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.
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.
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.
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.
Lithium Reverses Some White Matter Abnormalities in Youth with Bipolar Disorder
Multiple groups of researchers have reported the presence of white matter tract abnormalities in patients with bipolar disorder. Some of these abnormalities correlate with the degree of cognitive dysfunction in these patients. These white matter tract abnormalities, which are measured with diffusion tensor imaging (DTI), are widespread and can appear as early as childhood in people with bipolar disorder. Researcher Vivian Kafantaris mentioned at the 2019 meeting of the International Society for Bipolar Disorders that lithium treatment in children and adolescents normalizes these alterations, as described in an article she and her colleagues published in the journal Bipolar Disorders in 2017.
Editor’s Note: This is another reason to consider the use of lithium in children with bipolar disorder. Lithium treatment may help normalize some of the earliest signs of neuropathology in the illness.
Inflammation Associated With Duration of Untreated Unipolar Depression
Researcher Sophia Attwells and colleagues reported at a 2018 scientific meeting that the longer the time that a patient went without treatment for depression, the more inflammation they exhibited on positron emission tomography (PET) scans. Attwells and colleagues used the PET scans to assess the total distribution volume of TSPO, which is a marker of brain microglial activation, a form of inflammation.
Strikingly, in participants who had untreated major depressive disorder for 10 years or longer, TSPO distribution volume was 29–33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO distribution volume was 31–39% greater in these three important regions of gray matter in participants with long durations of untreated major depressive disorder than in healthy control participants.
Editor’s Note: In schizophrenia, the duration of untreated interval (DUI) is associated with a poor prognosis, but not with inflammation. Researcher Yvette Sheline has also reported that less time on antidepressants compared to more time treated with them was associated with greater hippocampal volume loss with aging in patients with major depression.
Given Attwells and colleagues’ remarkable finding about the adverse effects of the DUI in depression, including inflammation and brain volume loss, and other findings that associate more episodes with poorer functioning, cognition, and treatment responsiveness, physicians and patients should think hard about committing to long-term antidepressant treatment to prevent episodes, beginning early in the course of illness.
This editor (Robert M. Post) would propose that if a second depressive episode occurs after a first depression that responded well to treatment, this would be an appropriate time to start antidepressant prophylaxis. Most guidelines suggest that prophylaxis be started after a third episode, but these recommendations generally do not account for newer data on the pernicious effects of experiencing repeated depressive episodes. In addition to causing dysfunction and disability, going through four depressive episodes doubles the risk of dementia in old age, and this risk increases further with each successive episode, according to researcher Lars Kessing.
Having too many depressions is bad for the brain. In Kessing’s studies, two episodes of unipolar or bipolar depression did not increase the risk of dementia compared to the general population, while four depressions did. One could compare the effects of repeated depressions on the brain to the effects of heart attacks on the heart muscle. A heart might still function well after one or even two heart attacks, but the chances of significant loss of function and the risk of congestive heart failure increase as a function of the number of heart attacks. After even one heart attack, most patients change their lifestyle and/or go on prophylactic medications to reduce risk factors such as elevated blood pressure, cholesterol, triglycerides, weight, blood sugar, and smoking. The benefits of reducing heart attacks are a no brainer. Trying to prevent recurrent depression with pharmacotherapy and adjunctive psychotherapy after a second depressive episode should be a no brainer too.
In addition, if antidepressants are not effective enough in preventing depressions, lithium is an option, even in unipolar depression, for preventing both episodes and suicide. The evidence of efficacy in both instances is very strong according to an article by Mohammed T. Abou-Saleh in the International Journal of Bipolar Disorders in 2017. The renowned psychiatrist Jules Angst’s recommendation as to when to start lithium treatment was that if a patient had had one episode or more in the previous five years in addition to the present episode, then they were likely to have two further episodes in the following five years, and lithium prophylaxis would be recommended.
White Matter Abnormalities in Obesity
Researcher Ramiro Reckziegel and colleagues reported at a recent scientific meeting that white matter is abnormal in obese adults with bipolar disorder. In a 2018 article in the journal Schizophrenia Bulletin, Reckziegel reported that body mass index (BMI) was associated with reduced fractional anisotropy, a measure of brain fiber integrity, in the cingulate gyrus in patients with bipolar disorder. This finding implies that obesity may play a role in white matter microstructure damage in the limbic system.
