Schizophrenia is a severe and chronic mental illness that affects about 1% of the population worldwide. It typically begins in late adolescence or early adulthood and is characterized by hallucinations, delusions, disorganized thinking and behavior, and impaired cognitive functioning. Schizophrenia has long been known to have deleterious effects on the brain, but researchers are still working to understand exactly why and how this occurs.
Positive and Negative Symptoms
The symptoms of schizophrenia are generally divided into two categories – positive and negative. Positive symptoms refer to psychotic behaviors that are in excess or distorted compared to normal experiences. These include hallucinations, delusions, and disorganized thinking and speech. Negative symptoms refer to disruptions in normal emotions and behaviors, including flat affect, lack of motivation, reduced speech, and social withdrawal.
Both positive and negative symptoms are associated with cognitive and functional impairments. However, the negative symptoms tend to have a greater impact on overall functioning and correlate more strongly with structural brain changes.
Progressive Brain Changes
Schizophrenia has long been considered a neurodegenerative disorder, meaning that it is associated with a progressive loss or deterioration of brain cells over time. This view has been supported by evidence that people with schizophrenia show progressive loss of gray matter and enlargement of ventricles (fluid-filled cavities in the brain) as the illness progresses.
Brain imaging studies indicate gray matter loss in schizophrenia of about 1-2% per year, concentrated in the frontal and temporal lobes. Loss of gray matter is linked to reductions in dendrites, synapses, and neuropil (the spaces between cell bodies). Over the longer term, this process can result in overall brain volume reduction.
Neurochemical Imbalances
Many of the symptoms of schizophrenia are believed to stem from imbalances in neurotransmitters, the chemical messengers that allow communication between brain cells. Three neurotransmitters that have been implicated in schizophrenia are:
– Dopamine -elevated levels of dopamine may drive positive symptoms like hallucinations and delusions. The dopamine hypothesis is one of the earliest and most enduring explanations for schizophrenia.
– Glutamate -glutamate is the main excitatory neurotransmitter in the brain and is important for cognitive functions disrupted in schizophrenia like memory and attention. Problems with the NMDA glutamate receptor may be linked to symptoms.
– GABA -GABA is the brain’s main inhibitory neurotransmitter. Disruption in GABAergic interneurons may underlie cognitive deficits and possibly negative symptoms as well.
Medications used to treat schizophrenia generally act by blocking dopamine receptors (antipsychotics) or altering glutamate or GABA function. This brings neurochemical balance closer to normal levels.
Oxidative Stress
Oxidative stress refers to disturbances in the antioxidant system and elevated levels of free radicals – unstable molecules that can damage cells. There is considerable evidence that people with schizophrenia have increased indicators of oxidative stress and reduced antioxidant capacity.
Oxidative stress can damage neurons through lipid peroxidation, disruption of proteins and enzymes, and DNA damage. This may contribute to the structural brain changes and gradual neural degeneration associated with schizophrenia. Anti-inflammatory drugs and antioxidant supplements are being investigated for their ability to reduce oxidative stress in schizophrenia.
Neuroinflammation
Neuroinflammation involves activation of the immune system’s inflammatory response in the brain. Markers of neuroinflammation like cytokines and activated microglia are elevated in people with schizophrenia.
Chronic neuroinflammation is damaging to the brain because it can destroy neurons, trigger toxicity from excess glutamate, and impair neuroplasticity and repair. Activated microglia can also causes changes to neural circuits during development that may lay the groundwork for schizophrenia later on.
Excitotoxicity
Excitotoxicity refers to neuronal death caused by overexposure to the neurotransmitter glutamate. Because glutamate is critical for communication between neurons, excess activity at glutamate receptors leads to calcium influx, oxidative stress, and inflammation, ultimately destroying neurons.
Some theories suggest NMDA receptor hypofunction on particular neurons could lead to compensatory release of glutamate elsewhere. Disruption of cellular energetics may also increase vulnerability to excitotoxicity. The cumulative excitotoxic effect may underlie much of the progressive brain tissue loss in schizophrenia.
Impaired Neuroplasticity
Neuroplasticity refers to the ability of the brain to reorganize and rewire itself in response to learning and experiences. This ability is impaired in schizophrenia and likely contributes to cognitive deficits and difficulties with social functioning and independent living over the long-term.
Research indicates problems with synaptic plasticity, reduced dendritic spines, and altered neuronal connectivity in people with schizophrenia. Medications improve symptoms but do not appear to restore plasticity. Treatments that target plasticity directly hold promise for improving functioning.
Genetic and Environmental Factors
Schizophrenia has a strong genetic component, with a 10% risk of developing schizophrenia if you have a first-degree relative with the disorder. However, genes alone do not determine who will develop schizophrenia – environmental influences are also important.
How do genes and environment interact to impact the brain in schizophrenia? First, those at genetic risk may have slight differences in brain development that cause them to be more sensitive to environmental insults. Second, exposure to stress, trauma, viruses, malnutrition, or substance use may help trigger onset of illness. These environmental impacts likely act on vulnerable neural circuits to initiate progressive brain changes.
Genetic Risk
| Gene(s) | Effect |
| DISC1 | Involved in neural development and plasticity |
| NRG1 | Important for expression and function of NMDA receptors |
| DTNBP1 | Role in glutamate signaling |
Key Environmental Factors
| Factor | Impact on Brain |
| Childhood trauma | Can alter HPA axis function, prime microglia |
| Substance abuse | Oxidative stress, neuroinflammation, excitotoxicity |
| Prenatal infection | May prime fetal immune system and microglia |
Brain Circuitry Differences
Modern imaging and postmortem techniques have allowed researchers to identify subtle differences in the brains of people with schizophrenia compared to healthy individuals. Many of these circuitry differences are present early on and even before psychosis develops.
For example, altered connectivity affecting the frontal lobe, hippocampus, thalamus, and cerebellum can be detected in first-episode patients. Disruptions to cortical microcircuits involving inhibitory interneurons also appear early. Determining when and how these brain differences emerge will be key to understanding schizophrenia pathogenesis.
Altered Neural Circuits
| Circuit | Alteration |
| Dopaminergic (mesocortical) | Excess subcortical dopamine activity |
| Prefrontal cortex | Reduced activity and connectivity |
| Thalamocortical | Reduced coordination of activity |
Cognitive and Social Cognitive Deficits
In addition to psychotic symptoms, most patients with schizophrenia experience significant cognitive deficits that affect attention, memory, planning, problem-solving and more. Impairments in social cognition – the ability to perceive and process social and emotional information – are also common.
These cognitive challenges tend to predate full onset of illness and persist even when psychotic symptoms are in remission. The cognitive deficits of schizophrenia stem from underlying brain changes like loss of gray matter, altered connections between regions, and neurotransmitter imbalance. However, their precise neural basis remains poorly understood.
Key Cognitive Domains Disrupted
| Working memory | Holding information temporarily to complete tasks |
| Attention | Focusing on relevant stimuli and ignoring distractions |
| Cognitive flexibility | Shifting thinking and behavior to suit context |
| Social cognition | Processing social and emotional cues |
These deficits contribute to challenges with independent living and difficulty participating in psychosocial treatments. Patients struggle to maintain employment and relationships. Cognitive remediation therapy may help somewhat but cannot fully restore normal functioning.
Disrupted Developmental Trajectories
Schizophrenia is increasingly recognized as a neurodevelopmental disorder – one that arises from problems in brain maturation and development processes that begin years before onset of diagnosable illness. Subtle behavioral, cognitive, and motor delays are often detectable in childhood.
During adolescence and young adulthood, a period of heightened vulnerability combines with genetic risk and environmental factors to trigger onset of overt psychosis and deterioration. However, the seeds are planted much earlier through disrupted neurodevelopmental trajectories.
Evidence suggests neurodevelopmental processes like synaptic pruning and myelination may go awry, laying the foundation for emergence of schizophrenia symptoms down the line. Brain differences are often detectable before overt disease develops, supporting the neurodevelopmental model.
When Does Pathology Emerge?
| Time Period | Developmental Disruption |
| Prenatal | Genetic influences, infection, maternal stress |
| Childhood | Cognitive, motor and social delays |
| Adolescence | Pruning and myelination problems |
| Early Adulthood | Onset of overt symptoms |
Understanding how risk factors disrupt neurodevelopmental trajectories to cause schizophrenia will be essential for developing interventions that could restore normal brain maturation. This could allow prevention in those at risk.
Lack of Neuroregeneration
After onset of schizophrenia, structural brain changes like gray matter loss appear to progress in a neurodegenerative pattern, without the ability for regeneration and repair. Why the brain is unable to effectively repair and renew itself in schizophrenia is unclear.
Contributing factors likely involve inflammation, oxidative stress, problems with growth factors like BDNF, and lack of appropriate stimulation for neuroplastic processes. The accumulated damage over time results in worsening cognitive deficits and functional impairment.
Treatments that can encourage neuroplasticity and neurogenesis – the production of new neurons – may help counteract the brain deterioration seen in schizophrenia. Aerobic exercise, cognitive training, and medications that target plasticity-related pathways are some options under investigation. However, current therapies do not seem capable of enabling true neuroregeneration.
Abnormal Neurodevelopment + Neurodegeneration
In summary, research indicates schizophrenia is associated with both abnormal neurodevelopmental processes and neurodegenerative patterns of progressive brain deterioration. Subtle brain changes emerge early in life and make an individual vulnerable to onset of illness. Then later, toxic factors like inflammation and oxidative stress contribute to loss of brain tissue and worsening of symptoms.
The relationship between the neurodevelopmental disruptions and neurodegenerative processes remains unclear. Some evidence suggests the early problems could establish neural vulnerabilities that lead downstream to cell death and atrophy when exposed to additional hits. However, not all patients show clear progressive deterioration, highlighting the heterogeneity of the disorder.
Dual Hit Model
| Early disruption | Later factors |
| Prenatal infection | Drug use in adolescence |
| Childhood trauma | Stress |
| Developmental genes | Toxic inflammation |
More research on the interactions between genetic risks, neurodevelopmental processes, and neurotoxicity will be needed to clarify the complex, multifactorial pathogenesis of schizophrenia at the neural level.
Conclusion
Schizophrenia involves progressive brain deterioration that arises from both early neurodevelopmental problems and later neurodegenerative processes. Disruptions to synaptic pruning, neurotransmitter systems, and neural connectivity combine with factors like inflammation, oxidative stress, and excitotoxicity to damage the brain. This results in worsening of psychotic symptoms, cognitive decline, and functional impairment over the course of illness. Treatments to enhance plasticity and prevent further loss of brain tissue are important areas for future research, but currently this damage appears irreversible. Understanding the complex interplay between genes and environment that sets the stage for schizophrenia will be key to developing interventions that may someday prevent or cure this devastating mental disorder.