Why do memory abilities vary so greatly across individuals and cognitive domains? Although memory functions are highly heritable, what exactly is being genetically transmitted? Here we review evidence for the contribution of both common and partially independent inheritance of distinct aspects of memory function. We begin by discussing the assessment of long-term memory and its underlying neural and molecular basis. We then consider evidence for both specialist and generalist genes underlying individual variability in memory, indicating that carving memory into distinct subcomponents may yield important information regarding its genetic architecture. And finally we review evidence from both complex and single-gene disorders, which provide insight into the molecular mechanisms underlying the genetic basis of human memory function.

Callosal volume reduction has been observed in patients with bipolar disorder, but whether these deficits reflect genetic vulnerability to the illness remains unresolved. Here, we used computational methods to map corpus callosum abnormalities in a population-based sample of twin pairs discordant for bipolar disorder. Twenty-one probands with bipolar I disorder (mean age 44.4 ± 7.5 years; 48% female), 19 of their non-bipolar co-twins, and 34 demographically matched control twin individuals underwent magnetic resonance imaging. Three-dimensional callosal surface models were created to visualize its morphologic variability and to localize group differences. Neurocognitive correlates of callosal area differences were additionally investigated in a subsample of study participants. Bipolar (BPI) probands, but not their co-twins, showed significant callosal thinning and area reduction, most pronounced in the genu and splenium, relative to healthy twins. Altered callosal curvature was additionally observed in BPI probands. In bipolar probands and co-twins, genu and splenium midsagittal areas were significantly correlated with verbal processing speed and response inhibition. These findings suggest that aberrant connections between cortical regions—possibly reflecting decreased myelination of white matter tracts—may be involved in bipolar pathophysiology. However, findings of callosal thinning appear to be disease related, rather than reflecting genetic vulnerability to bipolar illness.

Background

No objective diagnostic biomarkers or laboratory tests have yet been developed for psychotic illness. Magnetic resonance imaging (MRI) studies consistently find significant abnormalities in multiple brain structures in psychotic patients relative to healthy control subjects, but these abnormalities show substantial overlap with anatomic variation that is in the normal range and therefore nondiagnostic. Recently, efforts have been made to discriminate psychotic patients from healthy individuals using machine-learning-based pattern classification methods on MRI data.

Methods

Three-dimensional cortical gray matter density (GMD) maps were generated for 36 patients with recent-onset psychosis and 36 sex- and age-matched control subjects using a cortical pattern matching method. Between-group differences in GMD were evaluated. Second, the sparse multinomial logistic regression classifier included in the Multivariate Pattern Analysis in Python machine-learning package was applied to the cortical GMD maps to discriminate psychotic patients from control subjects.

Results

Patients showed significantly lower GMD, particularly in prefrontal, cingulate, and lateral temporal brain regions. Pattern classification analysis achieved 86.1% accuracy in discriminating patients from controls using leave-one-out cross-validation.

Conclusions

These results suggest that even at the early stage of illness, psychotic patients present distinct patterns of regional cortical gray matter changes that can be discriminated from the normal pattern. These findings indicate that we can detect complex patterns of brain abnormality in early stages of psychotic illness, which has critical implications for early identification and intervention in individuals at ultra-high risk for developing psychosis/schizophrenia.

Although schizophrenia is highly heritable, the search for susceptibility genes has been challenging. The “endophenotype” approach is an alternative method for measuring phenotypic variation that may make it easier to identify susceptibility genes in the context of complexly inherited traits. Neuroimaging methods in particular offer a powerful way to bridge the neurobiology of genes and behavior. Such investigations may be further empowered by complementary strategies involving chromosomal abnormalities associated with schizophrenia, which can help to localize causative genes and better understand the genetic complexity of the illness. Here, we illustrate our use of these convergent approaches, with a focus on neuroimaging studies using novel computational brain mapping algorithms, to investigate genetic influences on brain structure in the development of psychosis. These studies provide compelling evidence that specific genetic loci suspected to predispose to schizophrenia may affect quantitative variation in neural indicators underlying the neurobehavioral phenotype, and illustrate how genetic-neuroimaging paradigms can improve our understanding of the pathogenesis of this highly disabling mental illness.

Objectives

Language processing abnormalities are a hallmark feature of schizophrenia. Yet, no study to date has investigated underlying neural networks associated with discourse processing in adolescents at clinical high risk (CHR) for developing psychosis.

Methods

Forty CHR youth and 24 demographically comparable healthy controls underwent functional magnetic resonance imaging while performing a naturalistic discourse processing paradigm. We assessed differences in blood oxygenation level-dependent (BOLD) activity between task conditions (Topic Maintenance vs. Reasoning) and between groups. Furthermore, we examined the association of regional brain activity with symptom severity and social outcome at follow-up, 6 to 24 months after the scan.

Results

Relative to controls, CHR participants showed increased neural activity in a network of language-associated brain regions, including the medial prefrontal cortex bilaterally, left inferior frontal (LIFG; BA44/45, 47) and middle temporal gyri, and the anterior cingulate (BA24&32). Further, increased activity in the superior temporal gyrus (STG), caudate, and LIFG distinguished those who subsequently developed psychosis. Within the CHR sample, severity of positive formal thought disorder at follow-up was positively correlated with signal change in the LIFG, superior frontal gyrus, and inferior/middle temporal gyri, whereas social outcome was inversely correlated with signal change in the LIFG and anterior cingulate.

Conclusions

These findings are consistent with a neural inefficiency hypothesis in those at greatest risk for psychosis, and additionally suggest that baseline activation differences may predict symptomatic and functional outcome. These results highlight the need to further investigate the neural systems involved in conversion to psychosis, and how language disruption changes over time in at-risk adolescents.

Patients with schizophrenia show altered patterns of functional activation during working memory processing; specifically, high-performing patients appear to hyper-activate and low-performing patients appear to hypo-activate when compared with controls. It remains unclear how these individual differences in neurophysiological activation relate to the clinical presentation of the syndrome. In this study, this relationship is examined using partial least squares (PLS), a multivariate statistical technique that selects underlying latent variables based on the covariance between two sets of variables, in this case, clinical variables and regional fMRI activations during a verbal working memory task. The PLS analysis extracted two latent variables, and the significance of these associations was confirmed through permutation. Lower levels of activation during task performance across frontal and parietal regions of interest in the left hemisphere was found to covary with poorer role functioning and greater severity of negative and disorganized symptoms, while lower activation in right frontal and subcortical regions of interest was found to covary with better social functioning and fewer positive symptoms. These results suggest that appropriately lateralized patterns of functional activation during working memory processing are related to the severity of negative and disorganized symptoms and level of role and social functioning in schizophrenia.

Previous neuroimaging studies of working memory (WM) in schizophrenia have generated conflicting findings of hypo- and hyper-frontality, discrepancies potentially driven by differences in task difficulty and/or performance. This study proposes and tests a new model of the performance-activation relationship in schizophrenia by combining changes by load with overall individual differences in performance. Fourteen patients with recent-onset schizophrenia and eighteen controls underwent functional magnetic resonance imaging while performing a parametric verbal WM task. Group level differences followed a linear “cross-over” pattern, such that in controls, activation in the dorsolateral prefrontal cortex (DLPFC) increased as performance decreased, while patients showed the opposite. Overall, low performing patients were hypoactive and high performing patients hyperactive relative to controls. However, patients and controls showed similar functions of activation by load in which activation rises with task difficulty but levels off or slightly decreases at higher loads. Moreover, across all loads and at their own WM capacity, higher performing patients showed greater DLPFC activation than controls, while lower performing patients activated least. This study establishes a novel framework for predicting the relationship between functional activation and WM performance by combining changes of activation by WM load occurring within each subject with the overall differences in activation associated with general WM performance. Essentially, increasing task difficulty correlates asymptotically with increasing activation in all subjects, but depending on their behavioral performance, patients show overall hyper-versus hypofrontality, a pattern potentially derived from individual differences in underlying cellular changes that may relate to levels of functional disability.

Background

Schizophrenia and related psychoses are associated with brain structural abnormalities. Recent findings in ‘at risk’ populations have identified progressive changes in various brain regions preceding illness onset, while changes especially in prefrontal and superior temporal regions have been demonstrated in first-episode schizophrenia patients. However, the timing of the cortical changes and their regional extent, relative to the emergence of psychosis, has not been clarified. We followed individuals at high-risk for psychosis to determine whether structural changes in the cerebral cortex occur with the onset of psychosis. We hypothesized that progressive volume loss occurs in prefrontal regions during the transition to psychosis.

Methods

35 individuals at ultra-high risk (UHR) for developing psychosis, of whom 12 experienced psychotic onset by 1-year follow-up (‘converters’), participated in a longitudinal structural MRI study. Baseline and follow-up T1-weighted MR images were acquired and longitudinal brain surface contractions were assessed using Cortical Pattern Matching.

Results

Significantly greater brain contraction was found in the right prefrontal region in the ‘converters’ compared with UHR cases who did not develop psychosis (‘non-converters’).

Conclusions

These findings show cortical volume loss is associated with the onset of psychosis, indicating ongoing pathological processes during the transition stage to illness. The prefrontal volume loss is in line with structural and functional abnormalities in schizophrenia, suggesting a critical role for this change in the development of psychosis.

The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome, 22q11.2DS) involves cardiac and craniofacial anomalies, marked deficits in visuospatial cognition, and elevated rates of psychosis. Although the mechanism is unknown, characteristic brain alterations may predispose to development of psychosis and cognitive deficits in 22q11DS. We applied cortical pattern matching and new methods for measuring cortical thickness in millimeters to structural magnetic resonance images of 21 children with confirmed 22q11.2 deletions and 13 demographically matched healthy comparison subjects. Thickness was mapped at 65 536 homologous points, based on 3-dimensional distance from the cortical gray-white matter interface to the external gray-cerebrospinal fluid boundary. A pattern of regionally specific cortical thinning was observed in superior parietal cortices and right parietooccipital cortex, regions critical for visuospatial processing, and bilaterally in the most inferior portion of the inferior frontal gyrus (pars orbitalis), a key area for language development. Several of the 30 genes encoded in the deleted segment are highly expressed in the developing brain and known to affect early neuronal migration. These brain maps reveal how haploinsufficiency for such genes can affect cortical development and suggest a possible underlying pathophysiology of the neurobehavioral phenotype.

AKT1, encoding the protein kinase B, has been associated with the genetic etiology of schizophrenia and bipolar disorder. However, minuscule data exist on the role of different alleles of in measurable quantitative endophenotypes, such as cognitive abilities and neuroanatomical features, showing deviations in schizophrenia and bipolar disorder. We evaluated the contribution of AKT1 to quantitative cognitive traits and 3D high-resolution neuroanatomical images in a Finnish twin sample consisting of 298 twins: 61 pairs with schizophrenia (8 concordant), 31 pairs with bipolar disorder (5 concordant) and 65 control pairs matched for age, sex and demographics. An AKT1 allele defined by the SNP rs1130214 located in the UTR of the gene revealed association with cognitive traits related to verbal learning and memory (P=0.0005 for a composite index). This association was further fortified by a higher degree of resemblance of verbal memory capacity in pairs sharing the rs1130214 genotype compared to pairs not sharing the genotype. Furthermore, the same allele was also associated with decreased gray matter density in medial and dorsolateral prefrontal cortex (P < 0.05). Our findings support the role of AKT1 in the genetic background of cognitive and anatomical features, known to be affected by psychotic disorders. The established association of the same allelic variant of AKT1 with both cognitive and neuroanatomical aberrations could suggest that AKT1 exerts its effect on verbal learning and memory via neural networks involving prefrontal cortex.

The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome) is a neurogenetic condition associated with visuospatial deficits, as well as elevated rates of attentional disturbance, mood disorder, and psychosis. Previously, we detected pronounced cortical thinning in superior parietal and right parieto-occipital cortices in patients with this syndrome, regions critical for visuospatial processing. Here we applied cortical pattern-matching algorithms to structural magnetic resonance images obtained from 21 children with confirmed 22q11.2 deletions (ages 8–17) and 13 demographically matched comparison subjects, in order to map cortical thickness across the medial hemispheric surfaces. In addition, cortical models were remeshed in frequency space to compute their surface complexity. Cortical maps revealed a pattern of localized thinning in the ventromedial occipital–temporal cortex, critical for visuospatial representation, and the anterior cingulate, a key area for attentional control. However, children with 22q11.2DS showed significantly increased gyral complexity bilaterally in occipital cortex. Regional gray matter volumes, particularly in medial frontal cortex, were strongly correlated with both verbal and nonverbal cognitive functions. These findings suggest that aberrant parieto-occipital brain development, as evidenced by both increased complexity and cortical thinning in these regions, may be a neural substrate for the deficits in visuospatial and numerical understanding characteristic of this syndrome.

Regional gray matter (GM) abnormalities are well known to exist in patients with chronic schizophrenia. Voxel-based morphometry (VBM) has been previously used on structural magnetic resonance images (MRI) data to characterize these abnormalities. Two multisite schizophrenia studies, the Functional Biomedical Informatics Research Network and the Mind Clinical Imaging Consortium, which include 9 data collection sites, are evaluating the efficacy of pooling structural imaging data across imaging centers. Such a pooling of data could yield the increased statistical power needed to elucidate effects that may not be seen with smaller samples. VBM analyses were performed to evaluate the consistency of patient versus control gray matter concentration (GMC) differences across the study sites, as well as the effects of combining multisite data. Integration of data from both studies yielded a large sample of 503 subjects, including 266 controls and 237 patients diagnosed with schizophrenia, schizoaffective or schizophreniform disorder. The data were analyzed using the combined sample, as well as analyzing each of the 2 multisite studies separately. A consistent pattern of reduced relative GMC in schizophrenia patients compared with controls was found across all study sites. Imaging center-specific effects were evaluated using a region of interest analysis. Overall, the findings support the use of VBM in combined multisite studies. This analysis of schizophrenics and controls from around the United States provides continued supporting evidence for GM deficits in the temporal lobes, anterior cingulate, and frontal regions in patients with schizophrenia spectrum disorders.

Neuroimaging methods offer a powerful way to bridge the gaps between genes, neurobiology and behavior. Such investigations may be further empowered by complementary strategies involving chromosomal abnormalities associated with particular neurobehavioral phenotypes, which can help to localize causative genes and better understand the genetics of complex traits in the general population. Here we review the evidence from studies using these convergent approaches to investigate genetic influences on brain structure: 1) Studies of common genetic variation associated with particular neuroanatomic phenotypes, and 2) Studies of possible ‘genetic subtypes’ of neuropsychiatric disorders with very high penetrance, with a focus on neuroimaging studies using novel computational brain mapping algorithms. Finally, we discuss the contribution of behavioral neurogenetics research to our understanding of the genetic basis of neuropsychiatric disorders in the broader population.

The nature, neural underpinnings, and etiology of deficits in verbal declarative memory in patients with schizophrenia remain unclear. To examine the contributions of genes and environment to verbal recall and recognition performance in this disorder, the California Verbal Learning Test was administered to a large population-based Finnish twin sample, which included schizophrenic and schizoaffective patients, their non-ill monozygotic (MZ) and dizygotic (DZ) co-twins, and healthy control twins. Compared with controls, patients and their co-twins showed relatively greater performance deficits on free recall compared with recognition. Intra-pair differences between patients and their non-ill co-twins in hippocampal volume and memory performance were highly positively correlated. These findings are consistent with the view that genetic influences are associated with reduced verbal recall in schizophrenia, but that non-genetic influences further compromise these abnormalities in patients who manifest the full-blown schizophrenia phenotype, with this additional degree of disease-related declarative memory deficit mediated in part by hippocampal pathology.

Deficits in learning and memory are among the most robust correlates of schizophrenia. It has been hypothesized that these deficits are in part due to reduced conscious recollection and increased reliance on familiarity assessment as a basis for retrieval. The Remember-Know (R-K) paradigm was administered to 35 patients with chronic schizophrenia and 35 healthy controls. In addition to making “remember” and “know” judgments, the participants were asked to make forced choice recognition judgments with regard to details about the learning episode. Analyses comparing response types showed a significant reduction in “remember” responses and a significant increase in “know” responses in schizophrenia patients relative to controls. Both patients and controls recalled more details of the learning episode for “remember” compared to “know” responses, although, in particular for “remember” responses, patients recalled fewer details compared with controls. Notably, patients recognized fewer inter-item but not intra-item stimulus features compared with controls. These findings suggest deficits in organizing and integrating relational information during the learning episode and/or using relational information for retrieval. A Dual-Process Signal Detection interpretation of these findings suggests that recollection in chronic schizophrenia is significantly reduced, while familiarity is not. Additionally, a unidimensional Signal Detection Theory interpretation suggests that chronic schizophrenia patients show a reduction in memory strength, and an altered criterion on the memory strength distribution for detecting new compared with old stimuli but not for detecting stimuli that are remembered versus familiar. Taken together, these findings are consistent with a deficit in recollection and increased reliance on familiarity in making recognition memory judgments in chronic schizophrenia.