kofi

A number of studies over the years have shown the benefits of
low-glycemic index diets for the treatment of attention deficit and drug
addiction. (I've searched my records and, sadly, I seem to have missed
entering those studies into my database when I came across them).

We now have direct evidence that blood sugar affects "prediction error"
or time horizon calculations involving the dopamine subsystem - although
not in the way these authors think. These researchers discovered that a
single dose of sugar allows someone to focus more on long term reward
and resist more immediate temptations (this test is, by the way, when
administered to young children a major predictor of success in their
future education). Administering sugarless diet soda encouraged
indulgence on the part of the study participants.

You would conclude "glucose" is great for addiction, right?

Wrong.

Repeated consumption of soft drinks results in insulin resistance and
insulin/glucose spikes. This produces lows as well as highs. This
experiment only looked at one-off consumption, not chronic consumption.
These lows should cause the same phenomena as seen with the diet soda.

There's also evidence that diet sodas may trip these systems even more
severely. While people consuming regular soft drinks gain abnormal
amounts of weight, those consuming diet drinks have an even more severe
problem with obesity. In short, this is what's probably going on: you
consume a low calorie "sweet" drink and your body says, "Hm. That drink
is sweet. I should be getting some calories." And then when you don't
get the expected calories, your body says, "Holy shit! I've got some
sort of a parasite or a disease or something. Where's the sugar?! I
better start eating more! I can't hold on to calories!" In other
words, the sweet taste appears to prepare the body for a dose of
calories and when it doesn't arrive, a signaling circuit doesn't close
and appetite remains high - triggering overeating. (Once again, I don't
have a reference handy.)

Given what we know, I suggest it likely that the effects of regularly
consuming normal soft drinks would quickly converge on the diet soda
model. That is to say, not only would you become more prone to obesity
by consuming regular soda you would also become more prone to addiction.
This chronic stress can also reinforce cravings for fatty and/or sugary
foods - possibly in some sort of failed attempt to resolve it. In
periods of crisis, we often need a quick and dirty burst of calories to
escape danger and sugar provides it. Unfortunately, trouble sets in
when the sugar doesn't resolve the problem. It's when the stress axis
remains chronically activated that sugar cravings become a pathological
problem. (And herein we see the connections to the sympathetic nervous
system on which I've been working.)

On the other hand, a low glycemic index diet - which has proven benefits
in treating addiction - has a high amount of fiber to slow the digestion
of and release of sugar into the blood. This leads to an even supply of
glucose to the brain over time and, one would think, a smoother release
of dopamine and greater impulse control. The fiber also nourishes the
gut and affects epigenetic regulation via butyrate synthesis, which
involves OCTN2, PPARalpha and carnitine uptake (and there are also some
interesting connections to GDNF here, if you're interested).

On a separate note, prenatal vitamin D3 has a profound effect on
creating dopamine-producing cells in the brain. Its role in adult
dopaminergic cells has been harder to elucidate but there is good
evidence that the inflammation associated with hyperglycemia elevates
p65/RelA and this can lead to a sort of vitamin D3 resistance making it
more difficult for D3 to do its transcriptional duties [PMID 15211579].

Over the last two generations, we have shifted to a more processed,
sugary diet and we've had to deal with the obvious health consequences.
What hasn't been so obvious is the shift this may have had on our
political and economic behavior. I think this link between sugar
consumption and cognitive time horizons may help to explain some of the
political trends we have seen in the population as Americans have been
more likely to opt for short-term tax cuts and banking deregulation even
if it causes long-term levee failures and economic depressions. It's
been hard to learn, to summon up the patience to read the newspaper and
educate yourself about the issues. So we don't; we fall back on
propaganda because it's the equivalent of junk food - stirring, even
emotionally nourishing but ultimately unhealthy and unsustainable. We
do it because all-too-often we don't have the patience and attention to
question it. This nutritional link may also explain why so many people
have been prone to taking credit card loans at insanely high interest
rates and rolling them over instead of exercising some self-control and
going to the bank for a straight loan - or better yet, saving the money
first before buying the item in question. The refined sugar lobby has
been undermining our collective capacity for self-reflection.


<http://www.sciencedaily.com/releases/2010/01/100125173444.htm>


Sweet Future: Fluctuating Blood Glucose Levels May Affect Decision Making

ScienceDaily (Jan. 25, 2010) ‹ Would you choose to receive a small
amount of money today or a larger sum next month? We know that it is
worth it to wait longer for a larger reward, but sometimes the
temptation for the smaller, immediate reward becomes too great and we
simply cannot resist it. Selecting the immediate reward is known as
"future discounting" and often suggests a lack of self-control.

Studies have indicated that there may be a link between blood glucose
levels (our body's energy) and thinking. For example, making difficult
choices uses up cognitive resources (or brain power) and these resources
can be restored by increasing blood glucose.

Psychological scientists X.T. Wang and Robert D. Dvorak from the
University of South Dakota investigated how blood glucose levels impact
the way we think about present and future rewards. Volunteers answered a
series of questions asking if they would prefer to receive a certain
amount of money tomorrow or a larger amount of money at a later date.
They responded to seven of these questions before and after drinking
either a regular soda (containing sugar) or a diet soda (containing the
artificial sweetener aspartame). Blood glucose levels were measured at
the start of the experiment and after the volunteers drank the soda.

The results, reported in Psychological Science, a journal of the
Association for Psychological Science, reveal that people's preferences
for current versus later rewards may be influenced by blood glucose
levels. The volunteers who drank the regular sodas (and therefore had
higher blood glucose levels) were more likely to select receiving more
money at a later date while the volunteers who drank the diet sodas (and
who had lower blood glucose levels) were likelier to opt for receiving
smaller sums of money immediately. These findings are suggestive of an
adaptive mechanism linking decision making to metabolic cues, such as
blood sugar levels.

The results indicate that when we have more energy available (that is,
higher levels of blood glucose), we tend to be more future-oriented. The
authors note that "the future is more abstract than the present and thus
may require more energy to process. Blood glucose as brain fuel would
strengthen effortful cognitive processing for future events."
Conversely, having low energy (or low blood glucose levels) may make an
individual focus more on the present. The finding that a diet soda drink
increased the degree of future discounting suggests that artificial
sweeteners may alarm the body of imminent caloric crisis, leading to
increased impulsivity.

The authors conclude that if controlling blood glucose levels may affect
our decisions for later versus current rewards, then "reducing the
degree of fluctuation in blood glucose may offer a possible means for
the treatment and intervention of some impulsive disorders, anorexia,
drug addiction, and gambling addiction."

------------------------------------------------------------------------
Story Source:
Adapted from materials provided by Association for Psychological Science.
------------------------------------------------------------------------


<http://www.sciencedaily.com/releases/2010/01/100120211027.htm>

Novel Computational Model: How Parkinson's Medications Affect Learning
and Attention

ScienceDaily (Jan. 20, 2010) ‹ A new brain-based computational model is
helping to understand how Parkinson's disease and dopamine
medications‹used to treat motor symptoms caused by the disease‹ can
affect learning and attention.

As reported in a forthcoming article in the Journal of Cognitive
Neuroscience, a new computational model, developed by Drs. Ahmed
Moustafa and Mark Gluck, at the Center for Molecular and Behavioral
Neuroscience at Rutgers University, Newark, has shown*how Parkinson¹s
disease affects attentional performance during learning.

The same model also shows that dopamine medications enhance attentional
performance in Parkinson¹s patients in agreement with*past observations.
Future lab experiments with Parkinson¹s patients will be conducted by
Moustafa and Mark Gluck to test further model predictions.

Parkinson's is a disease that mainly affects dopamine levels in a brain
area known as the basal ganglia, which is important for motor control.
Hence, damage to this area leads to movement disorders, including
shaking and difficulty moving--key symptoms of Parkinson's disease.

Over the past two decades, it became known to neurologists and
experimental neuroscientists that Parkinson¹s disease also affects
non-motor functions, including memory, learning, and attention.
Impairment in these processes affect the quality of life of the
patients, thus, understanding the neural basis of motor and non-motor
dysfunction in Parkinson¹s disease is equally important.

Dopamine is also projected to other parts of the brain, including the
prefrontal cortex, an area important for higher-level thinking, decision
making, and attention. Dopamine projected to the prefrontal cortex is
also reduced in Parkinson¹s disease, as reported in many experimental
studies with humans and animal models of Parkinson¹s disease.

According to Moustafa and Gluck, until recently, existing computational
models of Parkinson¹s disease ignored any role played by dopamine in the
prefrontal cortex. Moustafa and Gluck have designed a new computational
model that shows how dopamine in the prefrontal cortex is important for
attentional performance, and how dysfunction of dopamine in the
prefrontal cortex can explain many of the non-motor deficits seen in
Parkinson¹s patients.

³Computational models are increasingly being used in the neurosciences
and neurology to understand how neurological disorders affect brain and
behavior,² said Moustafa. ³This relatively new field‹known as
computational neuroscience‹ is promising to aid in designing new
pharmacological and surgical intervention tools to treat neurological
and psychiatric diseases.²

This research was funded by the National Institute for Neurological
Disorders and Stroke (NINDS) and by a grant from the Bachman-Strauss
Foundation's Dekker Foundation Fund.
------------------------------------------------------------------------
Story Source:
Adapted from materials provided by Rutgers University.
------------------------------------------------------------------------

Journal Reference:

1. Ahmed A. Moustafa, Mark A. Gluck. A Neurocomputational Model of
Dopamine and Prefrontal*Striatal Interactions during Multicue Category
Learning by Parkinson's Patients. Journal of Cognitive Neuroscience,
2010; (early access): 100104044127045 DOI: 10.1162/jocn.2010.21420


the tendency to make a compulsive choice, even when faced with
substantial negative outcomes and alternative choices, is characteristic
of aberrant gambling or shopping behaviors. Abnormalities in "prediction
error," which serves as a kind of teaching signal to update our future
predictions and influence future choices, have been hypothesized to play
a role in substance abuse disorders. Prediction error has not yet been
linked to such human behavioral pathologies. Compulsive behaviors can be
triggered in Parkinson's disease patients treated with drugs that
stimulate the brain's dopamine system including gambling, shopping,
binge eating, and hyper***uality; These behaviors are associated with
factors predisposing to general substance abuse disorders, emphasizing a
common underlying susceptibility."; dopamine agonists elicited an
increase in the rate of learning from beneficial outcomes and a greater
prediction error, signifying a better than expected outcome, in
susceptible individuals with Parkinson's disease; this is consistent
with a model whereby a distorted estimation of the gain underpins a
choice bias towards gains; dopamine agonists dysregulate a key
decision-making process in a population susceptible to compulsive
behaviors and provide clues to mechanisms that underlie behavioral
escalation in a disorder of behavioral addiction. The mechanism may also
explain why anecdotally some patients describe the onset of their
gambling symptoms after experiencing a 'win'."
<http://www.sciencedaily.com/releases/2010/01/100113122251.htm>

diets high in saturated fat and sugar (refined carbohydrates) have an
adverse effect on learning and memory in mice and also enhance the
effects of stress on learning and memory and particularly may do so in
individuals prone to sleep apnea (intermittent hypoxia) by decreasing
CREB phosphorylation; these diets particularly impair the body¹s ability
to handle neurotoxins
<http://www.sciencedaily.com/releases/2004/10/041030132026.htm>

dopamine is important to decision-making and learning likes/dislikes;
Parkinson¹s patients have a hard time relying on ³gut feelings² to make
decisions - these are contextual decisions based on positive or negative
past events; Parkinson¹s patients on their medication (with greater
levels of dopamine) were overly influenced by positive outcomes (and
inclined to gambling bouts; other compulsions include *** and shopping;
the drug Mi****x which targets dopamine receptors is particularly
notorious for these adverse events and can also cause extreme sudden
sleepiness) and relatively insensitive to loss whereas those off their
medication were overly influenced by negative outcomes; by keeping
dopamine levels higher in the brain, ritalin may block certain forms of
learning
<http://www.sciencedaily.com/releases/2004/11/041108021208.htm>; ritalin
(methylphenidate) injections cause a release of dopamine; those with a
lot less dopamine receptors report a pleasant feeling whereas others
report unpleasant effects; people with more dopamine receptors are
probably less likely to abuse drugs (perhaps even thrill averse); it¹s
not the winning of money that releases dopamine but the uncertainty
associated with the act of gambling
<http://www.nytimes.com/2005/06/20/menshealth/20friedma.html>; ritalin
(MPH) administration to impulsive adolescent rats causes permanent brain
changes in the reward-related circuits which may account for increased
self-control as adults; there were long term changes in the dorsal
striatum (STR), nucleus ac***bens (NAcc), and prefrontal cortex (PFC) of
ritalin-exposed rats; total creatine and taurine, metabolites
respectively involved in bioenergetics and synaptic efficiency, were
upregulated in the STR and conversely down-regulated in the NAcc of
MPH-exposed rats; a strong correlation was evident between
non-phosphorylated creatine in the STR and behavioral impulsivity;
moreover, unaltered total creatine and increased
phospho-creatine/creatine ratio were detected in the PFC, suggesting
improved cortical energetic performance; because of this enduring
rearrangement in the forebrain function, MPH-exposed animals may be more
efficient when faced with delay of reinforcement [PMID 17196789]; a
defect in dopamine transport in the brain (a certain allele) is linked
to ADHD and substance abuse via extracellular ac***ulations of dopamine
<http://www.sciencedaily.com/releases/2005/06/050607001516.htm>

in addition to vagus nerve stimulation working in epilepsy, it can also
relieve severe hiccups; many folk remedies for hiccups - eating a
spoonful of sugar, drinking cold water, throwing up - are all methods of
stimulating the vagus nerve
<http://www.nytimes.com/2006/01/10/health/10hicc.html>

abundant gut bacterium Bacteriodes thetaiotaomicron (B. Theta) activates
more than 25% of its genes when host diet changes from sugar to complex
carbohydrates; B theta breaks down fiber and other otherwise
indigestible carbohydrates; in a sugar environment, B theta changes its
surface proteins to switch from dining on complex particles to digest
host-produced musuc carbohydrates; these changes may play a role in
maintaining host immune response
<http://www.sciencedaily.com/releases/2005/03/050326003133.htm>

SIRT6 deficiency triggers a switch in glucose processing, which is a
process that regulates longevity and the proliferation of tumor cells;
absence of SIRT6 induces a fatal drop in blood sugar in mice by
triggering a switch between two critical cellular processes; SIRT6 acts
as a master regulator of glucose levels by maintaining the normal
processes cells use to convert glucose into energy; SIRT6 is one of
seven mammalian sirtuins; mice lacking it die in the first month of life
from acute hypoglycemia; normally cells convert glucose into energy
through a two-step process; glycolysis - the first stage - takes place
in the cytoplasm, where glucose is broken down into pyruvate (an acid)
and a few molecules of ATP (a cellular fuel); pyruvate is taken up by
mitochondria and further processed to release greater amounts of ATP
through cellular respiration; SIRT6-deficiency hypoglycemia is caused by
increased cellular uptake of glucose and not by elevated insulin levels
or defects in the absorption of glucose from food; glycolysis increased
and mitochondrial respiration was reduced in SIRT6-knockout cells,
something usually seen when cells are starved for oxygen or glucose;
activation of the switch from cellular respiration to glycolysis is
controlled through SIRT6's regulation of HIF-1alpha; normally, SIRT6
represses glycolytic genes through its role as a compactor of chromatin
- the tightly wound combination of DNA and a protein backbone that makes
up chromosomes; absent SIRT6, this structure is opened, causing
activation of these glycolytic genes; there is increased expression of
glycolytic genes in living SIRT6-knockout mice - animals which also had
elevated levels of lactic acid, characteristic of a switch to glycolytic
glucose processing; SIRT6's control of critical glucose-metabolic
pathways could signify a contribution to lifespan regulation; elevated
glycolysis is common in tumor cells, suggesting that a lack of SIRT6
could contribute to tumor growth; since knocking out SIRT6 causes blood
sugar to drop, limited SIRT6 inhibition could be a novel strategy for
treating type 2 diabetes; it¹s unknown if SIRT6 acts as a tumor
suppressor and how it might help lower glucose levels in diabetes
<http://www.sciencedaily.com/releases/2010/01/100121140332.htm>; SIRT6
deficiency leads to shortened lifespan in mammals and an aging-like
phenotype in mice, but the underlying molecular mechanisms are unclear;
SIRT6 functions at chromatin to attenuate NF-kappaB signaling (NFKB);
SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone
H3 lysine 9 (H3K9) at NF-kappaB target gene promoters; in
SIRT6-deficient cells, hyperacetylation of H3K9 at these target
promoters is associated with increased RELA/p65 promoter occupancy and
enhanced NF-kappaB-dependent modulation of gene expression, apoptosis,
and cellular senescence; increased activity of NF-kappaB-driven gene
expression programs in multiple Sirt6-deficient tissues in vivo;
haploinsufficiency of RelA rescues the early lethality and degenerative
syndrome of Sirt6-deficient mice; SIRT6 could attenuate NF-kappaB
signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB
signaling may contribute to premature and normal aging [PMID 19135889]
(p65/RelA expression leads to a kind of Vitamin D3 resistance); SIRT6
dampens NF-kappaB-dependent gene expression, thus unveiling a potential
link between inflammation, aging, and metabolism [PMID 19135883]

old fat stored in peripheral tissues - thigh, abdomen, etc - can¹t be
burned efficiently unless new fat is eaten or manufactured in the liver;
mice lacking fatty acid synthase (which converts glucose into fat) in
the liver can¹t maintain normal sugar fat and cholesterol metabolism
unless they take in dietary fat; the mice developed fatty liver disease
when placed on a low fat diet; old fat stores mobilized into the liver
but couldn¹t be burned and just ac***ulated; also blood sugar dropped;
effects were reversed with dietary fat or by activating PPARalpha; new
fat in the liver may initiate the PPARalpha pathway; fish oils and other
dietary fats might more effectively activate PPARalpha for people with
insulin resistance
<http://www.sciencedaily.com/releases/2005/05/050509173826.htm>

PPAR¹s determine how cells respond to energy resources; when the intake
of calories exceeds the ability of the body to use and store them,
insulin stops working as well and blood sugar rises; the problem starts
with the diversion of fats to muscle triggering abnormal activation of
PPARalpha which tells cells to stop responding to insulin resulting in
higher levels of blood sugar; PPARalpha is unusually active in the
hearts and skeletal muscles of diabetic mice trying to rev up the
machinery cells use to make energy from fat and ignore glucose to get
rid of the fat; mice with extra PPARalpha in their muscles can chew up
fat without getting obese but they have insulin resistance and glucose
intolerance; PPARalpha shuts down genes involved in glucose uptake and
use; mice without PPARalpha got just as fat as normal mice on a high fat
diet but did not develop early signs of diabetes
<http://www.sciencedaily.com/releases/2005/02/050222194340.htm> (recall
that PPARalpha should have epigenetic effects on histones via a
OCTN2/carnitine/butyrate pathway)

the loss of epigenetic regulators causes mental retardation; developing
neurons need access to the right genes at the right times; improper
functioning of one specific protein complex that normally suppresses
gene activation is responsible for a mental retardation-like syndrome in
mice; malfunction of this protein complex causes mental retardation in
mice and humans and may even play a role in promoting susceptibility to
drug addiction; the complex is a key regulator of neuronal
transcriptional identity; genes provide the fixed template that instruct
cells how to grow; gene activity is governed by proteins called
histones; histones are subjected to chemical modifications (acetylation)
that can permit or prevent genes from becoming active; these
modifications are established by specific enzymes that add well-defined
chemical residues to the amino acids localized within the tails of the
histone proteins; GLP/G9a is an enzyme pair responsible for inducing an
epigenetic mark widely known to silence gene expression in mammals,
including humans; by attaching two methyl groups to a specific amino
acid on a specific histone, GLP/G9a suppresses gene activity; there is a
strain of mice that enables conditional removal of this complex in
various cell types, including neurons in the adult brain; when subjected
to a battery of behavioral tests these mice behave much like humans with
a mental retardation syndrome called the 9q34 deletion syndrome, in
which the region of chromosome 9 that codes for the GLP genes is
missing; mice lacking GLP/G9a, unlike their normal counterparts, were
not afraid of open space, were lethargic (and as a result, obese) and
had problems learning to adapt to their environment; there were no
structural differences between the brains of normal mice and the
conditional knockouts; this suppressive epigenetic mark completely
disappears in these mice, but the neurons themselves do not die and
appear normal; mice maintain many of their default behaviors like eating
and breeding, but they behave abnormally in response to various
environmental signals; loss of GLP/G9a increases expression of genes
usually found in muscles and the hear; several nonneuronal genes,
normally suppressed by the epigenetic mark, were upregulated in the
GLP/G9a conditional knockouts; it's also possible that genetically
predetermined or environmentally induced changes of the epigenetic
regulators controlling the methylation mark on histone H3 may be
responsible for individual differences in learning and social
adaptation; Schaefer et al. Control of Cognition and Adaptive Behavior
by the GLP/G9a Epigenetic Suppressor Complex. Neuron, 2009; 64 (5): 678
DOI: 10.1016/j.neuron.2009.11.019,
<http://www.sciencedaily.com/releases/2010/01/100114225326.htm>

GDNF and NT-4 protect midbrain dopaminergic neurons from toxic damage by
iron and nitric oxide [PMID 10785444]; GDNF in the ventral tegmental
area has also been used to protect against drug addiction; addiction
often lowers GDNF levels
<http://www.newscientist.com/channel/health/mg18524834.200>; injecting
GDNF in the ventral tegmental area immediately and drastically cut back
on the alcoholic drinking impulse in rats without interfering in other
pleasure-seeking activities like appetite
<http://www.sciencedaily.com/releases/2008/06/080609170806.htm>; histone
deacetylase inhibitors like butyrate upregulate GDNF and BDNF gene
transcription in astrocytes and protect dopaminergic neurons; HDAC
inhibitors might protect against Parkinson¹s; Parkinson's disease causes
the progressive loss of dopaminergic (DA) neurons in the midbrain
substantia nigra; valproic acid (VPA), a mood stabilizer, anticonvulsant
and histone deacetylase (HDAC) inhibitor, increases the expression of
glial cell line-derived neurotrophic factor (GDNF) and brain-derived
neurotrophic factor (BDNF) in astrocytes to protect DA neurons in
midbrain neuron-glia cultures; two additional HDAC inhibitors, sodium
butyrate (SB) and trichostatin A (TSA), mimic the survival-promoting and
protective effects of VPA on DA neurons in neuron-glia cultures; both
increased GDNF and BDNF transcripts in astrocytes in a time-dependent
manner similar to VPA; marked increases in GDNF promoter activity and
promoter-associated histone H3 acetylation were found in astrocytes
treated with all three compounds, where the time-course for acetylation
was similar to that for gene transcription; astrocytes may be a critical
neuroprotective mechanism of HDAC inhibitors [PMID 18611290]

insulin reduces the presence of the molecule that transports dopamine in
the brain and thus influences food and alcohol consumption and drug
addiction; PKA modifies sensitivity to alcohol; inhibiting PKA reduces
the amount of alcohol necessary to cause inebriation; higher levels of
insulin increases sensitivity to alcohol
<http://www.sciencedaily.com/releases/2004/12/041219180504.htm>

biogenic amines (norepinephrine, dopamine, homovanillic acid, serotonin
and 5-hyroxyindole acetic acid) were measured by HPLC method in adult F1
generation rats' brain regions (brainstem, hypothalamus, hippocampus,
striatum and frontal cortex), whose mothers (P generation) were treated
with vitamin A or vitamin D neonatally (hormonal imprinting). Many
significant differences were found, related to the maternally untreated
controls. In the earlier studied P generation females, vitamin A
consistently influenced the serotonerg system (5HIAA), while vitamin D
the dopaminerg system (DA or HVA). Vitamin A imprinting always resulted
in reduced, while that by vitamin D always in increased tissue levels.
In the present case (directly untreated F1 generation) the
transgenerational effect was not unidirectional, however biogenic amine
tissue levels were strongly disturbed and brain-area dependent. The
results call attention to the transgenerational effect of hormonal
imprinting in the case of receptor level acting vitamins which are
frequently used in the most imprinting-sensitive period (perinatally) of
human life and suggests that caution is warranted [PMID 19091501],
"Transgenerational hormonal imprinting caused by vitamin A and vitamin D
treatment of newborn rats. Alterations in the biogenic amine contents of
the adult brain"

taka

HFCS responsible for our economic crisis but at least the drug
companies will profit ...