Cognitive Function and White Matter Integrity in Individuals With Bipolar Disorder

Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego

Jennifer McDowell reported that they found “significantly reduced FA (fractional anisotropy) values in 85 bipolar probands compared to 66 controls” in multiple (n=8) white matter tracts. There were significantly lower scores in bipolar probands compared to controls on composite scores, ( p = 0.007), verbal fluency, ( p < 0.001), and symbol coding, (p = 0.023). They concluded that: “ Impacted connectivity in critical fiber tracts may be key to understanding the neural underpinnings of deficits, like cognition, observed in this clinical population.”

Editors note: It is of interest that lithium has been shown to normalize some white matter abnormalities in youngsters and help preserve cognitive function in older individuals. On this and many other accounts, way too little lithium is being used in the treatment of patients with bipolar disorder. Lithium not only increases neurogenesis (new grey matter neurons) and hippocampal volume, but also has positive effects on white matter tracts and even increases the length of one’s telomeres (which keeps you more healthy). In other ungrammatical words, “If your brain is not connected right, it don’t work right.”

Higher Brain Temperature in Youth Bipolar Disorder Using a Novel Magnetic Resonance Imaging Approach

Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego

Ben Goldstein of the University of Toronto reported that “Brain temperature was significantly higher in BD (bipolar youth) compared to CG (control group) in the precuneus. Higher ratio of brain temperature-to-CBF [cerebral blood flow] was significantly associated with greater depression symptom severity in both the ACC [anterior cingulate cortex] and precuneus within BD.”

These finding are of particular interest in light of the Unspecified Bipolar Disorder subtype called Temperature and Sleep Dysregulation Disorder (TSDD), where patients are over heated and respond to clonidine and other cooling techniques along with lithium and repeated intranasal ketamine insufflations.

Serotonin is Back

A review by Moncrieff et al in Molecular Psychiatry 2022 concluded that : “there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.” This was widely reported in the news media.

A new analysis by 26 experts in the field finds many faults with this analysis (Jauhar et al 2023). Instead, they conclude “A more accurate, constructive conclusion would be that acute tryptophan depletion and decreased plasma tryptophan in depression indicate a role for 5-HT in those vulnerable to or suffering from depression, and that molecular imaging suggests the system is perturbed. The proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position.” Long live serotonin’s role in depression.

6 Minutes of Intense Cycling Produces Major Increases in BDNF

Brain derived neurotrophic factor (BDNF) is necessary for new synapses and call survival.  A new study in J. Physiology (2023) reports that the increases in BDNF from short intense cycling exercise are much greater than from prolonged (90-minute) light cycling.  The authors think that this is cause by the increases in lactate produced which helps up regulate BDNF production. This could be good for fighting depression and Alzheimer’s disease, where BDNF levels are low. 

Bottom line:  If you don’t have much time, bust your buns.

Chronic Fatigue, Depression and Anxiety Symptoms in Long COVID Are Strongly Predicted by Neuroimmune and Neuro- Oxidative Pathways Which Are Caused by the Inflammation during Acute Infection

HK Al-Hakeim et al in Michael Maes’ lab report in J. Clinical Medicine (2023) on very important findings about immune and oxidative changes in long COVID with “physio- somatic (chronic fatigue syndrome and somatic symptoms) and affective (depression and anxiety) symptoms. The severity of the long COVID physio-affective phenome is largely predicted by increased peak body temperature (BT) and lowered oxygen saturation (SpO2) during the acute infectious phase…..  We recruited 86 patients with long COVID (3–4 months after the acute phase) and 39 healthy controls and assessed serum C-reactive protein (CRP), caspase 1, interleukin (IL) 1?, IL-18, IL-10, myeloperoxidase (MPO), advanced oxidation protein products (AOPPs), total antioxidant capacity (TAC), and calcium (Ca), as well as peak BT and SpO2 during the acute phase. Results: Cluster analysis revealed that a significant part (34.9%) of long COVID patients (n = 30) show a highly elevated NT (neurotoxicity) index as computed based on IL-1?, IL-18, caspase 1, CRP, MPO, and AOPPs. Partial least squares analysis showed that 61.6% of the variance in the physio-affective phenome of long COVID could be explained by the NT index, lowered Ca, and peak BT/SpO2 in the acute phase and prior vaccinations with AstraZeneca or Pfizer. The most important predictors of the physio-affective phenome are Ca, CRP, IL-1?, AOPPs, and MPO. Conclusion: The infection–immune–inflammatory core of acute COVID-19 strongly predicts the development of physio-affective symptoms 3–4 months later, and these effects are partly mediated by neuro-immune and neuro-oxidative pathways.”

Editors Note:  These finding are important as they may lead to new treatment interventions.  BNN readers are reminded of a previous BNN article by investigators from Yale (written by by Isabella Backman on Dec. 13, 2022) that in a new case study, they found that guanfacine plus N-acetylcysteine (which is an anti-inflammatory, anti-oxidant, and glutathione precursor) “mitigated and sometimes eliminated the cognitive impairment known as “brain fog” that often accompanies long COVID.

Adolescent Delta-9-tetrahydrocannabinol  induces long-term neuronal  disturbances in dorsal vs. ventral hippocampus

December 6, 2022 · Posted in Neurobiology, Neurochemistry, Risk Factors · Comment 

De Felice et al reported in Neuropsychopharmacology (2022) how adolescent THC exposure in a rodent model can induce significant morphological disturbances and glutamatergic signaling abnormalities in the hippocampus.  The dorsal hippocampus is critical for cognitive and contextual processing, whereas the ventral region is critical for affective and emotional processing.  Adolescent THC exposure induces long-lasting memory deficits and anxiety like-behaviors concomitant with a wide range of differential molecular and neuronal abnormalities in dorsal vs. ventral hippocampal regions.

Editors Note:  While these data are in rodents, they provide insights into how THC use in adolescents exerts memory deficits and anxiety-like behavior in adulthood by dysregulation of glutamate signaling in the hippocampus.  These data converge with data in humans.  The bottom line is: use of marijuana in adolescence is not good for brain function, cognition, and behavior in adulthood.


November 2, 2022 · Posted in Brain Imaging, Neurobiology · Comment 

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).

An image from the review article shows the effects of various psychedelic drugs on different receptors.

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

man touching head

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.  

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