thirty-nine patients with DSM–III diagnoses of schizophrenia were examined for age disorientation, an inability to produce one's correct chronological age upon request. Six patients were age-disoriented and demented (as defined by Mini-Mental State evaluation), while two patients had delusions concerning their age, but were not demented. Age-disoriented, demented patients had very large cerebral ventricles and very low Mini-Mental State scores. This group differed on the cognitive and neuroanatomic variables from other demented, but not age-disoriented, patients, as well as from non-demented patients who were age-oriented. The age-disoriented patients appeared to be at an extreme end of the dementia spectrum in schizophrenia.