Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
WO 2021/194796
PCT/US2021/022517
METHOD FOR TREATMENT OF NEUROLOGICAL DISORDERS USING SYNAPTIC
PATHWAY TRAINING
BACKGROUND OF THE INVENTION
Technical Field
[0001] This invention relates to methods for the treatment of a
neurologic condition. In
particular, the invention relates to methods of treating depression, bipolar
disorder, mania,
alcoholism and post-traumatic stress disorder by training synaptic pathways in
the brain and
affecting the hippocampus by changing its structure.
State of the Art
[0002] Depression is common, and a significant public health
problem in the United States.
It is estimated that one in ten persons in the U.S. suffer from clinical
depression. In addition,
studies estimate that one in eight adults (12.7%) in the U.S. meet the
diagnostic criteria for
alcoholic use disorder.
[0003] Persons suffering from depression or bipolar disorder may
experience a constellation
of debilitating symptoms, including a lack of interest and pleasure in daily
activities, significant
weight loss or gain, insomnia or excessive sleeping, lack of energy, inability
to concentrate,
feelings of worthlessness, helplessness, excessive guilt, and recurrent
thoughts of death or
suicide. Depression can occur as a primary mental health disorder or may arise
secondary to an
unrelated primary illness. Similarly, alcohol abuse has significant negative
physical, social and
emotional effects.
[0004] Available treatments for depression include cognitive
behavioral therapy (CBT),
medications, and electroconvulsive therapy (ECT). CBT is effective in many
cases, particularly
when symptoms are mild to moderate and of recent onset, but less so in chronic
or severe
depression. CBT has been shown to be more effective with combined with
medications, and
vise-versa. Treatment of depression with medications is generally safe,
however, onset of a
therapeutic effect is gradual and may take at least several weeks to manifest,
with maximal
1
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
improvement seen only after eight weeks. If medications are discontinued, the
symptoms
generally return, often necessitating lifetime pharmacologic therapy.
Moreover, medications
alone are effective in only forty to sixty percent (40% - 60%) of cases,
combined CBT and
medications are only effective in sixty to seventy percent (60% - 70%) of
cases. ECT is useful in
up to ninety percent (90%) of patients and immediately effective, however, ECT
does cause a
level of brain damage and is associated with significant side effects,
including effects on memory
and cognitive impairment. Only about twenty percent (20%) of those with
depression receive
any treatment, and a significant percentage of those who are treated do not
achieve significant or
lasting improvement. Available treatments for alcohol abuse include programs
such as
Alcoholics Anonymous and application often of a twelve-step program and a
buddy system to
resist the urge to imbibe. Such treatments if they work are quoted as
effective in thirteen percent
(13%) at five years. It deals with resisting the urge but does not reprogram
the individual so they
no longer desire alcohol.
[0005] Currently available treatments for depression, therefore,
are 1) effective only in a
subset of patients; and 2) relatively short-lived. Similarly, programs to
treat alcoholism have
varying degrees of success and are based upon the belief that once an
alcoholic always an
alcoholic because they don't address the underlying cause.
[0006] Accordingly, what is needed is a safe and rapid-onset means
for treating depression,
bipolar disorder, alcoholism and other related diseases that is widely
efficacious and which
provides relief of symptoms and urges over an extended period of time.
DISCLOSURE OF EMBODIMENTS OF THE INVENTION
[0007] Embodiments of the present invention include methods for
treatment of a neurologic
condition by synaptic training and treatments effecting the structure of the
hippocampus to lessen
or eliminate the compulsion to consume alcohol. The foregoing and other
features and
advantages of the invention will be apparent to those of ordinary skill in the
art from the
following more particular description of the invention and the accompanying
drawings.
[0008] Disclosed is a method of treating a neurologic condition by
synaptic pathway training
comprising steps of activating a synaptic pathway with a pharmacologic agent;
and stimulating
2
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
the activated synaptic pathway. In addition, some of the embodiments of the
subject invention
combines the application of a preselected drug therapy with a non-drug
stimulus therapy to
enhance and prolong the drug therapy effect.
[0009] In some embodiments, the pharmacologic agent comprises an N-
methyl-D-aspartate
receptor antagonist. In some embodiments, the pharmacologic agent comprises
ketamine. In
some embodiments, the pharmacologic agent is a member selected from the group
of
pharmacologic agents consisting of scopolamine, Nam enda, dextromethorphan,
amantadine,
dextropropoxyphene, and ketobemidone.
[0010] In some embodiments, the pharmacologic agent is psilocybin.
In some embodiments,
the pharmacologic agent is phencyclidine. In some embodiments, the
pharmacologic agent is
lysergic acid diethylamide. There may be other embodiments, pharmacologic
agents which
produce additional synaptic connections in specific areas of the brain. These
embodiments will
treat other conditions reflecting disease processes of specific areas of the
brain effected.
[0011] In some embodiments, the neurologic condition is depression.
In some embodiments,
the neurologic condition is bipolar disorder. In some embodiments, the
neurologic condition is
post-traumatic stress disorder. In some embodiments the condition is
alcoholism and possibly
other conditions which negatively alter and impact the size and/or functioning
of the
hippocampus or other areas
[0012] In some embodiments, stimulating the synaptic pathway
comprises performance of a
cognitive training exercise. In some embodiments, the stimulating step
comprises exposure of a
person to a sensory stimulus. In some embodiments, the stimulating step
comprises applying a
magnetic field to a region of a brain. In some embodiments, the stimulating
step comprises
applying a potential voltage difference to a region of a brain. In some
embodiments, the
stimulating step comprises providing an auditory stimulus. In some
embodiments, the
stimulating step comprises providing a visible-wavelength light stimulus. In
some embodiments
the initial step is the application of a pharmacological agent followed by a
regimen of non-
pharmacological cognitive stimuli.
3
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
[0013] Disclosed is a method of enhancing treatment of a neurologic
condition comprising
steps treating the condition with a pharmacologic agent to alter the synaptic
pathways; and
extending a treatment result by repeatedly activating the synaptic pathway
with a neural
stimulating means.
[0014] In some embodiments, activating the synaptic pathway
comprises performance of a
cognitive training exercise. In some embodiments, activating the synaptic
pathway comprises
providing an external source of stimulation. In some embodiments, the external
source is a
magnetic field, a potential voltage difference, an auditory stimulus or a
combination of stimuli.
[0015] Disclosed is a method of treating a neurologic condition or
alcoholism by synaptic
pathway training comprising steps activating a synaptic pathway by
administering at least one
dose of ketamine, at least 0.5 mg/kg; and stimulating the activated synaptic
pathway by
performing a cognitive exercise for at least thirty (30) minutes daily.
[0016] In some embodiments, the neurologic condition is bipolar
disorder, depression,
mania, or post-traumatic stress disorder.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a flowchart showing steps of a method for treating
alcoholism or a
neurologic condition using synaptic pathway training;
[0018] FIG. 2 is a flowchart showing steps of an additional method
for treating alcoholism
or a neurological condition using synaptic pathway training; and
[0019] FIG. 3 is a flowchart showing steps of another method for
treating alcoholism or a
neuroglial condition using synaptic pathway training.
[0020] FIG. 4 is a flowchart showing more detailed steps of another
method of treatment for
alcoholism or other neurological condition.
=
4
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0021] As mentioned herein above, the disclosed invention relates
to methods for the
treatment of alcoholism or a neurologic condition. In particular, the
invention relates to methods
of treating alcoholism, bipolar disorder, depression, mania, post-traumatic
stress disorder, and
other neurologic conditions by training synaptic pathways in the brain.
[0022] As used herein, the following terms are intended to have a
meaning as defined below,
unless otherwise indicated.
[0023] "Synaptic density" means the number of synapses per unit
volume of neural tissue,
including brain tissue
[0024] "Synaptic pathway- is used to describe a micro-anatomic
pathway communicating a
neural impulse between two neurons, wherein the two neurons form a focal
anatomic association
with one another. The synaptic pathway includes a presynaptic neuron, the
anatomic association
comprising a synapse, and a postsynaptic neuron.
[0025] "Pharmacologic agent" means a biologically active substance
delivered to the body
with the intent to render a therapeutic effect on a tissue or organ.
Pharmacologic agents include
any recognized drug and any substance used or acting as a drug.
[0026] "Stimulating" means delivering a physiologic provocation
with the intent to activate a
synapse
[0027] "Cognitive training exercises" means an activity relating to
or involving conscious
intellectual activity, including but not limited to thinking, reasoning, or
remembering
[0028] Chronic or recurrent depression leads to neuroanatomic
changes in the brain.
Noninvasive brain imaging studies, such as computed tomography and magnetic
resonance
imaging (MRI), demonstrate volume loss in the hippocampus of patients with
chronic or
chronically recurring depression. Functional magnetic resonance imaging has
been used to show
micro-changes in blood flow within multiple regions of the brain in persons
suffering from
depression. These regions include the hippocampus, areas within the prefrontal
cortex, basal
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
ganglia, and limbic system. A corresponding decrease in synaptic density is
also seen in these
areas of depressed persons.
[0029] As discussed herein, currently available treatments for
depression include CBT,
pharmacologic agents, and ECT. The mechanism of action of antidepressant
medications is
incompletely understood, however, it is widely believed to involve
manipulating levels of
neurotransmitters; namely, serotonin, norepinephrine, and dopamine. CBT
neuronal
mechanisms are not well characterized. To the extent that CBT improves anxiety
and depression
it must affect the hippocampus, at least in some patients. ECT does not
"activate" neurons;
rather, ECT causes a simultaneous depolarizing a broad area of brain tissue,
and induces seizure
activity which spreads neuronal depolarization. This results in brain injury
and memory loss and
although certain of these therapies may be effective in an individual patient,
the beneficial effects
of the therapy are typically short-lived, disappearing soon after the therapy
is discontinued.
[0030] Similarly, alcoholism also negatively effects traffic
(synaptic transmissions) through
the hippocampus and decreases the size of the hippocampus. Treatment with
certain
pharmacological s including but not limited to Ketamine increase both the
traffic within and size
of the hippocampus. However, these pharmacological treatments are of limited
duration such
that shortly, generally between nine and twenty-one days, after treatment
traffic decreases and
the size shrinks to the extent that the symptoms return.
[0031] The methods described herein combine pharmacologic and
stimulation therapies to
achieve a surprising result¨temporary improvements in mood and behavior
experienced
following initial treatment with a pharmacologic agent are made long-lasting
by adding
stimulation therapy. This combination treatment has been named "synaptic
pathway training"
because the method "trains" a group of synaptic pathways activated by an
initial treatment to
continue functioning in the desired way by using regular and repeating
neurologic stimulation.
[0032] A non-limiting but representative example of such a method
is provided. Ketamine
is a N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor
activity. The
structure of ketamine comprises an aryl cyclohexylamine. When administered in
moderate
doses, ketamine acts as a dissociative anesthetic. As an anesthetic, ketamine
is rapid acting and
has a short duration of action. Because moderate doses do not typically
produce decreases in
respiration or blood pressure, ketamine is useful in providing anesthesia in
children and in
6
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
various non-hospital settings. Ketamine may be parenterally administered using
an intravenous,
intramuscular, or trans-nasal route.
[0033] Administration of ketamine by intravenous infusion at a dose
of about 0.5 milligrams
per kilogram of patient body weight (mg/kg) over between about forty-five (45)
and about sixty
(60) minutes is used to produce relief of symptoms of depression. Higher doses
may be used,
although doses of about 1.0 mg/kg intravenously over 45 to 60 minutes produces
a state of
sedation with vivid visual sensory changes. Patients who experience these
vivid visual sensory
changes, however, experience a stronger anti depressive effect of the
treatment. Administration
of single-dose intravenous ketamine infusions is also associated with a
transient increase in
hippocampal volume corresponding with an increase in synaptic density. It is
thought that that
the increase in hippocampal volume and synaptic density resulting from the
administration of
single-dose ketamine allows non-depressive thought patterns to occur_ This
increase in
hippocampal volume, synaptic pathways and synaptic density also lessens or
eliminates the
compulsion for an alcoholic to consume alcohol. Within as little as two hours
after an initial
treatment of a drug such as ketamine new synapses can be formed in the
hippocampus along
with the above-mentioned increases in volume and synaptic density.
[0034] The anti-depressant effects of ketamine persist from about
seven (7) to about twenty-
one (21) days, after which symptoms of depression or the urge to consume
alcohol begin to re-
emerge. If a second dose of ketamine is given by intravenous infusion usually
six (6) days after
the first dose, symptoms of depression or the urge to consume alcohol do not
return until
approximately twenty-eight (28) days after the second treatment. Treating
depression or
alcoholism with two doses of intravenous ketamine six days apart, therefore,
may result in as
much as approximately thirty-four (34) days of symptom relief.
[0035] Stimulation targeting the associated neural synaptic
pathways activated by the
ketamine, however, results in a profound prolongation of symptom relief.
Stimulation may be
intrinsic, extrinsic, or a combination of both. "Intrinsic stimulation" is
stimulation delivered to
the synaptic pathway by the patient engaging in active cognition, whereas -
extrinsic stimulation"
is the application of an external stimulus, the effects of which passively
activate the synaptic
pathway without any conscious participation by the patient. With delivery of
either an active
cognitive or passive sensory stimulus to the activated synaptic pathway, given
repeatedly over an
7
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
extended period of time, relief of symptoms of depression or the urge to
consume alcohol can be
extended for between twelve months and eighteen months.
[0036] For example, one patient with a fifty-year history of
bipolar disorder underwent
unsuccessful treatment with multiple conventional antidepressant medications
and combinations
of medications as well as CBT. Following this unsuccessful first-line therapy,
multiple
treatments with intravenous ketamine resulted in good relief from the
depression, but the longest
period of relief lasted only approximately twenty-eight (28) days. In an
effort to prolong the
results of treatment, synaptic training using cognitive activities ("brain HQ
exercises") (an
intrinsic stimulus) was undertaken for a single session of thirty-minutes each
day.
[0037] Augmenting the ketamine infusions with synaptic training in
this patient resulted in
the obliteration of depressive symptoms for greater than one year. Symptoms of
mania were also
not experienced. The patient characterized the first four-month period
starting with the first
ketamine dose as feeling the best. The second four-month period, the patient
felt "good," but not
as well as during the first four-month period. During the third four-month
period, the patient still
felt much, much better than baseline (prior to ketamine treatment), although
was subjectively
looking forward to receiving an additional ketamine dose sometime in the
future.
[0038] In an alcoholic patient he requested treatment for
depression and was treated with the
standard protocol of a ketamine infusion with a second treatment six days
later. This patient was
immediately started on synaptic training as well. The patient followed up
after more than a year.
He reported at that time that he had no symptoms of depression and that he had
two and a bottle
of beer in the refrigerator. When questioned about the significance of the
beer he reported that he
no longer drank a bottle of gin a day. At a year and half, he sought another
treatment. He lost his
job and started drinking vodka. He was given a single IV infusion and no
longer had the desire to
drink. (He reported that he got another job shortly thereafter.)
[0039] A novel aspect of this method is using a pharmacologic agent
in combination with a
neural stimulation means, whether extrinsic or intrinsic, to subsequently
target the brain area
(synaptic pathway) activated by the pharmacologic agent. It should be noted
that the use of
many other pharmacologic agents other than ketamine may be used, depending on
the synaptic
pathway to be activated and the neurologic condition to be treated. It should
also be noted that
use of many different means of targeted stimulation of the activated synaptic
pathways are also
contemplated. It should additionally be noted that alcoholism as well as many
neurologic
8
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
conditions other than depression may be treated with a combination of
pharmacologic synaptic
pathway activation following by training the activated synaptic pathway with
repeated targeted
stimulation.
100401 The result of combining pharmacologic activation with
targeted stimulation of the
activated synaptic pathway is an increase in the efficacy and duration of
effect of the treatment
much, much longer than with the use of drug therapy or directed synaptic
pathway stimulation
alone. The exact mechanism of this effect is unknown; however, it is thought
that the
pharmacologic activation of a synaptic pathway in the brain, resulting in
growth of new synapses
between the neurons in the pathway, is made durable by "training- the synaptic
pathway by
regular and repeated stimulation of the pathway's presynaptic neuron.
[0041] FIG. 1 is a flowchart showing steps of a method for treating
a neurologic condition
using synaptic pathway training. In some embodiments, the neurologic condition
is depression.
"Depression" means either clinical diagnosis of either unipolar or bipolar
depression. It should
be understood, however, that treatment of many other neurologic conditions
using method 100 is
contemplated, including mental health conditions such as mania, post-traumatic
stress disorder
("PTSD"), schizophrenia, dysthymia, chronic pain syndromes including complex
regional pain
syndrome, substance abuse disorders including but not limited to alcoholism,
neuropathic pain,
dysesthesia, traumatic brain injury, and other neurologic illnesses and
conditions.
[0042] FIG. 1 shows a method 100 comprising an activating step 110
and a stimulating step
120.
[0043] Activating step 110, in some embodiments, comprises
activating a synaptic pathway
with a pharmacologic agent. In some embodiments, the pharmacologic agent
comprises an N-
methyl-D-aspartate (NMDA) receptor antagonist. For example, as discussed
herein, ketamine is
an NMDA receptor antagonist used to activate various synaptic pathways
associated with
relieving symptoms and physical signs depression. Ketamine, other NMDA
receptor
antagonists, and other pharmacologic agents also activate synaptic pathways of
many other
neurologic conditions, including but not limited to conditions noted herein
above. The
pharmacologic agent, in some embodiments, is used to activate synaptic
pathways to treat any of
these aforementioned of other neurologic conditions.
9
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
[0044] In some embodiments, the pharmacologic agent is a serotonin
receptor agonist, such
as psilocybin, for example. In some embodiments, the pharmacologic agent is a
muscarinic
receptor agonist, such as scopolamine, for example.
[0045] Ketamine is administered at a standard dose of about 0.5
milligrams per kilogram
body weight ("mg/kg") as an intravenous infusion, in some embodiments. In some
embodiments, the dose of intravenous ketamine is about 1.0 mg/kg. In some
embodiments, the
dose of intravenous ketamine is between about 0.5 mg/kg and about 1.0 mg/kg.
[0046] A relief of symptoms of depression indicates activation of
the synaptic pathways
targeted for training. "Activation" of the synaptic pathway means an increase
in the absolute
number of functioning synaptic connections between axonal terminals of a
presynaptic neuron
and dendrites or cell bodies of one or more postsynaptic neurons. In some
embodiments, the
synaptic pathway is a prefrontal cortex synaptic pathway. In some embodiments,
the synaptic
pathway is a hippocampal synaptic pathway. In some embodiments, the synaptic
pathway is a
limbic system synaptic pathway.
[0047] The pharmacologic agent, like ketamine, for example, causes
an increase in synaptic
density between the presynaptic and postsynaptic neurons of the synaptic
pathway which
correlates to relief from symptoms of depression, or some other neurologic
condition including
the urge to consume alcohol. As noted herein, some patients experience a
relief of depressive
symptoms following one dose of intravenous ketamine. Some patients, however,
do not
experience a full relief of depression until receiving two doses of
intravenous ketamine
administered usually six (6) days apart. Some patients require greater than
two intravenous
ketamine doses, each dose following the preceding dose by a period of one to
two days.
Consequently, in some embodiments, activating step 110 comprises administering
two doses of
the pharmacologic agent. In some embodiments, activating step 110 comprises
administering
three doses of the pharmacologic agent. In some embodiments, activating step
110 comprises
administering greater than three doses of the pharmacologic agent. There is a
direct correlation
between providing a therapeutic amount of the pharmacological agent which
results in the
patient experiencing a temporary dissociative state and achieving a sufficient
increase in the
number of synapses, hippocampal volume and synaptic density to achieve a
reduction or
elimination of the targeted symptoms including alcoholism and the urge to
consume alcohol.
Dosages need to be administered in the lowest amount necessary to achieve the
desired
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
temporary dissociative effect without reaching the anesthetic dose. Other
hallucinogens such as
psychedelics and deliriants may also be effective but typically not at the
same time.
[0048] Individuals react differently to the pharmacological agents
discussed above such as
Ketamine for a variety of reasons. It appears while some patients are simply
more sensitive
others, especially those who have a history of using pharmacologic agents,
require a higher
dosage to achieve the desired temporary dissociative effect. Accordingly, an
initial dosage of 0.5
mg per kilogram of weight is a preferred starting point. This dosage has shown
to be effective for
relatively young, healthy patients without significant pharmacological (drug)
experiences. Where
that treatment is not completely effective it is common for the patient to
experience improved
sleeping patterns. Improved sleep patterns indicate that while the treatment
is partially effective a
higher dosage is required to obtain the desired temporary dissociative effect.
Once the chosen
dosage is effective in achieving a temporary dissociative state in the patient
there will be an
accompanying decrease or elimination of symptoms confirming the described
positive changes
to the hippocampus. This can be confirmed if necessary, by before and after
scans. The described
cognitive exercises are initiated immediately after the first treatment to
maintain the
hippocampal changes for a period far beyond the time achieved with only the
pharmacological
treatment.
[0049] The length of time reduced or eliminated symptoms can be
sustained will vary from
patient to patient. Assuming adherence to the cognitive exercise protocol it
is common to obtain
an extension of the desired effect for twelve to eighteen months. As some
point the symptoms
will begin to gradually appear thus giving the patient time to notify their
medical provided and
obtain another pharmacological treatment followed by continued cognitive
exercises.
[0050] Ongoing studies, including brain mapping will correlate
particular medical conditions
such as those discussed above to particular areas of the brain. Specific
pharmacological drugs are
then selected for treatment based upon their effect on the particular area
which needs to be
treated, namely increasing volume, synaptic pathways and synaptic density in
the portion of the
brain being treated. Similarly, the selected cognitive training exercise or
external stimulation is
chosen based upon the effect it has on the treated areas of the brain to
maintain the increased
volume, synaptic pathways and synaptic density.
[0051] Stimulating step 120, in some embodiments, comprises
stimulating the activated
synaptic pathway. The importance of achieving activation of the synaptic
pathway prior to
11
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
performance of stimulating step 120 should be noted, because stimulating step
120 acts to
potentiate the activated state, but not to cause activation. Stimulating
synaptic or brain pathways
that have been activated by prior treatment, such as treatment with ketamine
or another
pharmacologic agent, for example, potentiate the favorable treatment result.
Activation of the
synaptic pathway, therefore, must be present for stimulating step 120 to have
the intended effect
of prolonging the relief of symptoms of the neurologic condition by prolonging
the time period
wherein the synaptic pathway remains activated.
[0052] As noted herein, stimulation of the activated synaptic
pathway undertaken during
stimulating step 120 may be intrinsic (cognitive) stimulation or extrinsic
(sensory) stimulation.
Intrinsic (cognitive) stimulation is actively initiated by the patient.
Extrinsic (sensory)
stimulation is passively received through an extrinsic sensory stimulus.
[0053] Cognitive stimulation is delivered to the activated synaptic
pathway, in some
embodiments, by performance of various cognitive exercises commonly known as
"brain
training" exercises. The exercises include, but are not limited to, daily
cognitive exercises
performed for a minimum of about thirty (30) minutes to any longer time
wherein the patient is
able to focus on the activity. Cognitive exercises comprise games and thought-
activities
designed to increase attention, memory, problem solving, focus, and the like.
An example of a
cognitive exercise that may be utilized in stimulating step 120 is a
proprietary set of exercises
known as Brain HQ " which has been shown to address the pathways resulting
from
Ketamine treatment for neurological disorders including but not limited to
Bipolar and
alcoholism
[0054] A non-limiting example of providing extrinsic stimulation
includes placement of a
potential voltage difference across the brain. For example, low-voltage direct
current devices,
such as a transcranial direct-current stimulation device, may be used in some
embodiments to
provide an extrinsic stimulus to the activated synaptic pathway. The
electrodes to create the
potential are positioned with a polarity to depolarize the pre- and post-
synaptic neurons of the
synaptic pathway.
[0055] Additional examples of providing extrinsic stimulation
include placing the brain in a
magnetic field. In some embodiments, the extrinsic stimulus comprises a sound.
In some
embodiments, the extrinsic stimulus comprises light. In some embodiments, the
extrinsic
12
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
stimulus comprises a tactile stimulus, such as a touch or a vibration
delivered to an area of the
body.
[0056] In some embodiments, cognitive stimulation comprises periods
of physical aerobic
exercise. In some embodiments, the period of exercise is less than about
twenty (20) minutes per
day. In some embodiments, the period of exercise is between about twenty (20)
and about forty-
five (45) minutes per day. In some embodiments, the period of exercise is
between about forty-
five (45) minutes and about one (1) hour per day. In some embodiments, the
period of exercise
is greater than about one 1) hour per day.
[0057] FIG. 2 is a flowchart showing steps of a method for treating
a neurologic condition
using synaptic pathway training. As shown by FIG. 2, method 200 comprises a
treating step 210
and an extending step 220.
[0058] Neurologic conditions successfully treated using method 200
include depression,
bipolar disorder, alcoholism, mania and PTSD. Use of method 200 is effective,
durable, and
does not create any of the side-effects associated with long-term therapy with
pharmacologic
agents, ECT, or other currently available treatments. Moreover, wherein
ketamine is used as the
synaptic pathway altering agent, relief from sleep disorders
_____________________ particularly insomnia which
accompany depression, mania, and PTSD is immediate and persists for months, so
long as
regular stimulation of the activated synaptic pathway undertaken in the
extending step continues.
The use of method 200 to treat mania or the manic component of bipolar disease
is particularly
effective. Currently, treatment of mania requires use of psychotropic
medications with a very
high incidence of undesirable side effects, including weight gain, increased
risk of type-2
diabetes, hypercholesterolemia, dysphoria/apathy from blunted moods, and
tardive dyskinesia.
Method 200 is dramatically effective for the treatment of mania, in some
persons, and none of
the aforementioned side effects have been observed.
[0059] Method 200 is particularly useful in treating persons with
PTSD, for at least four
reasons. First, method 200 is an effective treatment for PTSD. Second, initial
activation of the
synaptic pathway may be accomplished immediately, essentially, during the
treating step. Third,
means for provision of regular stimulation to the activated synaptic pathway,
particularly
intrinsic cognitive means, are readily available in field-settings, including
some battlefield
settings. Four when used in the setting of PTSD with TBI (Traumatic Brain
Injury) it may help
reverse the TBI particularly if done shortly after the TBI occurs. Use of
method 200, therefore,
13
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
is particularly efficacious for use during deployment, where rapid, simple,
and durable treatment
of PTSD and PTSD/TBI in a soldier is essential.
[0060] Treating step 210, in some embodiments, comprises treating
the neurologic condition
with a pharmacologic agent to alter a synaptic pathway. The neurologic
condition may be
depression, bipolar disease, dysthymia, or any number of other neurologic
conditions including,
but not limited to, those neurologic conditions listed herein. "Treating"
means administering one
or more therapies over one or more discrete time periods with the intent to
either treat the
condition, cure the condition, or relieve symptoms caused by the condition.
The therapies may
comprise: administration of a pharmacologic agent; administration of a
treatment, such as
transcrani al direct-current stimulation; or the like. Alteration of the
synaptic pathway means
"activation" of the pathway manifest directly by an increase in synaptic
density, or manifest
indirectly by relief of improvement of symptoms of the neurologic condition.
[0061] Extending step 220, in some embodiments, comprises extending
a treatment result by
repeatedly stimulating the synaptic pathway with a neural stimulating means.
"Extending a
treatment result" means causing the favorable results of treatment resulting
from treating step
210 to remain manifest for a period of time longer than that period absent
extending step 220. In
some embodiments, extending step 220 comprises stimulating an activated
synaptic pathway
with an intrinsic stimulus, as described herein. In some embodiments,
extending step 220
comprises stimulating an activated synaptic pathway with an extrinsic
stimulus, as described
herein. In some embodiments, extending step 220 comprises performance of
physical exercise
during recurring periods, such as daily, for a period of days, weeks, or
months.
[0062] FIG. 3 is a flowchart showing steps of another method for
treating a neurological
condition using synaptic pathway training. FIG. 3 shows a method 300 for
treating a
neurological condition comprising an activating step 310 and a stimulating
step 320. In some
embodiments, the neurologic condition is depression. In some embodiments, the
neurological
condition is mania or bipolar disease In some embodiments, the neurological
condition is
PTSD.
[0063] In some embodiments, activating step 310 comprises
activating a synaptic pathway
by administering at least one dose of ketamine, at least 0.5 mg/kg. This is a
baseline dose, which
may need to be repeated one or more times, at intervals of about one to two (1-
2) days. It is
foreseeable that some patients would respond more readily to a higher dose, up
to the 1.0 mg/kg
14
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
WO 2021/194796
PCT/US2021/022517
dose which is typically used to induce a dissociated state of anesthesia. The
dose may need to be
repeated two, three, or more times to obtain the desired level of relief
Relief of symptoms is the
clinical marker which indicates activation of the synaptic pathway following
completion of
activating step 310, prior to performing stimulating step 320.
[0064] In some embodiments, stimulating step 320 comprises
stimulating the activated
synaptic pathway by performing a cognitive exercise for at least thirty (30)
minutes each day.
[0065] FIG. 4 is a flowchart showing steps of another method for
treating a neurological
condition using synaptic pathway training. FIG. 4 shows a method 400 for
treating a
neurological condition comprising initially consulting with a patient to be
treated the medical
provider will start by diagnosing the issue step 410. Once diagnosed the area
of the brain most
related to that issue is identified step 420. The pharmacological treatment,
including but not
limited to a dissociative or hallucinogenic which creates a positive effect on
that potion of the
brain by increasing synaptic pathways and synaptic density (synaptic volume)
is selected step
430. A therapeutic dosage is selected to achieve and increase in structures
such as volume,
synaptic pathways and synaptic density step 440 and administered to the
patient step 450. Once
the sought-after increase in structure are obtained a regimen of
nonpharmacological brain
stimulus is selected that effects the targeted area of the brain to maintain
the increased structural
changes step 460, and the brain stimulus training is initiated step 470.
Observation of and
discussions with the patient determines whether the dosage was sufficient to
achieve patient
experience step 480 indicating the desired increases in structure step 490.
[0066] The embodiments and examples set forth herein were presented
in order to best
explain the present invention and its practical application and to thereby
enable those of ordinary
skill in the art to make and use the invention. However, those of ordinary
skill in the art will
recognize that the foregoing description and examples have been presented for
the purposes of
illustration and example only. The description as set forth is not intended to
be exhaustive or to
limit the invention to the precise form disclosed. Many modifications and
variations are possible
in light of the teachings above.
CA 03172981 2022- 9- 22 SUBSTITUTE SHEET (RULE 26)
