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Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having “an orchestra without a conductor.” Kraepelin further speculated that this “conductor” was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.

Reduced brain-derived neurotrophic factor (BDNF) may underlie age-related synaptic loss, in turn contributing to cerebral atrophy, cognitive decline, and increased risk for psychiatric disorders. However, the specific contribution of BDNF to the age-related expression changes in synaptic markers and their temporal trajectories remain uncharacterized. Using microarray data from orbitofrontal cortex of control subjects (n=209; 16-96 years), we identified genes whose expression positively correlates with BDNF (r>0.575; n=200 genes) and analyzed them for enriched biological pathways. qPCR was performed to measure the expression level of transcript variants of BDNF, NTRK2, and selected BDNF-coexpressed genes in younger and older subjects. We confirmed age-related downregulation of BDNF and show 78 of the top 200 BDNF-coexpressed genes are associated with synaptic function. Both excitatory and inhibitory synaptic genes show decreased expression with age and are positively correlated with BDNF and NTRK2 expression and negatively correlated with dominant-negative truncated NTRK2 level. Results were validated at the RNA level in an independent cohort and at the protein level for selected findings. We next tested the causal link between the correlative human findings using mice with conditional blockade of BDNF/NTRK2 signaling. Blockade of NTRK2 activity in adult mice recapitulate the age-like pattern in the expression of markers for inhibitory presynaptic but notably not for excitatory synaptic genes. Together, these findings suggest that age-dependent decrease in BDNF signaling may cause synaptic alterations through an initial and preferential effect on GABA presynaptic genes. These results have implications for neuropsychiatric disorders characterized by accelerated aging molecular profiles, such as major depression.

Key Points Cannabis contains more than 100 unique ingredients that are known as 'cannabinoids', and the proportions of these vary widely across different strains of the plant. High-Δ 9 -tetrahydrocannabinol (Δ 9 -THC) varieties with negligible levels of cannabidiol (CBD) now dominate many Western markets and are more harmful than lower-Δ 9 -THC, higher-CBD varieties. Like other recreational drugs, Δ 9 -THC increases release of dopamine and opioid peptides (in preclinical studies) and alters endocannabinoid processing in the mesocorticolimbic reward system. Long-term Δ 9 -THC exposure leads to a downregulation of brain cannabinoid receptor function that reverses following abstinence. People who try cannabis are ninefold more likely to become addicted to it than to develop psychosis. Cannabis addiction is an increasing problem globally, and no effective pharmacological treatments currently exist — this remains a major unmet clinical need. The association between cannabis use and psychosis can be influenced by several vulnerability factors, including genetics, environmental factors and the frequency and type of cannabis used. Evidence linking cannabis use with the development of depression and anxiety is less consistent, although these disorders are often comorbid with cannabis addiction. The acute effects of cannabis on cognitive function are well documented, and the most robust, dose-related decrements are to working and episodic memory. Its long-term cognitive effects remain controversial, are influenced by many confounds and appear to subside a month after stopping use of the drug. We should ensure that global legislative changes are informed by neuroscience and public health. They should mitigate against adolescent uptake and the availability of highly potent products, including synthetic agents such as 'spice', that act as full cannabinoid receptor agonists. Cannabis is used widely as a recreational drug, and its legalization is an ongoing issue in several countries. Curran et al . review the cognitive effects of acute and chronic cannabis use, before discussing cannabis addiction and the psychiatric problems often comorbid with it. In an increasing number of states and countries, cannabis now stands poised to join alcohol and tobacco as a legal drug. Quantifying the relative adverse and beneficial effects of cannabis and its constituent cannabinoids should therefore be prioritized. Whereas newspaper headlines have focused on links between cannabis and psychosis, less attention has been paid to the much more common problem of cannabis addiction. Certain cognitive changes have also been attributed to cannabis use, although their causality and longevity are fiercely debated. Identifying why some individuals are more vulnerable than others to the adverse effects of cannabis is now of paramount importance to public health. Here, we review the current state of knowledge about such vulnerability factors, the variations in types of cannabis, and the relationship between these and cognition and addiction.

Abstract Schizophrenia (SCZ) and bipolar disorder (BP) share a number of features. For example, multiple transcriptome analyses have reported molecular alterations common to both diagnoses, findings supported by the considerable overlap in the genetic risk for each disorder. These molecular similarities may underlie certain clinical features that are frequently present in both disorders. Indeed, many individuals with BP exhibit psychosis, and some individuals with SCZ have prominent mood symptoms that warrant the diagnosis of schizoaffective disorder (SA). To explore the potential relationships between molecular alterations and certain clinical features among subjects with these diagnoses, we analyzed RNA sequencing data from the dorsolateral prefrontal and anterior cingulate cortices, provided by the CommonMind Consortium, in subjects from the University of Pittsburgh Brain Tissue Donation Program. Relative to unaffected comparison subjects, in each brain region, robust differential gene expression was present only in SCZ, including a lower expression of genes involved in mitochondrial function and an elevated expression of immune-related genes. However, correlation analyses showed that BP subjects had similar, although less pronounced, gene expression alterations. Comparisons across subgroups of subjects revealed that the similarities between SCZ and BP subjects were principally due to the BP subjects with psychosis. Moreover, the gene expression profile in BP subjects with psychosis was more similar to “pure” SCZ and SA subjects than to BP subjects without psychosis. Together, these analyses suggest that similarities in gene expression between SCZ and BP are at least partially related to the presence of psychosis in some BP subjects.

With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.

In this paper, we propose a methodology for the fusion of shape from focus and reflectance transformation imaging. This fusion of two seemingly disparate methods of computational imaging is proposed with the purpose of leveraging their strengths in understanding overall surface structure (low-frequency detail) and surface texture/micro-geometry (high-frequency detail), respectively. This fusion is achieved by our new proposal of the integration of varying light images at different focus distances. We compare three methods of integration: the mean gradient response, the maximum gradient response, and the full vector gradient (FVG). The validation of the tested methods was conducted using different focus measure window sizes and multi-light integration methods to provide a clear demonstration of the effectiveness of the proposed method. The FVG is determined to provide a higher-quality shape recovery of a complex object with the trade-off of increasing the scope of the image acquisition.

The core features of schizophrenia include deficits in cognitive processes mediated by the circuitry of the dorsolateral prefrontal cortex (DLPFC). These deficits are associated with a range of molecular and morphological alterations in the DLPFC, each of which could be a cause, consequence, or compensation in relation to other changes, and thus reflect the neuroplasticity of the brain in response to the underlying disease process. In this review, we consider disturbances in excitatory, inhibitory, and modulatory connections of DLPFC circuitry from the perspective of disease- and development-related neuroplasticity and discuss their implications for the identification of novel therapeutic targets.

Identifying the molecular alterations that underlie the pathophysiology of critical clinical features of schizophrenia is an essential step in the rational development of new therapeutic interventions for this devastating illness. Cognitive deficits, such as the impairments in working memory that arise from dysfunction of the dorsolateral prefrontal cortex, are a major determinant of functional outcome in schizophrenia. Here we consider the contributions of disturbances in glutamate, dopamine and GABA neurotransmission to the pathophysiology of working memory impairments in schizophrenia, suggest a cascade of molecular events that might link these disturbances, and argue that the molecular alterations most proximal to the pathophysiology of prefrontal dysfunction offer the most promise as targets for new drug development.