A NEW VIEW ON MEMORY TO REMEMBER
Steven Ramirez PhD of Boston University gave a talk (8/9/22) on memory for the BBRF hosted by Jeffrey Borenstein President & CEO of the Brain & Behavior Research Foundation. Ramirez showed that positive (food) and negative (shock) memories of different places were stored in different neurons of the hippocampus. If he turned on the positive memories with optical stimulation while a mouse was in a negative memory place and would ordinarily show freezing representing fear behavior, much less freezing occurred with the insertion of the positive memory. Positive memories appear to trump negative memories.
Ramirez found score of genes were activated or turned off in the positive memory cells, some of which, but not all, overlapped with the negative memory cells. Remarkably, the bulk of the unique positive memory genes were related to synaptogenesis and neuroprotection, while the bulk of genes unique to the negative memory cells were related cell death and other toxic factors. Ramirez hopes these data will provide clues to not only helping people with PTSD, but also ultimately providing targets for providing protection against degenerative diseases.
When Ramirez was asked by Borenstein what people could do now, he related his own experience of every morning filling out a form for gratitude and gratefulness for at least 3 things he could be grateful for the previous day or anticipated for the current day. The positive memories that this invoked in him set up his positive and optimistic attitudes for the rest of the day. He recommends this approach of positive memories modulating the current pervasive stressors of the day. For people interested in the details of his experiments summarized above, they should look for the in press articles of Grella et al Nature Communications and Shpokayte et al Nature Communications.
Review Describes Latest Findings on the Mechanisms of Psychedelic Drugs and Their Therapeutic Potential
In a 2021 review article in a special issue of the Journal of Neurochemistry devoted to “Psychedelics and Neurochemistry,” researcher Alaina M. Jaster and colleagues summarized recent findings on psychedelic drugs, including their potential as treatments for psychiatric disorders and the structural changes they produce in the brain. The review article focused on findings in humans and provided background context based on findings in animals, particularly rodents.
In the article, Jaster and colleagues write that psychedelics “have in common a battery of acute (within minutes to hours) effects in humans that include profound changes in processes related to perception, cognition, sensory processing, and mood.” They are not considered to be addictive, and recent research has identified fast-acting and long-lasting therapeutic effects of psychedelics, particularly for the treatment of depression and substance abuse.
While psychedelic drugs interact with the brain in complicated ways, the role of serotonin 5-HT2A receptors seems to be crucial to their effects. Psychedelics have classically been divided into two groups based on their chemical structures: phenethylamines (which include mescaline and its synthetic analog DOI) and tryptamines (which include psilocybin/“magic mushrooms,” DMT/ayahuasca, and ergolines like LSD, which are sometimes separated into a third category). The authors of the review highlight that other substances with different chemical structures that do not fit into this classification can also function as psychedelics. Examples include efavirenz and quipazine, which both activate serotonin 5-HT2A receptors and change rodent behavior in the same way that other psychedelic drugs do. These drugs are providing new directions for research into how psychedelics work at both serotonin 5-HT2A receptors and monoaminergic G protein-coupled receptors (GPCRs).
Rodent studies are often used to investigate how psychedelic drugs work. Rodent behaviors such as ear scratching and head twitching increase when the rodents are given drugs that have psychedelic effects in humans. These behaviors return to normal when rodents are given drugs that function as serotonin 5-HT2A receptor antagonists, preventing the stimulation of these serotonin receptors.
While it has been established that serotonin 5-HT2A receptors play an important role in the hallucinogenic effects of psychedelic drugs, how serotonin receptors are involved in some of the therapeutic effects of psychedelics, such as antidepressant effects and changes to synaptic plasticity, is not yet clear.
According to the review, “A number of studies in animal models as well as postmortem human brain samples from subjects with depression and controls has provided evidence that mood disorders occur in conjunction with a reduction in the density of dendritic spines, particularly in the frontal cortex.” Dendrites are the projections from the cell bodies of neurons upon which nerve endings from the axons of other neurons synapse. The surface of these dendrites is covered in mushroom-shaped spines that help create these synaptic connections. The review describes in vitro and in vivo research on mice that suggests that the psychedelics DOI, DMT, and LSD can remodel dendritic spines.
At a recent scientific meeting, researcher Javier González-Maeso, one of the authors of the review, described findings from a recent study of mice given DOI. The structure of the dendritic spines in the prefrontal cortex changed rapidly in these mice. They had also been conditioned to produce a fear response, and the extinction process to get rid of this learned fear was sped up in the mice given DOI. These effects occurred via the serotonin 5-HT2 receptors. The exposure to the psychedelic also affected the regulation of genes involved in synaptic assembly for days, suggesting that epigenetic-induced changes in synaptic plasticity may underlie some of the long-lasting therapeutic effects of psychedelics.
The review also addressed “microdosing,” the recreational practice of consuming small amounts of psychedelics such as psilocybin or LSD, based on the theory that amounts too small to create a hallucinogenic effect may instead produce therapeutic results. The authors find limited data to support microdosing. Most studies in humans and rodents have found no effect or, in the case of one rat study, a worsening of dendritic spine density following microdosing.
Surface Area of Cortex Is Reduced After Multiple Manic Episodes
In a 2020 article in the journal Psychiatric Research: Neuroimaging, researcher Rashmin Achalia and colleagues described a study of structural magnetic resonance imaging (MRI) that compared 30 people with bipolar I disorder who had had one or several episodes of mania to healthy volunteers. Compared to the healthy volunteers, people with bipolar disorder had “significantly lower surface area in bilateral cuneus, right postcentral gyrus, and rostral middle frontal gyri; and lower cortical volume in the left middle temporal gyrus, right postcentral gyrus, and right cuneus.”
The surface area of the cortex in patients with bipolar I disorder who had had a single episode of mania resembled that of the healthy volunteers, while those who had had multiple manic episodes had less cortical surface area.
The data suggest that compared to healthy volunteers, people with bipolar disorder have major losses in brain surface area after multiple episodes that are not seen in first episode patients. In addition, the researchers found that both the number of episodes and the duration of illness was correlated with the degree of deficit in the thickness in the left superior frontal gyrus. These decreases in brain measures occurred after an average of only 5.6 years of illness.
Editor’s Note: These data once again emphasize the importance of preventing illness recurrence from the outset, meaning after the first episode. Preventing episodes may prevent the loss of brain surface and thickness.
Clinical data has also shown that multiple episodes are associated with personal pain and distress, dysfunction, social and economic losses, cognitive deficits, treatment resistance, and multiple medical and psychiatric comorbidities. These and other data indicate that treatment after a first episode must be more intensive, multimodal, and continuous and include expert psychopharmacological and psychosocial support, as well as family education and support. Intensive treatment like this can be life-saving. The current study also supports the mantra we have espoused: prevent episodes, protect the brain and the person.
Left Prefrontal Strokes Linked to Depression
In a 2021 article in the journal Stroke, researcher Julian Klingbeil and colleagues reported that left, but not right, ventrolateral prefrontal stroke lesions were associated with increased risk of depression at six months post-stroke.
The study included 270 participants who had their first-ever stroke. Six months following their strokes, 19.6% of the participants had depression. Those who scored higher on a scale of depression and anxiety symptoms in the first month after their stroke were more likely to have depression six months after the stroke.
The researchers identified a cluster of locations for stroke lesions, mostly within the left ventrolateral prefrontal cortex, that they linked to depression symptoms six months post-stroke. Klingbeil and colleagues hope that recognizing lesions in this region as risk factors for depression will help with early diagnosis of depression among people who recently had a stroke.
Editor’s Note: Antidepressants have been shown to improve post-stroke recovery of neurological functional (and depression) that is caused by the cutoff of blood supply during a stroke (ischemia). Patients and their family members should talk with their neurologist about treatment of ischemic strokes with antidepressants, especially when the lesions occur on the left side of the brain.
White Matter Disturbances in Bipolar Disorder
At the 2020 meeting of the International Society for Bipolar Disorders, researcher Clare Beasley described the cellular and molecular underpinnings of the white matter abnormalities typically seen in children and adults with bipolar disorder. Researchers consistently see white matter abnormalities in neuroimaging studies of bipolar disorder, but not much is understood about what creates these deficits.
Beasley and colleagues studied autopsy specimens and found that compared to controls, people with bipolar disorder had a number of abnormalities affecting glial cells, lipid composition, and axons.
The researchers found increased density of oligodendrocytes (glial cells that produce the myelin that wraps around axons, the long fibers of nerve cells where impulses travel out to other cells) and an associated protein called CNP in the prefrontal cortex. The myelin is what makes up white matter, while gray matter consists of cell bodies of neurons and glial cells.
People with bipolar disorder also had differently-shaped astrocytes, another type of glial cell that abuts synapses. The researchers found changes in lipid composition, including phospholipid and fatty acid levels, in the white matter of people with bipolar disorder. There were also problems with axons. Beasley and colleagues noted lower density of axon-associated proteins, which are involved in transport of substances along the axons in people with bipolar disorder.
The authors conclude that these data implicate specific disturbances in oligodendrocytes and axonal function associated with the white matter alterations usually seen in neuroimages of people with bipolar disorder.
Endocannabinoid System May Help Explain Tourette Syndrome
Endocannabinoids are neurotransmitters produced by the human body that attach to cannabinoid receptors in the brain, the same receptors that are affected by the consumption of cannabis products.
Tourette syndrome, a neurodevelopmental disorder characterized by tics and psychological symptoms, is probably caused by some dysfunction involving the neurotransmitter dopamine. The syndrome is usually treated with dopamine receptor blockers but is also eased by cannabis use and treatment with THC, the main psychoactive component in cannabis. Recently, researchers set out to determine whether concentrations of endocannabinoids in the cerebrospinal system are related to Tourette syndrome.
In an article published in the journal Neuropsychopharmacology in 2020, researcher Kirsten R. Müller-Vahl and colleagues report that endocannabinoid concentrations were significantly higher in the cerebrospinal fluid of 20 people with Tourette’s syndrome than in 19 control participants without Tourette’s.
The researchers found elevations in the endocannabinoids AEA and 2-AG, the endocannabinoid-like ligand PEA, and the metabolite AA in the participants with Tourette’s syndrome. Levels of 2-AG in the cerebrospinal fluid correlated with severity of attention-deficit hyperactivity disorder symptoms, an aspect of the syndrome.
It is possible that higher concentrations of endocannabinoids are present in the syndrome because they compensate for the overactive influence of dopamine. This explanation would fit with the effectiveness of cannabis in treating Tourette’s. However, that has not yet been determined, and it is also possible that the endocannabinoids are a reaction to dysfunction involving other neurotransmitters, are incidental to the syndrome, or in the best case that they are a direct cause of the syndrome.
Müller-Vahl and colleagues suggest that based on the effectiveness of cannabis in treating Tourette’s, it may turn out that the syndrome is a sort of endocannabinoid deficiency. They believe this hypothesis is not counteracted by the high levels of cannabinoids they found in Tourette’s patients in this study, because these high levels may be accompanied by a reduced number or reduced sensitivity of the cannabinoid receptors or overactivity in the enzymes that break down endocannabinoids, such that it is difficult to maintain normal levels of these neurotransmitters.
Translocator Protein Levels in Brain Predict Response to Anti-Inflammatory Celecoxib in Major Depressive Disorder
Gliosis describes changes in glia that result from damage to the central nervous system. Researchers can use PET scans (positron emission tomography) to measure the extent of gliosis in the brain. But a new study explored whether these PET scans could instead be used to determine who might respond to a given medication.
Researcher Sophia Attwells and colleagues reported in the journal Biological Psychiatry in 2020 that people with high levels of translocator protein (TSPO), a measure of gliosis and inflammation, had a better antidepressant response to the anti-inflammatory drug celecoxib than patients who started out with lower levels of TSPO.
The study participants, who had treatment-resistant depression, all received 200mg of the anti-inflammatory drug celecoxib twice/day for eight weeks on an open (non-blind) basis. Before they began taking celecoxib, the participants received PET scans to measure translocator protein total distribution volume (TSPO VT) in the prefrontal cortex and the anterior cingulate cortex.
Patients with high levels of TSPO showed greater reductions in depression ratings over the course of the study than those with normal levels of TSPO at baseline.
Attwells and colleagues conclude that “this personalized medicine approach of matching a marker of gliosis to [an anti-inflammatory treatment] …should be applied in early development of novel therapeutics, in particular for [treatment-resistant depression].”
Editor’s Note: These findings are of considerable importance, as they are among the first to indicate that measures of inflammation may predict response to an anti-inflammatory medication such as celecoxib. In a 2013 article in the journal JAMA Psychiatry, Charles L. Raison and colleagues reported that patients with high levels of the peripheral inflammatory marker CRP saw marked improvement in their depression when they received the anti-inflammatory treatment infliximab while those with lower or normal levels of inflammation actually worsened.
Quetiapine Reduced Childhood Mania, Especially in Those with Thicker Frontal Temporal Regions
In a symposium at the 2019 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Melissa P. Delbello reported that six weeks of treatment with either lithium or quetiapine was effective in childhood mania, but quetiapine had a higher response rate of 71% versus 46% for lithium. Delbello found two types of structural changes on functional magnetic resonance imaging (fMRI). Some children had thicker frontal temporal regions, while others had thinning in these areas. The first group of patients had a 100% response to quetiapine, but only 53% of the second group responded to quetiapine.
In contrast, other researchers have found lithium superior to quetiapine. Vivian Kafantaris showed that patients who respond well to lithium show improvements in white matter abnormalities. Michael Berk and colleagues found that a year on lithium was superior to quetiapine on all measures including cognition and brain imaging in patients having their first episode of mania.
Inflammation Predicts Lower Frontal and Temporal White Matter Volumes in Early-Stage Bipolar Disorder
At the 2019 meeting of the International Society for Bipolar Disorders, researcher David Bond found that seven inflammatory cytokines predicted lower white matter volumes in the left frontal and bilateral temporal lobes, as well as in the cingulate and inferior frontal gyri. Cytokines are secreted by some immune cells and send signals that can produce an effect in other cells.
Bond noted that greater inflammation did not predict lower parietal or occipital white matter volumes, suggesting that inflammation had a greater effect on white matter volume in those parts of the brain most closely linked to mood disorders.
Lithium Reverses Thinning of the Cortex That Occurs in Bipolar Disorder
In a 2018 article in the journal Molecular Psychiatry, researcher Derrek P. Hibar reported findings from the largest study to date of cortical gray matter thickness. Researchers in the ENIGMA Bipolar Disorder Working Group, which comprises 28 international research groups, contributed brain magnetic resonance imaging (MRI) from 1837 adults with bipolar disorder and 2582 healthy control participants.
Hibar and colleagues in the working group found that in adults with bipolar disorder, cortical gray matter was thinner in the frontal, temporal, and parietal regions of both brain hemispheres. They also found that bipolar disorder had the strongest effect on three regions in the left hemisphere: the pars opercularis, the fusiform gyrus, and the rostral middle frontal cortex.
Those who had had bipolar disorder longer (after accounting for age at the time of the MRI) had less cortical thickness in the frontal, medial parietal, and occipital regions.
A history of psychosis was associated with reduced surface area.
The researchers reported the effects of various drug treatment types on cortical thickness and surface area. In adults and adolescents, lithium was associated with improvements in cortical thickness, and the researchers hypothesized that lithium’s protective effect on gray matter was responsible for this finding. Antipsychotics were associated with decreased cortical thickness.
In people taking anticonvulsant treatments, the thinnest parts of the cortex were the areas responsibly for visual processing. Visual deficits are sometimes reported in people taking anticonvulsive treatments.
