Etiology of Schizophrenia

Investigation into how neurodevelopmental disruptions may lead to schizophrenia.

Proposed by Emil Kraepelin in 1887 through the term Dementia Praecox.
- Kraepelin recognized that patients often exhibited behavioral changes years before the manifestation of illness.
- His focus on dementia overshadowed early observations regarding the etiology of schizophrenia.
Crow (1980) distinguished between Type I and Type II Schizophrenia.
- Emphasis on structural brain changes post-onset of illness.

Examination of biological origins of schizophrenia has evolved with advancements in imaging technology.
1970s: Introduction of Computerized Axial Tomography (CAT or CT) by Allan McLeod Cormack and Godfrey Newbold Hounsfield.
- They were awarded the 1979 Nobel Prize for their contributions.
- CT involves taking multiple X-ray images from various angles and synthesizing them into a 3D image.
Early 1980s: Development of radioligands allowed for Positron Emission Tomography (PET), utilizing CT-like imaging processes.
Concurrently, Magnetic Resonance Imaging (MRI) was developed by Peter Mansfield and Paul Lauterbur.
- This work earned the 2003 Nobel Prize for Physiology or Medicine.

Computerized Tomography (CT): Involves taking a series of X-ray images from various angles, processed via a computer program to create detailed images.
Magnetic Resonance Imaging (MRI): Utilizes strong magnetic fields, gradients, and radio waves to produce comprehensive brain images.

Positron Emission Tomography (PET): Visualizes and measures changes in metabolic processes using radioactive substances known as radiotracers.
Functional MRI (fMRI): Measures brain activity by detecting changes in blood flow, providing insights into physiological activities.
Diffusion Tensor Imaging (DTI): An MRI technique that assesses the diffusion of water in tissue, producing neural tract images.

CT Studies: Early findings suggest larger lateral ventricles, indicative of potential brain tissue loss.
MRI Studies: Initial studies noted reductions in overall brain size, implying inadequate growth.
Later MRI studies indicate reductions in cortical thickness present at disease onset, which deteriorates with disease progression.

Cortical Thickness: Represents the distance between the pial surface (outermost surface) and the gray-white matter boundary.
- Influenced by several factors including neuronal size and density, synaptic density, and myelination.
- Does not solely indicate neuron loss but signifies microstructural simplifications in cortical circuitry, such as reduced synaptic and dendritic complexity, leading to inefficiencies in brain communication.

Weinberger (1987) states compelling evidence shows that schizophrenia correlates with structural and physiological brain pathologies, suggesting these defects form long before diagnosis.

Basic brain structure is established during prenatal development and remains similar at adulthood.
Significant maturation occurs through fine-tuning to achieve adult-level functionality and microstructure over several years.

Synaptogenesis: Neurons form connections by sending projections to nearby neurons, contributing to rapid synapse formation that leads to gray matter growth.

Young children's brains operate at higher consumption levels (approximately 60-100% of body energy) but less efficiently than adults.

Myelination Increases: Enhances connectivity and efficiency, while cortical thickness decreases during development.
Synapses are rearranged and pruned to improve overall brain efficiency.

Synapse density increases dramatically in early years:
- Newborn, 1 Month, 9 Months, 2 Years to Adult showing marked changes in synapse number.

Changes in grey matter volume observed in a trajectory across years:
- Synapses density detailed in synapses/mm³ from gestation to adulthood.

Development of prefrontal cortex involves shifts in excitatory vs. inhibitory signaling;
- Maturation of inhibitory signaling occurs later, especially during adolescence, which is crucial for cognitive functions.

Neurodevelopmental Abnormalities: Disruptions identified at various developmental stages.
- Key differences include:
- Deficits in myelination (reducing communication).
- Early decline in prefrontal excitatory synapses (excessive pruning).
- Delayed development of inhibitory synapses (lower interneuron activity).
- Imbalances in inhibitory and excitatory processes ultimately manifest as symptoms of schizophrenia.

Possibility 1: Presence of an early developmental “insult” that remains latent until the brain can no longer compensate for the disruption.
Possibility 2: Imbalances in inhibitory and excitatory activity become critical during adolescence, necessitating fine-tuning for cognitive function.

Excessive pruning of synapses and abnormal functionality of inhibitory systems may hinder the coordination among brain regions.
This disruption in network communication can lead to hallucinations, delusions, cognitive deficits, etc.
- The essence of the Dysconnectivity Hypothesis is about how impaired integration across brain networks occurs due to these disruptions.

Stage I:
- Genetic vulnerability, environmental exposure, but no significant disability.
- Intervention Possibilities: Unknown.
Stage II:
- Cognitive, behavioral, and social deficits arise; help-seeking behavior occurs.
- Possible interventions: Cognitive training, family support.
Stage III:
- Characterized by abnormal thoughts and behavior, with a relapsing-remitting course.
- Clinical efforts include medication and psychosocial support.
Stage IV:
- Involves significant loss of function and chronic disability.
- Persistent interventions needed for rehabilitation and sustenance.