These functional neuroimaging methods (using ionizing radiation) have enabled clinicians to see abnormal blood flow patterns in the brains of living patients. One of the earliest findings was hypofrontality in patients with schizophrenia, implicating frontal pathology in this severe brain disorder. PET was also used for dopamine and serotonin receptor imaging.
Computerized axia tomography. Compared with skull X-rays, CT (“CAT”) scans provided a more detailed view of brain tissue, and began a structural neuroimaging revolution that enriched psychiatric research, but also was applied to organs other than the brain.
Magnetic resonance imaging (MRI) became the “big kahuna” of neuroimaging when arrived in the early 1980s and quickly supplanted CT research because it is safer (no ionizing radiation, and it can be repeated multiple times with or without tasks). It also provided exquisite neuroanatomical details of brain tissue with stunning fidelity. Subsequently, several MRI techniques/software programs were developed that advanced research in psychiatry to multiple new frontiers, including:
- Morphological neuroimaging with MRI
- Magnetic resonance spectroscopy (MRS), which acts like a living, noninvasive biopsy of several chemicals (such as choline, lactate, glutamine, adenosine triphosphate, and the neuronal marker N-acetylcysteine) in a small volume (≤1 cc) of neural tissue in various regions
- Functional MRI (fMRI), which measures blood flow changes during actual or imagined tasks in the brains of patients vs healthy controls
- Diffusion tensor imaging (DTI), which evaluates the integrity of white matter (60% of brain volume, including 137,000 miles of myelinated fibers) by measuring the flow of water inside myelinated fibers (anisotropy and diffusivity). DTI of the corpus callosum, the largest brain commissure that is comprised of 200 million interhemispheric fibers, has revealed many abnormalities. This was one of the structures I investigated during my fellowship, including a histopathological study.1
All 4 of these neuroimaging techniques continue to generate a wealth of data about brain structure and function in psychosis, mood disorders, anxiety disorders, borderline personality disorder, obsessive-compulsive disorder, eating disorders, and substance use disorders. All these discoveries were utterly impossible to predict during my residency. I am proud to have published the first reports in the literature of ventricular enlargement in patients with bipolar disorder,2 cortical atrophy in schizophrenia and mania,3 reductions of hippocampal volume in patients with schizophrenia using MRS,4 and progressive brain atrophy in patients with schizophrenia.5 It is especially gratifying that I played a small role in translating my science fiction fantasies into clinical reality!
Other breakthrough methodologies that are advancing psychiatric neuroscience today but were science fiction during my residency days include:
- Pluripotent stem cells, which enable the de-differentiation of adult skin cells and then re-differentiating them into any type of cell, including neurons. This allows researchers to conduct studies on any patient’s brain cells without needing to do an invasive, high-risk brain biopsy. As a young resident, I would never have predicted that this virtual brain biopsy would be possible!
- Optogenetics, which enables controlling cell behavior using light and genetically encoded light-sensitive proteins. This triggered a cornucopia of neuroscience discoveries by using optogenetics to modulate cell-signaling cascades to understand cellular biology. Halorhodopsin and bacteriorhodopsin are used as tools to turn neurons off or on rapidly and safely.
- Genome-wide association studies (GWAS) have revolutionized the field of molecular neurogenetics and are enabling clinicians to detect risk genes by comparing the DNA samples of thousands of psychiatric patients with thousands of healthy controls. This is how several hundred risk genes have been identified for schizophrenia, bipolar disorder, autism spectrum disorder, and more to come.
- Clustered regularly interspaced short palindromic repeats (CRISPR) is a remarkable genetic “scissors” (that earned its inventors the 2020 Nobel Prize) that allows splicing out a disease gene and splicing in a normal gene. This will have an enormous future application in preventing an adulthood illness at its roots during fetal life. The future medical implications for psychiatric disorders are prodigious!
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