Get the LATEST Research From Tass Lab
Parkinson's Community Los Angeles2023-12-07
Parkinson's#Parkinson's disease#PD#CR Stimulation#Tass Lab#Parkinson's Research
4K views|9 months ago
💫 Short Summary
The video discusses neuromodulation techniques for treating Parkinson's disease, emphasizing deep brain stimulation and coordinated reset stimulation to desynchronize abnormal neuronal activity. Non-invasive rhythmic stimulation shows promise in long-lasting effects. Pilot studies on patients with Parkinson's demonstrate improvement in motor function without medication. Virotactile treatment and glove systems have positive outcomes in balance and shuffling symptoms. The focus is on personalized stimulation patterns and FDA approval for accessible treatment. Collaboration among researchers is crucial for future development in neuromodulation approaches for neurological conditions.
✨ Highlights
📊 Transcript
✦
Neuromodulation techniques for treating neurological conditions like Parkinson's disease.
01:16Dr. Peter Tas emphasizes inducing long-lasting relief by stimulating the brain to unlearn abnormal activity patterns and change connectivity patterns.
Different neurons serve different purposes and excessive synchrony negatively impacts brain functioning.
Deep brain stimulation is a significant milestone in Parkinson's treatment, with a patient demonstrating benefits.
The video segment showcases the use of electrodes and implantable devices for deep brain stimulation.
✦
Limitations of deep brain stimulation treatment.
05:24Treatment may not effectively address all symptoms, such as gait balance and speech issues.
Approach aims to counteract abnormal neuronal synchrony by desynchronizing it.
Desynchronizing stimulation can lead to a decrease in synaptic connectivity.
By disrupting coherent structures in discharge patterns, a move from a pathological state to a healthier state may be possible.
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Coordinated reset in deep brain stimulation for restarting rhythmic activity in neurons.
10:00Gentle stimulation helps neurons reduce synaptic weights and reset connections.
Technique involves a mix of periodicity and randomness for physiological information processing.
Mptp neurotoxic substance severely impacts dopamine production and motor functions in monkeys.
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Results of Coordinated Reset Stimulation on Monkeys and Parkinson's Patient
15:25Monkeys stimulated externally for two hours with coordinated reset stimulation showed no difference in movement production rate compared to normal monkeys.
Patient with Parkinson's and dystonia experienced improvement after CR stimulation, with symptoms disappearing after one month.
Standard deep brain stimulation was less effective for dystonia than CR stimulation.
Unilateral stimulation showed persistent effects even one hour after stimulation was turned off.
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Non-invasive treatment through rhythmic stimulation of neurons has potential with effects lasting up to 4 hours.
17:30Manipulating the timing of neuron populations led to significant outcomes in patients with various conditions.
Stimulation of thalamus regions like the ventral cordal nucleus produced rhythmic responses tied to external stimuli.
This method, known since the 1980s, offers promising possibilities for long-lasting effects without invasive procedures, such as vibrating gloves.
Studies by neurosurgeons have provided valuable insights into understanding neural responses and optimizing treatment approaches.
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Importance of Entrainment in Brain Stimulation.
21:55Neuronal discharges must be timed properly for effective brain stimulation.
Changing neural networks is essential for learning.
Fingertips are targeted for stimulation due to their large cortical representation.
A non-invasive glove system with vibrators shows promising results in pilot studies.
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Study on motor function improvement in patients without medication.
24:52Patients in the study had to withdraw medication for 12-48 hours before exams.
Significant improvement in motor scores was observed even without medication.
Long-term effects were encouraging, with patients showing improvement after being off medication.
Study aimed to determine clinically significant effects using MCI, with a decrease in motor score greater than 3.25 deemed significant.
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Clinical improvements and reduced medication seen after 3 months of GL therapy for Parkinson's disease.
29:20Significant decrease in Parkinson's related abnormal brain rhythms observed post-treatment.
Lasting benefits up to 1.5 years post-treatment reported in patients.
Promising results from the therapy, but further research needed to validate findings against placebo effects.
✦
Virotactile treatment shows significant improvement in Parkinson's patient.
35:04Patient experienced reduced medication, improved motor functions, and enhanced sense of smell and taste.
Patient was able to return to work, run the New York Marathon, and participate in a Triathlon.
Case study emphasizes potential benefits of virotactile treatment for Parkinson's patients, showing unexpected improvements beyond motor symptoms.
Future studies will focus on systematically studying these additional benefits.
✦
Patient showed significant progress in walking stability after six months of treatment.
40:00Treatment involves a glove system and deep brain stimulation, showing favorable effects in patient response.
Investment in optimizing treatment and upcoming pilot studies for different patient populations.
Focus on improving motor symptoms and overall patient condition through innovative technology and research.
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Research aims to provide personalized stimulation patterns for patients through mathematical models that mimic brain activity.
42:48Pilot studies are being conducted to optimize treatment and prepare for larger scale studies.
Timeline for FDA approval and reimbursement is dependent on achieving substantial goals with competent team members.
Focus is on providing professional and accessible treatment to as many patients as possible.
Emphasis on thorough testing and minimizing risk factors for successful implementation.
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Importance of conducting placebo control trials for sensory treatments.
46:32Initial pilot studies and proof of concept trials are planned before FDA approval trials begin.
Goal is to provide treatment to all patients quickly, focusing on analyzing relaxing effects psychologically and through brain recordings.
Device may be usable for BBS patients, with no apparent reason for it to not be feasible.
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Conducting pilot studies is essential before larger trials for testing treatments on patients with conditions like Parkinson's Tremor and essential tremor.
51:34FDA approval is crucial in the process of testing treatments on patients with neurological conditions.
Promising results have been observed in early studies, particularly in non-motor symptoms.
Lack of networking among researchers using vibratory approaches for neuromodulation is identified as an area for future development.
Collaboration among researchers in the field of neuromodulation is necessary for further advancements in treatment options.
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The speaker discusses the expansion of symptoms in Parkinson's disease beyond cognitive and memory-related issues.
55:10Collaboration with different groups in computational research is highlighted as driving progress in the field.
The speaker expresses optimism for a product to reach the market by 2025 or 2026.
Appreciation is extended to Dr. Tass and sponsors, along with a call to support upcoming events and donate to help families affected by Parkinson's.
The video ends with expressions of gratitude and farewell messages.
00:00Welcome to our online event the latest
00:03research from Tas lab today's program is
00:06brought to you by Parkinson's Community
00:08Los Angeles today we are so fortunate to
00:11have with us Dr Peter aass
00:16mdphd I'm Angela nef pcla board member
00:20for those of you who don't know us we
00:22are a nonprofit that supports families
00:25living with Parkinson's through free
00:27education programs like this one online
00:31and in-person support groups social
00:34events and more today's conversation is
00:37brought to you by our generous sponsors
00:40Abbot Boston Scientific kioa Kieran
00:45medronic and
00:48suis and by important donations from
00:51people just like you in the Parkinson's
00:53Community if you appreciate our work
00:56please consider making a donation at
01:00your donation is 100% tax deductible so
01:03thank you in advance we rely on your
01:06generosity to help us continue this
01:08important work please join me in
01:11welcoming Dr Tas today Dr Peter Tas
01:16investigates and develops
01:18neuromodulation techniques for
01:20understanding and treating neurologic
01:23conditions such as Parkinson's disease
01:26epilepsy dysfunction following stroke
01:30antonitis he has pioneered a
01:33neuromodulation approach based on
01:35thorough computational modeling that
01:37employs Dynamic
01:39self-organization plasticity and other
01:42neuromodulation principles to produce
01:45sustained effects after stimulation
01:49can't wait to hear about this welcome Dr
01:51Tess thank you very much thanks Angela
01:53for the introduction it's a huge
01:55pleasure to join you this morning and
01:58I'm very grateful for the invitation
02:00so I want to tell you about this this
02:03entire approach and what it is about
02:05it's about basically
02:07stimulating um the brain in a way that
02:10the brain
02:11unlearns the production of abnormal
02:14activity patterns and also changes its
02:17connectivity patterns in a way that we
02:19induce longlasting
02:21sustained relief in Parkinson is
02:26characterized by abnormal neuronal
02:28synchrony synchrony sound sounds nice
02:31intuitively nice because um sounds like
02:33Harmony everybody's doing the same thing
02:35but the problem is if you for example
02:37imagine a company where all employees do
02:39the same things this wouldn't work and
02:40the same with neurons for neurons it's
02:43extremely important that different
02:44neurons that serve different purposes
02:47should be free and able to follow um uh
02:51and and to to um to process the
02:54information they have to process and
02:56therefore synchrony can be really can
02:59really m massively impair brain
03:00functioning if it's too strong and too
03:03longlasting
03:04and since um the activity is close brain
03:09activity in general neuronal activity is
03:11very closely related to synaptic
03:13connectivity meaning the connections
03:16neurons form um pins is also um
03:20characterized by abnormal synaptic
03:22connectivity so as a as a consequence of
03:25the lack of dopamine there a Cascade of
03:28of uh change
03:30of both connectivity and synchrony
03:34you're you're probably familiar with
03:36deep bra stimulation deep bra
03:38stimulation is a was the introduction of
03:41invention of deep bra stimulation and
03:43its introduction to the Parkinson's
03:45field was a huge milestone treatment
03:48Milestone so what you see here is a
03:50Parkinson patient right right-handed and
03:52right sided Parkins and patience 48
03:55years old was no longer to work and he
03:57was one of the patients who really
03:58nicely
04:00um benefited from the treatment so the
04:03electrodes implanted here the the cable
04:07goes to the implantable PS generate and
04:09the important message comes now so the
04:11the ipg the the stimulator has turned
04:14off now and you see the rebound effect
04:18and in general there's no longlasting
04:19effect and this is what attracted me I
04:23first started with medicine I got
04:25intrigued by self-organization processes
04:28wanted to use these S organization
04:30processes in a way to
04:32design um
04:34treatments effective but nevertheless
04:36gentle
04:38treatments and in the the early 90s I
04:41got uh um when I did my PhD in physics I
04:44also studied maths and physics and I did
04:46my PhD in physics in the field of
04:49oscillator Theory
04:51synchronization I was I was really
04:54stunned by the huge effect sies on the
04:56one hand of De brain simulation but also
04:58by the by there slightly weird type of
05:02stimulation pattern stimulus patterns
05:04that were used because they were so
05:06physiological it's a permanent high
05:08frequency type of stimulation high
05:09frequency means more than 100
05:11Herz and in the meantime we understand
05:14very well the limitations of of deep
05:16brain stimulations it's an very
05:19important treatment but it has
05:22limitations on the one hand um since
05:24there are no longlasting therapeutic
05:26effects you typically have to stimulate
05:28for a longer periods of time
05:30and this um this leads to side effects
05:34and in the meantime there's even the
05:36word the term deep bra simulation youth
05:39movement disord so depending on where
05:41the target is where the elect simulation
05:43electrod is locate at different typical
05:45groups of symptoms of side effects
05:48emerge and also deep brain stimulation
05:51is not good in treating all types of
05:54symptoms for example the so-called
05:57actual symptoms do not particularly not
06:00um significantly improve for example
06:03actual symptoms are gate balance and so
06:06on and other symptoms like speech deter
06:09uh Speech or voice impairment may even
06:10get worse um under
06:13DBS so the the approach and this is just
06:16one slide there's been a huge amount of
06:19work and many many many papers so far um
06:22it's very solid stuff it's
06:24mathematically solid biophysically solid
06:28the the the underlying principle is to
06:31counteract abnormal neuronal synchrony
06:34by desynchronizing it so in other words
06:36not surprise supressing it not
06:38inhibiting it but use a um let's say
06:42more gentle type of intervention just
06:45desynchronizing it but this um seemingly
06:49more gentle type of thing is way more
06:51powerful for a couple of reasons and
06:53I'll explain this
06:55now the important point is you even
06:59simple networks and you can show this in
07:01simulations and math mathematical
07:04analysis even simple networks newal
07:07networks with so-called CTIC plasticity
07:11they can be in in a stable different
07:13very different qualitatively different
07:15stable States for example can they can
07:17be strongly connected youve probably
07:19heard of the heum principles NE that
07:21fire together wire together so another
07:23words these neurons are strongly firing
07:25together they have also strong synaptic
07:28connections and here you see it's the
07:31time axis and this is the neuron index
07:33so neuron one up to neuron n n is a
07:36large number you see that all of them
07:38are firing more or less at the same time
07:41so they're strongly connected and strong
07:43synchron and what you can do with
07:45desynchronizing stimulation is you can
07:47desynchronize them so that there's no
07:50coherent structure anymore in their
07:52discharge pattern and and that's the
07:55important point this goes along with a
07:58decrease of the synaptic connectivity
08:00that's very importance and you can think
08:02of it as moving a ball in an attractor
08:07landscape from one pathological
08:09attractor stable state to into the Basin
08:12of Attraction more healthy attractor
08:14state where it remains and this is very
08:17different compared to standard e
08:18stimulation so our goal from the very
08:21beginning is to uce long lasting effects
08:23not to suppress immediately abnormal
08:27rhythms but to stimulate the brain and
08:29the way that bra
08:32unlearns uh its ability to produce
08:34massive abnormal
08:36activity and we've developed a number of
08:40stimulation techniques and are also
08:42currently further improving all them and
08:45optimizing stimulation parameters taking
08:47into account different types of
08:50plasticity mechanisms like synaptic
08:52plasticity structural plasticity where
08:54it's not just whe the sinapsis get
08:58stronger or weak about whether the
09:00entire cups for example
09:02Wes and coordinated reset is a technique
09:06that works in the following way it's
09:08very robust doesn't require difficult
09:11and
09:12sophisticated calibration if you have an
09:17population of neurons for example like
09:19these the SP balls gray balls each ball
09:22representing in urine what you do uh in
09:25the case of standard deep brain
09:27stimulation you position your electrode
09:29in a way that you can stimulate as much
09:32of them because you want to reach them
09:34the mechanism a mechanism of of debrand
09:37simul standard debrand simulation not
09:39yet really fully understood but
09:41basically it might be some sort of
09:43inhibition or blockage and you want to
09:46sort of suppress the
09:48activity what we do is we use for
09:51coordinated reset and this is in way if
09:53we come to the vi tactile later um we we
09:58simulate different subpopulations in a
10:00gentle way the only thing we want to do
10:02is we want to cause a reset meaning a
10:06restart of the rhythmic activity in all
10:09these different subpopulations so for
10:12example if you have if you stimulated
10:13different sites different times and the
10:16neurons are all in synchrony before we
10:18stimulate what happens after such a
10:20coordinated reset Coordinated Time and
10:23Space is that the neurons are no longer
10:27in in Phase their face is mutual phase
10:30difference is shifted if this goes on
10:33for a long period of time what basically
10:35happens is that they reduce their
10:37synaptic weights and so the strength of
10:41their connections and they unlearn their
10:43activity and this is how it looks like
10:45so we do not permanently stimulate but
10:48we have these patterns so it's a mixture
10:51of of periodicity and Randomness so you
10:54see um the period the underlying period
10:57like a clock and and then there's a
10:59random type of sequence Administration
11:03so the sequence is randomized from cycle
11:05to cycle there are off Cycles where we
11:07don't
11:08stimulate providing the urans um with
11:13sufficient time to do physiological
11:15information processing and also and also
11:18exploiting the the the desynchronized U
11:22the desynchronized state that lasts for
11:25a longer period of time and this is how
11:26it looks like in mptp monkeys so monkeys
11:30that are this is 16 fold velocity these
11:33are seconds that's a measurement cage
11:36where the monkeys were in for about um
11:3990 minutes every day and these monkeys
11:42are rendered par conson by mptp but
11:45neurotoxic substance that selectively
11:48destroys uh dopamine production so these
11:51monkeys only have between 5 and 10% of
11:55the docin producing cells left after
11:58this treat Tre men so they are severely
12:00affected as you can see here the monkey
12:01is basically always sitting some of them
12:04really have issues
12:06um um with with food and um the monkeys
12:12were not treated with any
12:15medication and this little hat served to
12:18protect the electrode from being pulled
12:20out because otherwise monkeys were
12:21pulling out the electrode and we
12:24stimulated them only for two hours a day
12:26that's important only two hours a day it
12:27was an external so we stimulate them
12:29from an external stimulator not
12:31implanted because simply because of the
12:33implant implantable generator was way
12:36too large for these little animals and
12:39this is the same
12:40monkey after two hours of coordinated
12:43reset stimulation so to our stimulation
12:46and then brought back into this
12:47measurement cage measurement cage used
12:50the light barrier
12:52system um where where it was that
12:55enabled to to measure the amount of
12:59movement
13:02production and you see that also based
13:05on a quantitive analysis there was no
13:08difference between uh the the monkeys
13:11after two hours of CR stimulation
13:12compared to normal monkeys when it came
13:14to movement production rate and the
13:18important um and the important goes on
13:21like this and let me just and this was
13:23also independently um verified by a
13:26number of other groups and this is just
13:29briefly so these are all these are this
13:32is the amount of this is basically monke
13:35Mobility this is before the five days of
13:39two hours per day treatment so they are
13:42they're not mobile that's the mean value
13:45standard deviation this is during the
13:48days of the five days and this is after
13:51these five days two hour stimulation and
13:53this is with classical DBS standard deep
13:56brain stimulation and there an increase
13:59there a slight after effect that decays
14:02within 30 minutes and this is what we
14:04see with CR with this really low
14:06intensity on purpose low intensity
14:09because we have to stimulate differ our
14:11populations selectively and we have an
14:13significant after effect therapeutic
14:16after effect for one month and this was
14:19important um on the one hand
14:22to move forward with in
14:26patience and we've shown this also in in
14:29externalized patients um where the
14:32electrodes are implanted the the the
14:34cables not yet so the patient was
14:36stimulated I means through an portable
14:39stimulator and this is how it looks
14:43like so this is a 49 years old patient
14:47Parkinson patient she was also a
14:49right-handed person she had
14:52a
14:53um uh dystonia for more than a year at
14:57that time so the patient was able to
14:59stretch her fingers she was instructed
15:01to stretch her fingers but it was
15:03impossible for her to do this this was
15:06now directly before CR
15:10stimulation and you see that fullblown
15:13symptoms Tremor and
15:14dystonia and um we measured the EMG
15:18muscular activity exomer EG and so on
15:23and this is about 20 minutes after
15:25turning on coordinated reset stimulation
15:27you see the symptoms are on and
15:29remarkably also dystonia because
15:31dystonia doesn't respond well when you
15:33use um standard deep brain stimulation
15:36in particular um when you deliver to the
15:39sdn and this was only unilateral
15:42stimulation that's important all our
15:44patients at that time were stimulated
15:45unilaterally for technical reasons and
15:48this is the important thing so this is
15:49now the situation one hour after turning
15:51off stimulation and you see that defect
15:54persists that's the important point and
15:57not only the Clint effect but also so
16:01rigidity was gone and so on but also the
16:04abnormal activity so this is what you
16:06see here so the x-axis is the frequency
16:11axis tells you when when you analyze
16:14signal and in this case the signal um in
16:17the brain it's like a small EG local EG
16:21it's called local field potential
16:23lfp directly at at the site where you
16:27where we stimulated then you can ask
16:30which uh Rhythm which component which
16:33oscillation which Rhythm contributes to
16:35the signal and that's a spectral
16:37analysis the y- axis is spectral energy
16:40and before stimulation you see the one
16:44very prominent Peak around five Herz
16:47that's the Tremor Associated Peak and
16:50this peak that's related to ainan
16:52rigidity and this is after 1 hour after
16:56in total 4 Hour stimulation you see that
16:58that these Peaks are gone and that's
16:59very different compared to standard deep
17:01brain stimulation where this peak
17:04returns within 12 seconds and this one
17:07even
17:08quicker and we've seen this in in all
17:10patients uh I don't want to go through
17:13unnecessary details we' seen this in all
17:15patients and this was very
17:18promising and also the effect size was
17:20very promising but one important point
17:22was the following if we are able to Del
17:26to deliver treatment that has
17:27longlasting effect we have a chance to
17:30do this non-invasively because you can't
17:32wear for example a vibrating glove or
17:35any type of non-invasive device Ty you
17:37typically can't wear it and you don't
17:39want to wear it
17:41247 therefore this longl lasting effect
17:44was um a huge import a huge milestone in
17:48the development of the glove
17:51treatment and there were predictions
17:54also again computat predictions that it
17:57should be possible to do this and this
18:00is simply because the the thing we use
18:02is um we have we it's known since 1980s
18:06of the last uh uh so the 80s of the last
18:09century it's known that we can reset we
18:12can
18:13restart rythmically active neurons I
18:15means all of all sorts of um stimuli not
18:18just electrical stimuli also thermal
18:22stimuli and another stimuli but the
18:24important thing is we can do this by
18:26stimulating the axle we can this by
18:28stimulating sinapsis it's a very
18:31fundamental mechanism we use this
18:33mechanism we don't want to suppress
18:35neurons we just wanted to restart
18:37different un at different times so in
18:39other words we want to manipulate the
18:42timing of different parts of a un
18:45population and there there's a series of
18:48beautiful studies um published by lenses
18:52lab lens is the US neurosurgeon great
18:57neur
18:58surgeon and what they've shown is the
19:02following in order to understand
19:04different parts of the thalamus because
19:08neurosurgeons really want to understand
19:10where they implant their electrodes for
19:12example for the treatment of
19:14corkin they've made the following
19:16observation in a very reliable Manner
19:19and they've done this in Perkinson
19:20patients in ental trauma patients
19:23patients with chronic
19:25stroke and what they've seen in distonia
19:28they've seen is the following if we um
19:32if the electrode is in the in the
19:35central heart for sensory inputs it's
19:38called ventral cordal uh nucleus of the
19:41thalamus so that's basically the heart
19:44that gets all in proceptive information
19:47from the periphery for example from the
19:49hands from
19:52skin then um and we vibrate different
19:56parts of the body can also be the pH
19:58it's a very very general phenomenon need
20:01be just the hands then there are neurons
20:05that do not just um randomly respond so
20:08to speak to the stimulus but they
20:09respond in a rhythmic way and the way
20:12they respond and their rhythms and the
20:16rhythmic responses are tied to the
20:18vibration so if this is the vibration
20:20for example urans VI urans discharge for
20:24example in synchrony with the vibration
20:27and this is shown here so what you see
20:29here is one cycle of the peripheral
20:32vibration of the the skin and the Y AIS
20:36is the
20:37percentage uh is is the number of of
20:39discharges so if there and assume that
20:42there were no uh in no relationships
20:45between the discharges and um the
20:49vibration is just be a noisy flat lines
20:52but what we see is this beautiful
20:54entrainment so what this means is when
20:57we entrain different parts of the brain
21:00can
21:01control the timing of discharges and
21:04that's what we need we don't need to
21:06suppress neuronal firing and we don't
21:09want it because neurons have to be
21:10active in order to learn and unlearn
21:13their connections we really want to
21:15change um these networks and and you
21:20shouldn't think of the brain as a like
21:23as an oldfashioned computer that has
21:25hard wirus um but it's a dynamic system
21:29that permanently changes and also when
21:31I've for example um given my
21:33presentation my goal is to cause a re
21:36wiring on your side and your brains in a
21:38way that you're able to memorize
21:40hopefully memorize what I'm
21:43presenting and now why did we choose the
21:46fingertips and this is because the
21:48fingertips have a huge representation so
21:51what you see here is the humulus there
21:53Al there's also on the Moto side a more
21:55modern version of it but the basic
21:57principle holds as uh as published in
22:01many many years ago by Penfield and that
22:04is the
22:05F not all parts of the body do have the
22:08same cortical representation so the
22:10volume enhance the number of urans in
22:13the cortex in the sensory cortex and
22:15also M cortex that are that are that
22:19process information from the skin of
22:21different parts of the body is very
22:23different it's not homogeneous or so for
22:26example as you can see here
22:28the hand has a huge representation if
22:31you for example compare it with the arm
22:33the arm anatomically is a larger object
22:36larger part of the brain but this Strate
22:39the the the fingertips and the hand are
22:41so strategically favorable simply
22:43because they're a small part of the skin
22:46overall skin but they have such a huge
22:48representation beautifully huge
22:50representation and that's what we want
22:52you want to enter the brain in in a
22:55non-invasive manner in a well defined
22:58Way by means of this phas locking by
23:01means of this entrainment type of
23:03stimulation and we want to um stimulate
23:07a hub part of the brain that is large
23:10large enough we can we can induce a
23:14desynchronizing effect and then as we
23:16know from other preclinical
23:17computational and also clinical studies
23:20desynchronizing effects typically
23:22propagate in the brain so this is the
23:26basic concept uh concept behind it and
23:28so what we've done this this is the
23:30first generation type of glove system we
23:32have vibrators attached to all four
23:35fingers to four fingers not not the
23:37thumb on both
23:38hands and what we do is we simply
23:41replaced vibrations to 150 Herz bursts
23:45by um sorry we we replace the electrical
23:49bursts delivered through depth
23:51electrodes by these vibrations that's
23:54the important thing so instead of
23:56implanting an El
23:58delivering electrical pulse electrical
24:02pulses we simply use vibrate vibrators
24:07well-defined
24:08vibrators and vibrating according to
24:11these well-defined spal temporal
24:15pars we've done a thre Monon pilot study
24:19we've done a number of pilot studies and
24:22this these These are data from a three
24:24months pilot study at that time this was
24:26the co era we wanted to do uh study in
24:3020 patients and follow up patients for
24:33at least two years but you took go we
24:36have to stop hospit was closed and then
24:38fortunately reopened quickly for medical
24:42care surgeries and so on but then later
24:45on we were also able to to restart our
24:48research so it was um therefore it was a
24:52three month pilot study turned out to be
24:54a three-month pilot study all of the
24:56data you've seen here you'll see here
24:59and in the following slide are all um
25:04exams um May done performed after proper
25:08medication withdrawal in order not to
25:11have any interference medication
25:13patients had to withdraw their
25:15medication for between 12 and 48
25:19hours and you see here the amount of
25:21mdss part three scores as I said off
25:25medication scores so the larger the
25:27number
25:28the more um the more impaired the
25:31patient is and the MDS upiter as part
25:33three many of you will be familiar with
25:36this covers all parts of movement
25:38production of the entire body from um
25:42from top to toe and what you see here is
25:45that all of these
25:47patients that's the mean well that's the
25:49Baseline so patients came in that's
25:51acute effects that was the first visard
25:53day was a day visard day um
25:58and deter um focusing on acute effects
26:01meaning effects emerging after two times
26:03two hours stimulation while patients did
26:06not get any medication so patients came
26:09in in the morning at
26:108:00 we did this exam and then we had
26:14two times two hours and in total four
26:16hours glove stimulation in between the
26:20two two times two hours in between a
26:22lunch break and patients didn't get any
26:25medication and then in around 3 3:30
26:27p.m. in the afternoon we did this mdsu
26:32part three this Moto motor exam again
26:34and you see that there a significant
26:36decrease although patients did not get
26:38any medications and some of them are
26:40really afraid of staying off medication
26:42for such a long time they significantly
26:45improved statistically significantly
26:48improved and this is the long-term
26:50effect and this is um most remarkable
26:53and and very encouraging and that is
26:55that's the following so this is patient
26:57then came again for first uh treatment
27:01day
27:02visit and we did the base socalled
27:05Baseline analysis again at 8:00 in the
27:07morning off medication and that's the
27:10mean well and C deviation so to speak
27:15and then after 3 months using the glove
27:18four hours a day or two to four hours a
27:21day patients came in again and at 8:00
27:24in the morning again this medication
27:27will all um this exam mod exam is
27:31repeated and you see this beautiful
27:33Improvement although patients were off
27:37medication and this was super
27:39encouraging of course to change the
27:42brains of the patients change their
27:44conditions on longterm
27:46scale
27:49and now the question is where these
27:51effects only statistically significant
27:53or they also clinically significant and
27:56if you want to talk about Clinic
27:57significance you have to use the
27:59socalled MCI clinically identifiable
28:03difference and the minim clinically
28:05identified gphin is a hurdle in this
28:07case it's minus 3.25 so a decrease of
28:11the motor score greater than 3.25 is
28:14significant and the green data the acute
28:18acute data the acute Improvement on this
28:22very first visit and you see that all
28:24patients at an acute um clinically
28:27significant fute Improvement except for
28:29patient three and cumulative um
28:33improvements after 3 months of of orange
28:36bars and you see that all patients a
28:38clinically significant improve more and
28:42the other thing that's important is that
28:45typically patients had a a reduction of
28:48their medication we did not instruct
28:50patients to reduce their medication
28:53patients um decrease their medication
28:55but of course patients were able to
28:57decrease their medication if needed and
29:01several of them were happy to reduce it
29:03because of side effects that were um
29:06that were bothersome to them so we what
29:09we've seen is a decrease of the
29:12medication and another finding that was
29:15also really surprising to me didn't
29:17expect it to be that pronounced because
29:20it's not so easy to detect Parkinson's
29:23related abnormal Rhythms on the cortex
29:26surface of the
29:28brain um in the depth in depth
29:31electrodes it's it's it's easy and
29:34they're very pronounced and you can see
29:36them by by simply visual by simple
29:39visual exraction but in the cortex it's
29:42it's more ingrate it's more complicated
29:44more sophisticated and what you see here
29:46is these are all patients off medication
29:49again after medication withdrawal before
29:53the treatment and 30 and and sorry 3
29:56months after the treatment with GL
29:58treatment and you see the um these are
30:02the primary motor and primary sensory
30:04cortex so the sensory motor cortex the
30:06primary target for our
30:09treatment and what you see colorcoded is
30:12the power in this High Parkinson's
30:15related very typical high beta B between
30:1821 and 30 Herz so we tested all
30:20frequency bands we didn't find any
30:22significant change compared to Baseline
30:25and three l um glove treatment but this
30:30Parkinson's related beta band had a huge
30:32decrease showed a huge decrease of the
30:36power that was very encouraging because
30:38we didn't expect it to be so
30:41pronounced and so we we did not only see
30:45a clinical substantial Improvement after
30:47medication withdrawals but also from an
30:50electrcal st the N Improvement then we
30:54had a couple of Case Case serious
30:57studies and what you see here is again
31:01the x-axis is St of treatment glove
31:04treatment and the Y AIS is again the
31:06motor score and it was an off medication
31:09again after with medication call off
31:12medication motor score what you would
31:14expect in par
31:16ination um if you think of the time
31:18access here time time rang as here this
31:21is about 9 months is that you would
31:24expect that power concentations get
31:26worse time because of the underlying
31:28condition and
31:31degeneration and the progress of this
31:33degeneration what we've seen here is a
31:36linear decrease in all of these patients
31:39and for example these this patient this
31:41is about half a year and this patient
31:43was stimulated for half a year two to
31:45four hours a day one month pre pause and
31:47then again six month we have um we were
31:52able to follow up due to co
31:53unfortunately only um not in person but
31:56we were following up three patients
31:58remotely that we're going through this
32:01regimen with um 6 month two to four
32:04hours and then one month PR paused and
32:07then in total six month
32:11um a maintenance dose were low dose only
32:14two to three times two hours a week so
32:18not much and all of them had after
32:20effect really lasting after effects for
32:23at least one up to one 1.5 years and
32:26still feeling better better than they
32:28were before so all this is very
32:31encouraging what we of course need is um
32:34very solid testing also against Placebo
32:36effects there are many reasons why we
32:38don't um believe that these are Placebo
32:40effects because Placebo effects
32:42typically are not that systematic the C
32:45effects um vary in time Theo effects
32:49rarely last for very long time and
32:52Tremor does not typically respond to
32:54placeo effects and we have in all our
32:56patients in these patients and all the
32:58other patients the trauma subscores were
33:00always significantly
33:02decreased but nevertheless and I come
33:05back to this later we'll do proper um
33:08control trials also with Placebo meaning
33:11sh so-called sham stimulation groups and
33:15in order to provide you um with I'd like
33:18to provide you with some patient videos
33:20because these are just numbers or dots
33:22and patient Med tell more
33:25comprehensive um
33:27stories and this is one
33:30patient and he was diagnosed in 2007 he
33:35took quite quite some quite a large
33:37number of of um Parkinson's pills was
33:41about 50% in off time every day um often
33:46lying in B often had ly in B because so
33:49stiff used the cane was supposed to use
33:51a wheelchair because it was falling
33:54increasingly often this was July
33:582018 and if
34:01I'm
34:06uh and you unfortunately are familiar
34:09with these
34:10[Music]
34:11um the typical symptoms so there's a
34:15slowness of movement it's difficult for
34:17Po and patients to enter or exit rooms
34:20to change direction turn
34:23around the facial expression M effect
34:27faal expression is decreased arms are
34:29not
34:40swinging and patient came to us in
34:43August
34:442018 and told him there was no
34:47instruction to reduce medication so the
34:50instruction was to use as much
34:52mats um uh as as as required to feel as
34:57as well as possible and this is the
35:00patient after in total two times two
35:02hours a day on the first
35:04evening and you see this pronounced
35:06change you see the Orin smiling again so
35:11their facial expressions there are large
35:13steps the arms are swinging he went down
35:16to from between 20 to 25 to six and
35:20basically this is this was his um his
35:24his level for longer period of time then
35:27and then this was the sixth day of virot
35:30tactile
35:35stimulation he was an
35:39outpatient
35:43uh he came to to the to the outpatient
35:47visits during three consecutive days and
35:49then continued stimulating at
35:52home and he was able
35:55to start re started working and the
35:57interesting thing is that he he was the
35:59first patient who alerted us because he
36:02told us that he was noticed an
36:04improvement of his sense of smell and
36:05taste and um we didn't expect this uh to
36:09be very
36:11open um and therefore we didn't did not
36:14systematically study this we have a
36:16study that will start early next year
36:20where will start we'll study
36:22improvements all all faction and also
36:24Vision because that's something we have
36:27observed um but nevertheless it has to
36:29be systematically studied in um by means
36:32of proper tests and so on but this is
36:34something a couple of our patients
36:36reported there was patients who had
36:38pronounced Al Factory
36:41impairment and then finally fortunately
36:43this was only November 2018 the patient
36:46was able to run his first New York
36:55Marathon
37:03and finally also he he ran Triathlon so
37:07quite amazing
37:08trajectory very happy extremely happy
37:11about this and this is a patient who had
37:15an early uh onset patient was diagnosed
37:18at the age of 25 this is the first day
37:21came to us off Ms prior to viot tactile
37:23treatment and here uh while having sort
37:29of um an athletic type
37:32of um shape patient simply because of
37:36the huge amount of workout he did he had
37:39huge
37:40um issues because of balance issues trem
37:44issues on the right side was scattered
37:46for
37:47DBS um in September 19
37:5219 and this is the the video he sent me
37:55after six weeks of vir Tech uh
38:07stimulation and he didn't need DBS since
38:10then so for quite a while this is
38:13another patient and this this shows you
38:15and that's quite encouraging for us
38:17because um shuffling balance issues
38:20socalled actual ISS actual symptoms are
38:23a huge problem when it comes when it
38:26comes to medication but also in
38:28particular when it comes to De brain
38:30stimulation um and we've seen in in the
38:33patients but this is of course something
38:35you have to verify in in larger cohort
38:38of patients in patient in our pilot
38:41patients what we've seen us that the
38:42effects of the glove treatment are very
38:45favorable so patients will respond to
38:47this um with respect um to to shuffling
38:51so
38:53shuffling
38:55destinations curve in patients want to
38:57for example exit room enter room change
39:02direction change velocity as you see now
39:04for example patient is able to walk in a
39:06more stable way now and then he has to
39:09stop and tries
39:12to get
39:14into normal walking mode and we provoke
39:17it by asking to turn around in a narrow
39:20how way and that's what you see now and
39:23for patient for this patient was really
39:26very difficult to properly
39:32walk even on medication even when he
39:35used his
39:37medication and this is after three
39:39months and that's also I think a nice
39:41illustration why we use these off
39:43medication um exams so why patients have
39:46withraw the medication for between 12
39:49and 48 Hours depending on the half life
39:51of the medication this is we want to see
39:54the patient we want to study the
39:55patient's condition irrespective of um
40:00medication what you see here is that the
40:03patient has greatly improved he told us
40:06that with
40:07medication shuffling was no long no
40:09longer an issue so he was really happy
40:12about it but you still see that the left
40:15arm is swinging right arm is not
40:16properly swinging also the gate is not
40:18really
40:20symmetric and then you see some
40:23shuffling when he turns around and
40:25that's the reason why we do this off
40:26medication type of exams to really see
40:31what's the condition of the patient and
40:34this is now after five
40:40months and this is after six months of
40:43treatment and one month of pre-planned
40:55pause
41:07let me let me finish in um mentioning or
41:10explaining what we've done with we've
41:12invested a huge amount of money and huge
41:15amount of work into further optimizing
41:18it the treatment and in order to come up
41:21with a stimulator with with a glove
41:23system that is able to do what we what
41:25we actually want want to do we have a um
41:28clear study clinical research and
41:31clinical study um strategy we are
41:35currently restarting we start uh start
41:38enrollment for patients in December
41:43January for a couple of pilot studies
41:46and these different types of pilot
41:48studies address different symptoms and
41:50different populations or subpopulations
41:53of patients for example late stage
41:55patients or early stage patients and the
41:59new um the new glove system and all this
42:02is driven computationally and also it's
42:04also relying on very fundamental
42:06physiological mechanisms that we use
42:09will have uh will provides the
42:12possibility to provide further improved
42:15stimulation patterns further and
42:18individualized
42:20stimulation uh stimuli so it's it'll be
42:23calibrated to each single patient each
42:25individual patients will be
42:27personalized the elementary stimulus
42:30that you're going to use and um we'll uh
42:35we will on a on a midterm type of
42:38perspective what we are doing is we'll
42:41also set up we're currently setting up
42:44for these Pilots um we're setting up um
42:48models mathematical models that so to
42:50speak mimic the patients brains like
42:52electronic twins so that we can really
42:54learn how
42:56the elementary stimuli that we deliver
42:59change brain
43:01activity and we measure these um the the
43:05changes and the responses to the simul
43:08both in our simulations and so so to
43:10speak the tronic twins but also in of
43:14course in our patients and all this is
43:16about further optimizing the treatment
43:19and the Cascade of studies is as follows
43:23we first start with a few very well
43:26trying very well elaborate already I I
43:30approved pilot studies not controlled so
43:32with no sham conditions so that we can
43:35nicely interact with patients ask
43:37patients without unblinding them for
43:40example ask them about how it feels how
43:43this difference to life feel and so on
43:46and of course how they feel and then the
43:49next step will be an randomized control
43:51trial is already Irv approved uh which
43:54will also be which will also to start um
43:57next year so second or at latest third
44:02quarter but I think second quarter and
44:04then as soon as we'll get um good
44:07interim results because there are many
44:10things to test for example also
44:12concerning Placebo stimulation groups
44:14sham effects we have to test them
44:17whether we do this properly then they
44:20will'll will'll be able and the
44:22investment is is ready for this to to
44:25come up with the large scale studies to
44:28that aim to provide um to achieve
44:32reimbursement as soon as possible so
44:34this is our goal and I'm super grateful
44:37that I have fantastic lab people who are
44:40really um working in a very dedicated
44:42very enthusiastic way many many good
44:46superb neurologists neurosurgeons um
44:49very strong funding fortunately and um
44:53thank you for your attention thank you
44:55so so much maybe we should start with
44:58this Dr Tess I'm sure you're used to it
45:00everybody wants to know when it's going
45:01to be available what you know what the
45:03timeline is can you you started to go
45:05into the timeline can you very slowly
45:08talk about the timeline that you expect
45:10at this point yeah the the timeline you
45:13see I don't want to make any uh
45:15inadequate promises also and um it's
45:19also it always depends on what what you
45:21want to achieve so to speak and um the
45:25goal here is is something substantial so
45:28fortunately I was was able to team up
45:31with people who are really extremely um
45:35extremely competent in mttech and have
45:39done um mtech approvals and FDA
45:43approvals and in particular
45:45reimbursements for many many times and
45:48the goal here is not just to quickly
45:51achieve FDA approval and and so to speak
45:55have some people make a bit of money but
45:58um do this in the in the most
46:01professional way in order to provide um
46:04reimbursement meaning access to
46:07treatment for as many patients as
46:09possible and as soon as possible and one
46:13thing is um that is very important here
46:16is it there are some unknown things that
46:19are risk factors for example just just
46:21as an
46:22example we want to show and that's
46:25that's important also for reimbursement
46:27but also for for the neurologists to
46:30understand this
46:32treatment um we want to show that the
46:35effects are certainly not Placebo
46:38effects and for this we have to do
46:40Placebo control trials when you have a
46:42sensory treatment you can't like for
46:45example comparing to comparing it to a
46:48pharmaceutical treatment you can't just
46:49take a pill and one pill is the real
46:52treatment contains the substance the
46:54other pill is the placeo it just con
46:56sugar whatever something totally
46:58inactive and um this is not possible in
47:02when you have sensory stimulation you
47:04have to you have to come up with a in
47:07inactive stimulation pattern but
47:10nevertheless the patient has to feel
47:12stimulation and this is important
47:15because patients should not be able to
47:16un blind themselves and we know what we
47:19want to do but we have to test this and
47:21therefore we do not start with an FDA
47:23approval trial but we start with
47:26first um pilot pilot studies also pilot
47:30studies where we test some of the basic
47:33ingredients of this sham
47:35stimulation and the next thing is uh a
47:38controlled proof of concept trial which
47:41hopefully will start in second quarter
47:42of next
47:44year and then and and then as soon as
47:48for example after let's say six months
47:51or something like that an interim
47:52analysis will provide good results an
47:56FDA approval trial that we've already
47:59preparing um should start and then it's
48:03difficult to tell how how fast this will
48:05be because it be very large very
48:07professional professional very large
48:08trial in many many many patients and
48:12there's and certainly not only one side
48:15study
48:16side um and probably also not only in
48:19the US um and this might take a year or
48:24potentially long
48:26so I hope that some like 20 25 20
48:3126ish should be a time at least this is
48:34our goal and we're not delaying anything
48:36it's not that we want to
48:38be unnecessarily slow or whatever over
48:42accurate or whatever we're doing we
48:45working as fast as we can and it's as
48:48professional uh as it I think as it can
48:51get and it's with people that do it in a
48:54very reliable way with a very very goal
48:56and the goal is to provide all patients
48:58with this treatment as soon as
49:00possible
49:02great um interesting question somebody
49:04wants to know when the stimulation is
49:06going on what is the effect and feeling
49:09on the body yeah what what our patients
49:13reported was that it's it's um they it's
49:18a convenient feeling many patients
49:20report a relaxing effect and when we for
49:24example tested the first stimulators the
49:27first glovs in healthy subjects at that
49:30time I was still in Germany before I
49:32moved to Stanford or Institute members
49:35at that time tested the gloves just for
49:37technical reliability and what basically
49:40everybody said was and these were
49:43healthy subjects is that it's that it
49:45had a zentab of effect meaning it was
49:48relaxing didn't make it tired but
49:50relaxing and that's also what the
49:51patients report we'll do a
49:54study where we specifically we will
49:56specifically analyze the relaxing
49:59effects not only psychophysically or not
50:01only psychologically but also by means
50:04of uh EG meaning brain recordings
50:08there's one question sorry s I've seen
50:11can a BBS patient utilize your
50:14device just briefly we um in principle
50:18there's no reason why this should not be
50:20possible so what we what we'll do is we
50:23have uh and what you typically do by the
50:25way is the following when you have such
50:27a question and you have an hypothesis
50:29and the hypothesis our hypothesis yes
50:32should be possible and then we have what
50:34we do is we first do a a pilot study and
50:37that's what we where we already planning
50:39for example we already have approval iob
50:41approval
50:43for postsurgery
50:46Perkinson
50:47patients um that that have no favorable
50:50outcome for example patients that had a
50:52lesioning treatment or a an ultrasound
50:55Sound Treatment have no not um no
50:58sufficient benef didn't have sufficient
51:01benefit from this treatment and in these
51:04patients we will try the glove treatment
51:06and the same we will do with deer
51:09stimulation patients but before I can
51:11make such claim that it actually
51:13benefits patients we have to go through
51:15this usual sequence we first tried in a
51:18pilot study then we go based on the
51:21effect size and the learnings in general
51:23the learnings uh obtained in the pilot
51:26study we go to a control trial with Sham
51:30soal Placebo type of stimulation and
51:32then we can make the claim that it work
51:34someone asked about Parkinson Tremor
51:37have you um do you have a subgroup that
51:40for people who ex excuse me not
51:43Parkinson's Tremor essential
51:45tremor I'm sure you have lots of
51:47different kinds of people who are
51:48participating I believe you said 10,000
51:51people 10,000 people are on the weight
51:53list yeah or on the wait list okay how
51:56many people actually have um for the
52:00next stage that will be
52:03parting so far we about 35 patients um
52:08experience from 35 treating 35 patients
52:12next stage will be um Pilots um about 60
52:18the first three pilots and then um 207
52:24234 in the in the control trial and then
52:28the
52:29larger um FDA approval trial will be a
52:32larger number probably 100 or more so
52:35this is these are the current numbers
52:38and your question concerning essential
52:39tremor we we absolutely want to to test
52:43this treatment also in a essential
52:45trauma patients Parkinson is now highest
52:48priority but essential trauma is
52:50definitely also a goal for us and this
52:53is because um we have we had patients in
52:56our pilot study for example we had a
52:58patient who had a pre-existing essential
53:00tremor and then later on also um
53:04presented with Parkinson symptoms and
53:07the patient had very pronounced trauma
53:10reduction due to the glove both
53:12concerning the ENT typical essential
53:14trauma symptoms but also the Parkinson
53:16trauma symptoms seems like you've had a
53:19lot of accidental good news through your
53:21studies so far yeah fortunately there
53:25were some there were some um some
53:27observations we definitely didn't expect
53:29and we focused of course on the typical
53:31motor effects unfortunately um we had um
53:36quite promising very early and still to
53:39be confirmed in control studies but very
53:42early surprising findings related to
53:45non-motor symptoms here's another
53:47question I'm not quite sure I understand
53:49it but you probably will do most of the
53:52neuromodulation researchers specifically
53:54those who are using the vibratory
53:56approach network with each other as in
53:59the q1 of Charco neurotech I guess it's
54:03just about do you have a large group of
54:05people who are doing similar research as
54:08to you that you um network with no not
54:12yet no not not actually not yet uh I
54:15think this uh this is something that is
54:17about to start and it always takes some
54:19time you see me if you if you look for
54:21example at the at the development of the
54:24deep brain stimul a um research
54:27community and this also took years
54:30initially it was focused on motor
54:31symptoms then it broadened to other
54:34types of symptoms cognitive memory
54:37related symptoms and and also um emotion
54:41emotional lyic symptoms and so on but um
54:45this this will take some time however
54:48concerning the um the underlying
54:51research the computational research
54:53that's driving our field and our
54:56approach I collaborate with several
54:59groups I've I've um PhD students also at
55:02other universities and so on so we are
55:04out of time but the million dooll
55:08question is when when is the updated
55:10timeline for the glove to come to Market
55:13um if all things go continually go to
55:17smoothly is that like two years three
55:19years well my hope is but I can't I I
55:22cannot I don't want to overstate or over
55:25promise or whatever and there are some
55:26things that you cannot can never can
55:29never um predict uh adequately but what
55:34I hope is that 2025
55:372026 okay I think that's a realistic
55:40number I that's I know that was a tough
55:42question to ask but everybody wanted to
55:43know the answer so I had to ask it so
55:46thank you again Dr Tass and thank you
55:48for all for joining us today today's
55:51event was made possible by our sponsors
55:53Abbot Boston scientist ific kioa Kiran
55:56medronic and suis we have some wonderful
56:00events coming up which I'll tell you
56:02about in a moment but if you enjoyed
56:04today's program please visit
56:11pcl.is to improve the lives of families
56:13in our community living with Parkinson's
56:16you can find our contact information at
56:19the bottom of this screen pcla is a
56:21nonprofit and all donations are tax
56:23deductible thank you every everyone and
56:25have a wonderful wonderful day byebye
56:29thank you very much for the invitation
56:31thank you Dr
56:36Tas
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