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FOG and other Dimensions of PD

> Falls occur mainly during posture changes, in particular during a half-turn, or while performing activities that require a double task demand (cognitive or motor).11 The more the second task is difficult, the more the balance control is altered and fall risk increased

> Usually, FOG is improved by visual (e.g. marks on the ground) or auditory cueing (rhythmic sounds). Paradoxically, running, cycling or climbing stairs are performed more easily than usual gait. Generally, freezing is defined as an abrupt difficulty in starting or continuing rhythmic and repetitive movements

> A hyperactivation has also been found in PD patients in the cerebellum, a structure known to be crucial for motor coordination and balance control.57 This hyperactivation was interpreted as a strategy of the central nervous system to compensate for the defective function of the basal ganglia and brainstem but could also be causative. Thus, unraveling the role of cerebellar dysfunction in gait and balance deficits in PD may represent a major challenge for the future. 

In a Phase 2 clinical trial, lixisenatide was found to have beneficial effects on Parkinson’s disease progression. This suggests that lixisenatide may have neuroprotective effects in the substantia nigra, potentially slowing down the neurodegeneration associated with Parkinson’s disease.

However, it’s important to note that while these findings are promising, further research and clinical trials are needed to fully understand the effects of lixisenatide on the substantia nigra and its potential as a treatment for Parkinson’s disease. < grok reply  

PDF.pdf

https://www.nejm.org/doi/

Lixisenatide

Trial of Lixisenatide in Early Parkinson’s Disease

exenatide

Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson’s disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The ‘Exenatide-PD3’ study

Multisensory mechanisms of gait and balance in Parkinson’s disease: an integrative review

>  the three dominant theoretical angles present in the field (Zhang et al., 2020). 

“ Inverse effectiveness” theories suggest that older adults depend more on multisensory integration for the maintenance of balance because of age-related deterioration in individual sensory modalities. 

“Attentional control deficit” theory attempts to explain the costliness of dual-task on gait and balance stability by suggesting that attentional resources that would otherwise be allocated to multisensory integration are diverted to the dual-task, leading to impairments in balance. 

Lastly, “larger time window of integration” theories suggest that multisensory integration depends on the binding of information within discrete temporal windows. With peripheral sensory deficits, such as those encountered in aging, these timeframes extend. This extension results in an amalgamation of incongruent multisensory information, ultimately disrupting the processing associated with maintaining balance. These theories need not be mutually exclusive, but none of them seem to emphasize the specific roles of individual sensory modalities.

> Most intriguing, this constellation of doorway-related gait impairments emerges early in the progression of PD, being present several years before the diagnosis 

> Failure of visual processing due to attentional misallocation towards the doorway stimulus prevents the acquisition of sufficient evidence about footholds 1.5–2 seconds into the future, which leads to a freezing event.

> Galvanic vestibular stimulation (GVS) is being actively pursued as a non-invasive treatment for postural instability and gait difficulty symptoms in PD

> PD freezers in medication OFF state were also recently shown to exhibit a profound difficulty with balance on unstable support surfaces in association with longer critical time intervals (Roytman et al., 2023)

> Lastly, recent findings demonstrate that suppression of the right hemispheric cortical cholinergic system in PD patients by high anti-cholinergic burden profoundly affects their ability to effectively integrate visual and vestibular cues for balance on an unstable support surface in medication OFF state (Roytman et al., 2023

 

Normal and pathological gait: what we learn from Parkinson’s disease

> However the most impairing gait disruptions are related with balance deficit and FOG episodes that tend to become resistant to levodopa, thus suggesting the involvement of extra-nigral lesions.1

> “Since these gait and balance deficits are resistant to dopaminergic drugs, their occurrence could be related to the development of extra-dopaminergic lesions in PD patients”

Axial symptoms predict mortality in patients with Parkinson disease and subthalamic stimulation

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Deep Seek

Deep seek

Naturally, phenomenology and neuroscience find a convergence of common interests. However, primarily because of ontological disagreements between phenomenology and philosophy of mind, the dialogue between these two disciplines is still a very controversial subject.[9]

Husserl himself was very critical towards any attempt to “naturalizing” philosophy, and his phenomenology was founded upon a criticism of empiricism, “psychologism“, and “anthropologism” as contradictory standpoints in philosophy and logic.[10][11] The influential critique of the ontological assumptions of computationalist and representationalist cognitive science, as well as artificial intelligence, made by philosopher Hubert Dreyfus has marked new directions for integration of neurosciences with an embodied ontology.

The work of Dreyfus has influenced cognitive scientists and neuroscientists to study phenomenology and embodied cognitive science and/or enactivism. One such case is neuroscientist Walter Freeman, whose neurodynamical analysis has a marked Merleau-Pontyian approach.[12]

Wiki Dreyfus <  Knowing-how and knowing-that. Research in psychology and economics has been able to show that Dreyfus’ (and Heidegger’s) speculation about the nature of human problem solving was essentially correct. Daniel Kahnemann and Amos Tversky collected a vast amount of hard evidence that human beings use two very different methods to solve problems, which they named “system 1” and “system 2”. System one, also known as the  adaptive unconscious, is fast, intuitive and unconscious. System 2 is slow, logical and deliberate.

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PD und so weider

Parkinson’s disease

Parkinson’s disease

Parkinson’s Disease: Gene Therapies

Calcium channel blocker

When more than 20 mg of simvastatin, a lipid-lowering agent, are given with amlodipine, the risk of myopathy increases.[40] The FDA issued a warning to limit simvastatin to a maximum dose of 20 mg if taken with amlodipine based on evidence from the SEARCH trial.[41] Giving amlodipine with Viagra increases the risk of hypotension.[7][10 < wiki amlodipine

The prion hypothesis suggests that alpha-synuclein aggregates are pathogenic and can spread to neighboring, healthy neurons and seed new aggregates. Some propose that the heterogeneity of PD may stem from different “strains” of alpha-synuclein aggregates and varying anatomical sites of origin

The incidence rate of falls in Parkinson’s patients is approximately 45 to 68%, thrice that of healthy individuals, and half of such falls result in serious secondary injuries. Falls increase morbidity and mortality.[227]Around 90% of those with PD develop hypokinetic dysarthria, which worsens with disease progression and can hinder communication.[228]Additionally, over 80%

of PD patients develop dysphagia: consequent inhalation of gastric and oropharyngeal secretions can lead to aspiration pneumonia.[229] Aspiration pneumonia is responsible for 70% of deaths in those with PD.[230]

< wiki

Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system[1] and is characterized by poor articulation of phonemes.[2] It is a condition in which problems effectively occur with the muscles that help produce speech, often making it very difficult to pronounce words

For instance, English philosopher Thomas Hobbes was diagnosed with “shaking palsy”—assumed to have been Parkinson’s—but continued writing works such as Leviathan.[289][290][291] Adolf Hitler is widely believed to have had Parkinson’s, and the condition may have influenced his decision making.[292][293][294] Mao Zedongwas also reported to have died from the disorder.[295]

https://en.wikipedia.org/wiki/Gene_therapy_in_Parkinson%27s_disease

https://en.wikipedia.org/wiki/Cell-based_therapies_for_Parkinson%27s_disease

https://en.wikipedia.org/wiki/Management_of_Parkinson%27s_disease#

https://en.m.wikipedia.org/wiki/Hypernasal_speech

The new treatments for PD are in clinical trials and most of them are centered on gene therapy. With this, researchers expect to compensate the loss of dopamine or to protect the dopamine neurons from degeneration.[2] The pharmacological and surgical therapies for PD focus on compensating the ganglia dysfunction caused by the degeneration of the dopaminergic neuron from substantia nigra

As the gut microbiome in PD is often disrupted and produces toxic compounds, fecal microbiota transplants might restore a healthy microbiome and alleviate various motor and non-motor symptoms.[300] Neurotrophic factors—peptides that enhance the growth, maturation, and survival of neurons—show modest results but require invasive surgical administration. Viral vectors may represent a more feasible delivery platform.[304] Calcium channel blockers may be restore the calcium imbalance present in Parkinson’s, and are being investigated as a neuroprotective treatment.[305] Other therapies, like deferiprone, may reduce the abnormal accumulation of iron in PD.[305]

 

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Notes on Pollan, The Botany of desire

Notebook Export
The Botany of Desire: A Plant’s-Eye View of the World
Pollan, Michael
Citation (Chicago Style): Pollan, Michael. The Botany of Desire: A Plant’s-Eye View of the World. Random House Publishing Group, 2001. Kindle edition.
Introduction
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All those plants care about is what every being cares about on the most basic genetic level: making more copies of itself.
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Design in nature is but a concatenation of accidents, culled by natural selection until the result is so beautiful or effective as to seem a miracle of purpose.
Chapter 1
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Apples were something people drank. The reason people in Brilliant wanted John Chapman to stay and plant a nursery was the same reason he would soon be welcome in every cabin in Ohio: Johnny Appleseed was bringing the gift of alcohol to the frontier.
Chapter 3
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These ingredients would be combined in a hempseed-oil-based “flying ointment” that the witches would then administer vaginally using a special dildo. This was the “broomstick” by which these women were said to travel.
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(ethnobotanists call them “entheogens,” meaning “the god within”)
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The literary critic David Lenson, for one, believes it was crucial. He argues that Samuel Taylor Coleridge’s notion of the imagination as a mental faculty that “dissolves, diffuses, dissipates, in order to re-create,” an idea whose reverberations in Western culture haven’t yet been stilled, simply cannot be understood without reference to the change in consciousness wrought by opium.
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‘dissolution, diffusion and dissipation’
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One of the things certain drugs do to our perceptions is to distance or estrange the objects around us, aestheticizing the most commonplace things until they appear as ideal versions of themselves. Under the spell of cannabis “every object stands more clearly for all of its class,” as David Lenson writes in On Drugs. “A cup ‘looks like’ the Platonic Idea of a cup, a landscape looks like a landscape painting, a hamburger stands for all the trillions of hamburgers ever served, and so forth.” A psychoactive plant can open a door onto a world of archetypal forms,
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Allen Ginsberg suggested that the negative feelings marijuana sometimes provokes, such as anxiety, fear, and paranoia, are “traceable to the effects on consciousness not of the narcotic but of the law.”
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Taking account of this phenomenon, Andrew Weil describes marijuana as an “active placebo.”
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In 1988 Allyn Howlett, a researcher at the St. Louis University Medical School, discovered a specific receptor for THC in the brain—a type of nerve cell that THC binds to like a molecular key in a lock, causing it to activate.
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The cannabinoid receptors Howlett found showed up in vast numbers all over the brain (as well as in the immune and reproductive systems), though they were clustered in regions responsible for the mental processes that marijuana is known to alter: the cerebral cortex (the locus of higher-order thought), the hippocampus (memory), the basal ganglia (movement), and the amygdala (emotions). Curiously, the one neurological address where cannabinoid receptors didn’t show up was in the brain stem, which regulates involuntary functions such as circulation and respiration.
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Raphael Mechoulam (working with a collaborator, William Devane) found it: the brain’s own endogenous cannabinoid. He named it “anandamide,” from the Sanskrit word for “inner bliss.”
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some of the various direct and indirect effects of cannabinoids: pain relief, loss of short-term memory, sedation, and mild cognitive impairment.
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The purpose of THC could be to protect cannabis plants from ultraviolet radiation; it seems that the higher the altitude at which cannabis grows, the more THC it produces. THC also exhibits antibiotic properties, suggesting a role in protecting cannabis from disease. Last, it’s possible that THC gives the cannabis plant a sophisticated defense against pests. Cannabinoid receptors have been found in animals as primitive as the hydra, and researchers expect to find them in insects. Conceivably, cannabis produces THC to discombobulate the insects (and higher herbivores) that prey on the plant; it might make a bug (or a buck or a rabbit) forget what it’s doing or where in the world it last saw that tasty plant.
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Ma, the ancient Chinese character for “hemp,” depicts a male and a female plant under a roof—cannabis inside the house of human culture.
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Cognitive dysfunction?
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The scientists I spoke to were unanimous in citing short-term memory loss as one of the key neurological effects of the cannabinoids.
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All talk about the difficulty of reconstructing what happened mere seconds ago and what a Herculean challenge it becomes to follow the thread of a conversation (or a passage of prose) when one’s short-term memory isn’t operating normally.
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Yes, forgetting can be a curse, especially as we age. But forgetting is also one of the more important things healthy brains do, almost as important as remembering. Think how quickly the sheer volume and multiplicity of sensory information we receive every waking minute would overwhelm our consciousness if we couldn’t quickly forget a great deal more of it than we remember.
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“If we could hear the squirrel’s heartbeat, the sound of the grass growing, we should die of that roar,” George Eliot once wrote.
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The first part of Nietzsche’s essay is a moving and occasionally hilarious paean to the virtues of forgetting, which he maintains is a prerequisite to human happiness, mental health, and action.
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Like the American transcendentalists, Nietzsche believes that our personal and collective inheritance stands in the way of our enjoyment of life and accomplishment of anything original.
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My lawyer father, once complimented on his ability to see ahead three or four moves in a negotiation, explained that the reason he liked to jump to conclusions was so he could get there early and rest. I’m the same way in my negotiations with reality.
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Colors,” in classical rhetoric, are tropes.)
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Sagan, who was convinced that marijuana’s morning-after problem is not a question of self-deception so much as a failure to communicate—to put “these insights in a form acceptable to the quite different self that we are when we’re down the next day.”
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Memory is the enemy of wonder, which abides nowhere else but in the present. This is why, unless you are a child, wonder depends on forgetting—on a process, that is, of subtraction. Ordinarily we think of drug experiences as additive—it’s often said that drugs “distort” normal perceptions and augment the data of the senses (adding hallucinations, say), but it may be that the very opposite is true—that they work by subtracting some of the filters that consciousness normally interposes between us and the world.
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From a brain’s point of view, the distinction between a natural and an artificial high may be meaningless.
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Hippocampus

Remapping revisited: how the hippocampus represents different spaces

André A. Fenton

Nature Reviews Neuroscience  volume 25, pages 428–448 (2024

  https://www.nature.com/articles/s41583-024-00817-x

Yassa, M.A., Stark, C.E.L. (2011) Pattern separation and the hippocampus. Trends in Neuroscience 34(10):515-525

Leal, S.L., Yassa, M.A. (2015) Neurocognitive aging and the hippocampus across species. Trends in Neurosciences 38(12): 800–812.

UC Irvine – Faculty Profile System

Remission from addiction: erasing the wrong circuits or making new ones? – Nature Reviews Neuroscience

 Time, Space and Memory  in the Hippocampal Formation, Derdikman et al.

This will come to you out of the blue. 

I am a 79 yo who retired in 2009 as Dean of Arts at uOttawa. I am also a PwP. Hence my interest in your lecture, which I shall attend with my wife, Nasrin Rahimieh, Associate Dean of Humanities for Academic Personal.

As a (concerned) amateur, I have been reading much popular neuroscience of late, including Erich Kandel, In Search of Memory; Linder,  The Accidental  Mind; MacDermott, 101 Theory Drive; and Brahic, The Power of Prions.

Also, I’ve written a blog piece on what happens when you have classic Parkinson’s, which I link here for what it’s worth: https://alteritas.net/GXL/?p=5189.

Could you suggest an article or two I should read before attending the Feb 4 lecture? I would be much obliged. 

George Lang