Cognitive Dysfunction in Psychiatric Disorders

Cognitive dysfunction does not just signify poor memory, the range of cognitive impairment is broader and more complex.

Basis of Cognitive Impairment in Disease

• Cerebral circuits and cellular cascades controlling cognition

Cognition can be best understood in terms of complex networks operating over multiple temporal scales and incorporating diverse dimensions: from cellular cascades to cerebral circuits and, ultimately, society. Specific domains such as executive function and social cognition are integrated across broad suites of interlinked and overlapping cerebral regions. Moreover, a diverse palette of neuromodulators, including acetylcholine, cytokines, and brain-derived neurotrophic factor (BDNF), influence cognitive performance.

Pharmacotherapy does not target cerebral circuits perse; rather, it targets G protein-coupled receptors (GPCRs), ion channels, transporters, and other proteins involved in the actions of neuromodulators. These molecular substrates of cognition constitute a vast repertoire of potential drug targets for countering cognitive impairment in psychiatric disorders.

Representing a level of integration that is intermediate between cells and cerebral circuits, neurons do not generally act in isolation; rather, they operate as synchronized and rhythmically active assemblies to encode, transmit and modulate information underpinning cognitive function.

Fig.1 Schematic representation of major cerebral circuits underpinning core cognitive domains that are disrupted in psychiatric disorders. (Millan, 2012)

• Disruption of cerebral networks as a cause of cognitive impairment

Cognitive deficits observed in schizophrenia have long been ascribed to reduced activation of the dorsolateral PFC (known as hypofrontality) but many cortical and subcortical structures are also affected, with a complex pattern of region-dependent hypo- or hyperactivation, increased activity may reflect an attempt to compensate for insufficient performance. Cognitive impairment in psychiatric disorders is characterized by a complex pattern of disconnection and over connection. An important issue, therefore, is whether the circuits controlling cognition can be reconstituted once they are disrupted, as certain structural perturbations may be irreversible.

• Genetic risk factors for cognitive deficits in psychiatric disorders

First, although psychiatric disorders have a moderate to high heritability, genetic risk factors are numerous and only have a small effect; they show low penetrance and epistasis. Second, if a mutation, deletion, or other genetic defect is associated with a psychiatric disorder, this does not necessarily indicate a role in the induction of cognitive impairment. Third, even if a genetic defect is implicated in the pathological mechanisms that lead to cognitive impairment, it is not an appropriate target for their alleviation. Fourth, some plasticity-related genes predispose individuals to cognitive deficits under adverse developmental conditions but have the opposite effect in a favorable environment. Last, the limited success of even genome-wide studies in finding genes that are major risk factors may also be ascribed to additional layers that can epigenetically control mask the effects of genetic defects.

Fig.2 An overview of molecular substrates targeted by drugs that are designed to enhance cognitive performance in psychiatric disorders. (Millan, 2012)

Strategies to Counter Cognitive Impairment

• Direct and indirect modulation of cognitive performance by pharmacotherapy
• Limited clinical feedback
• Complex effects on cognition: bell-shaped dose-response curves
• Normalization of pathological processes versus symptomatic strategies
• Domain-specific and generalized improvements in cognitive performance
• Intracellular targets
• Neurogenesis
• Epigenetics
• Modulation of miRNA-controlled neural circuits
• Coupling pharmacotherapy with alternative strategies

Clinical Development of Pro-cognitive Agents

Clinical studies of pro-cognitive agents can now use various techniques with experimental counterparts for estimating optimal drug doses for efficacy, tracking cognitive actions in a manner complementary to behavioral rating scales, improving stratification of patients for drug trials, and exploring cerebral mechanisms of pro-cognitive properties.

Fig.3 Overview of translational models for characterizing and predicting the influence of pharmacological agents on cognitive function in humans. (Millan, 2012)

Products We Can Provide for Cognitive Dysfunction Research

As there is no unitary cause of cognitive impairment, and no single solution for its control, many promising lines of research should be pursued. At Creative Biolabs, we have the expertise to optimize each stage in neurosciences research, particularly with a focus on the study of cognitive dysfunction in psychiatric disorders. We ensure that you get your desired outcome and achieve the highest level of efficiency throughout. Please feel free to contact us.

Reference

1. Millan, M.J.; et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nature reviews Drug discovery. 2012, 11(2): 141-168.