Ep. 184: Neuromodulation

00:00:00: Welcome to EANcast, your weekly source for education, research and updates from the European Academy of Neurology.

00:00:15: Hello and welcome to EANcast, Weekly Neurology.

00:00:19: My name is Gabriela Roussin.

00:00:20: I am co-chair of the EAN Scientific Panel on Clinical Neurophysiology.

00:00:25: Today we talk about non-invasive neuromodulation in neurology.

00:00:30: What works and what is coming next?

00:00:33: We focus on two big families of tools, magnetic pulses, RTMS, and weak electrical currents, TES.

00:00:42: Our guest is Professor Jakub Andrzak from University Hospital in Krakow, Poland.

00:00:47: Professor Andrzak works with transcranial magnetic stimulation, especially RTMS, in clinical practice and research.

00:00:54: Welcome, Professor Andrzak.

00:00:56: It is great to have you with us.

00:00:57: Thank you.

00:00:58: It's pleasure.

00:00:58: Thank you for having me.

00:01:00: Before we start.

00:01:01: One sentence for the listener.

00:01:03: What's the promise of neuromodulation in neurology?

00:01:07: It is to induce brain plasticity, optimally a long-term plasticity of the brain or the in general nervous system, which will improve the management of neurological disorders.

00:01:22: We often say neurological diseases are network disorders.

00:01:27: What does it mean in practice, and why does it matter for neuromodulation?

00:01:32: We say that because neurological disorders almost never are confined to a single structure of the nervous system.

00:01:40: There are maybe a few exceptions such as traumatic or entrapment, peripheral mononuropathies, but in general, even in the case of localized primary lesion, such as cerebral stroke, functional changes occur in many brain areas, not directly affected by cerebral vascular processes.

00:02:01: Areas interconnected via neuronal pathways and all networks change their functioning in response to any also clearly localized pathology.

00:02:12: It determines our approach with neuromodulation as a therapeutic option, which should take into consideration such complexity.

00:02:20: More and more frequently, it means stimulation in multiple sites.

00:02:24: also outside the primary religion.

00:02:28: What do we mean by non-invasive brain stimulation?

00:02:32: And how is it different from the brain stimulation and other techniques of the invasive neural stimulation?

00:02:41: The non-invasive brain stimulation is a group of techniques of the non-invasive neurostimulation subgroup of techniques of the non-invasive neural stimulation as we can stimulate also peripheral nervous system and the spinal cord.

00:02:58: The term neural stimulation in medicine means to act on nervous system with physical forces and not with chemical ones, for example, in the case of pharmacotherapy.

00:03:11: The term non-invasive brain stimulation means that we stimulate the brain with the stimulating force being localized outside the body of the stimulated person.

00:03:23: An ambiguity exists regarding the electroconvulsive therapy, which is the oldest technique of brain stimulation.

00:03:30: Pure anatomically, the technique is, of course, non-invasive.

00:03:34: It is, however, often not regarded as such.

00:03:36: And the reason is the need of general anesthesia, of anesthesiologic neuromuscular relaxation, and of invasive ventilation, which are together a deep intervention.

00:03:49: Maybe it is also worth to mention that in the broader sense, the neurostimulation does not need to be always therapeutic.

00:03:57: A frequently performed electrical stimulation of peripheral nerves to assess the nerve conduction is an example of a diagnostic stimulation.

00:04:05: Also, the transcranial magnetic stimulation, one of the most widely used techniques of non-invasive brain stimulation.

00:04:13: was initially designed not to induce elasticity for therapeutic pure poses, but to assess brain excitability and the conduction in central motor pathways.

00:04:23: This is also nowadays increasingly used to map the brain eloquent areas before neurosurgical operation.

00:04:32: For someone new to the topic... How would you explain the difference between RTMS, so magnetic pulses, and TES, electrical currents?

00:04:44: Beginning with what they have in common, they both are trans-cranial magnetic stimulation and trans-cranial electrical stimulation.

00:04:53: They both are the most widely used techniques of non-invasive brain stimulation, considering the electro-conversive therapy as invasive.

00:05:03: The key difference is that RTMS, repetitive transcranial magnetic stimulation, uses the pulses of magnetic field and transcranial TES, transcranial electrical stimulation, uses the electric current.

00:05:18: It is a weak current, considerably weaker than in case of electroconvulsive therapy, so there is no need for anesthesia, and it is possible to use this technique at home.

00:05:30: The current is also not strong enough to depolarize the brain cells, in other words, to trigger neuronal firing.

00:05:40: TES is rather able to modify the transmembrane potential, which will facilitate the firing and increase responsiveness, as well as to modify intrinsic brain oscillations.

00:05:53: In contrast, transparion magnetic stimulation depolarizes local neuronal population, both electric current and magnetic pulses.

00:06:01: will induce brain plasticity if done consequently and repetitively enough.

00:06:07: Depending on the settings of stimulation, this plasticity, as complex and multi-directional it may be, will go generally towards long-term potentiation with increased local neuronal activity, blood flow and synaptic plasticity, or towards long-term depression with opposite changes.

00:06:28: Both of them, potentiation and depression are used to achieve clinical improvement, depending on particular disease, with some diseases benefiting from both.

00:06:38: Of note, both techniques have their particular forms and submodalities.

00:06:45: Yet, while the term transplanar magnetic stimulation is relatively constantly used, regardless of which submodality is meant, the term transplanar electrical stimulation is used less frequently.

00:06:57: More often you will read in the literature the specific name of its particular submodality, and you will also hear it when you come to your physical laboratory.

00:07:08: These submodalities are trans-cranial direct current stimulation, trans-cranial alternative current stimulation, and trans-cranial random noise stimulation.

00:07:18: Which approach usually requires trained staff and a special life center?

00:07:25: And which ones can be simpler or potentially home-based under supervision?

00:07:32: Both approaches together with all-over techniques of neurostimulation require trained staff, a physician to qualify the patient, and a technician to perform the procedure.

00:07:44: It is wise to send your patient to a center specialized in neurostimulation, however, as the techniques become more common, they are also available in small psychiatric and neurologic ambulatories.

00:07:56: Transgranial magnetic stimulation must not be at home, mainly because of the risk of a seizure.

00:08:02: Whereas electrical stimulation can be home-based.

00:08:06: It must be initiated in the center in the medical facility, but thereafter it can be used at home safely.

00:08:16: And if I walked into a stimulation session, could I tell right away which method is being used?

00:08:22: What would I notice?

00:08:24: What should I look into?

00:08:27: At the beginning is similar for both methods.

00:08:32: You will sit in a comfortable reclining chair.

00:08:36: Then the personnel from the electric stimulation would wipe your head and then stick two big electrodes.

00:08:45: Whereas in Transparency Magnetic Stimulation Lab, they would place the stimulating coil over your scalp.

00:08:51: The stimulating coil is a disc or two combined disk which make up a figure of eight or sometimes it can have also L shape.

00:09:02: In TES lab you will feel the electric current passing between electrodes which may be sometimes a bit unpleasant.

00:09:10: In TMS laboratory the stuff will begin with moving the coil over your scalp and eliciting single pulses of magnetic field.

00:09:19: They will also be watching if there are no twitching of fingers.

00:09:24: or a hand contralateral to hemisphere.

00:09:27: they are stimulating.

00:09:29: In this way, they are looking for the primary motor cortex.

00:09:33: Once they find it, they start to stimulate at this site, determining what is the weakest magnetic field still capable to excite the motor pathways to the musculature of your hand and fingers.

00:09:44: In other words, they are estimating the motor threshold.

00:09:48: In some laboratories, they place electrodes which record the electric potential from twitching muscles instead of just watching the hand.

00:09:59: Next, they measure your head to determine the exact site of therapeutic stimulation.

00:10:05: Sometimes they use also magnetic resonance imaging of your head and the neural navigation system instead of measuring.

00:10:13: On the basis of estimated model threshold, they calculate the strength of therapeutic magnetic field.

00:10:19: Once therapeutic stimulation starts, you feel a train of stimuli elicited with constant frequency or in a more complex pattern.

00:10:28: Sometimes, especially when your prefrontal aleras areas are stimulated, TMS may be painful.

00:10:36: And what do we say target?

00:10:38: What do we usually mean?

00:10:40: What does it actually mean?

00:10:42: Is it a single brain area or the whole brain network?

00:10:48: I always act directly on a certain brain area with spatial resolution of three to five square centimeters for TMS and much lower resolution for TES.

00:11:02: Both methods don't reach deep.

00:11:05: Only the cortex can be effectively stimulated.

00:11:08: Maybe we could mention here the newer modalities of brain stimulation, which still are rather in experimental settings, but which allow stimulation of subcortical structures.

00:11:19: One is the transplanar focus ultrasound, which uses low intensity ultrasound waves, which to focus on a certain area with great spatial resolution, another is the Transparency Temporal Interference Stimulation, which uses two or more electric fields, based with high frequency.

00:11:36: Regardless of the technique used, regardless of its spatial resolution, we should always be aware that we influence the whole networks, including distant areas via trans-synaptic connections.

00:11:49: Can you briefly explain what the DL PFC is and why it's such a common target?

00:11:58: Indeed, it appears quite commonly in the literature.

00:12:01: It stands for Dorosolateral Prefrontal Cortex.

00:12:06: It is the core hub of the central executive network and is also involved in attention to executive function and working memory.

00:12:16: In psychiatry, it is the most frequently stimulated area, especially the left one on the left side.

00:12:23: with very good results in treatment of the drug-resistant depression and other psychoactive disorders of neurological indications.

00:12:32: It is a common target in treatment of dementia and other processes with impairment of cognitive function.

00:12:38: It is also one of the main targets of treatment of migraine.

00:12:43: It is also recently one of the main targets in childhood neurology, pediatric neurology during treatment trials to treat cerebral palsy.

00:12:56: In a recent paper in Nature Reviews Neurology, there is a summary of the advances in the field of neuromodulation neurology.

00:13:07: And the results described there often look inconsistent.

00:13:12: Why do you think that is?

00:13:16: Stimulation is rather constant.

00:13:20: Stimulation sites, stimulation strength and the frequency and pattern of the pulses vary across studies.

00:13:27: but only to some extent.

00:13:29: Of main neuropsychiatric diseases, which are a subject of stimulation, one can find several studies with the same stimulation parameters and the results will indeed vary.

00:13:41: The reason is probably the inter-individual heterogeneity, most important heterogeneity in the underlying pathology of given disease.

00:13:50: An example is the cortical versus sub-cortical stroke.

00:13:54: with the latter responding better to the stimulation.

00:13:58: Another example may be patients with cognitive impairment with or without marked cortical atrophy.

00:14:06: Atrophy increases the distance between stimulating electrode or coil and cortex, which will negatively impact the efficacy.

00:14:15: But there is probably much more yet undiscovered pathophysiologic heterogeneity within particular diseases which determines the responsiveness.

00:14:25: Recently, studies started to collect imaging neurophysiological, for example EEG, and laboratory data, for example BDNF level at baseline and also across the intervention and during the follow-up.

00:14:40: This may help in the future to select the patient's responsive to stimulation and to better understand the mechanism of action of particular neuro-stimulation modalities which may in turn improve the consistency.

00:14:54: One should also not forget that there is also an intra-individual variability.

00:15:00: It is known, for example, that the time of the day and the caffeine use affect the response to TMS.

00:15:08: So do you think that the source of this variability of the results might be because of the patient selection or targeting or dose or the outcome measures?

00:15:22: Yes, indeed, yes.

00:15:25: But I hope a systematic collection of the data I mentioned will allow in the future a reliable selection of potential responders, as well as a selection of suitable, stimulating protocols tailored for particular patients.

00:15:43: Outcome measures should also be more consistent across studies.

00:15:46: But on the other hand, use of multiple tools give more complete view of efficacy of neural stimulation.

00:15:56: So let's go condition by condition.

00:15:58: Starting with Alzheimer's disease.

00:16:01: What are the main targets and what's the rationale?

00:16:05: In Alzheimer's disease, we stimulate predominantly the prefrontal areas with protocols intended to induce the long-term potentiation.

00:16:15: In TDCS, it will be the anodized stimulation, whereas in RTMS, it will be the high frequencies from five hertz upwards.

00:16:26: and the more complex protocol called the Intermittent Tetherburst Stimulation.

00:16:32: Precisely, the target is the dorsolateral prefrontal cortex, which we mentioned already.

00:16:39: It might be bilateral or on the left side.

00:16:43: Some experts are concerned about inducing the long-term potentiation in the right prefrontal area as it may contribute to the development of depression.

00:16:53: The reason for prefrontal cortex is the fact We already mentioned that this area is the key hub of executive network and the key area for other higher community functions.

00:17:05: This approach is, however, evolving.

00:17:08: As our view of the neurodegenerative diseases is more and more network-oriented, so is the neuromodulation strategy.

00:17:16: Modern studies involve frequently a multi-site stimulation.

00:17:21: An example is the neuroad protocol where Besides the dorsodotroporfrontal cortex, also the pre-cunerous and the parietal cortex are stimulated.

00:17:32: In cerebral stroke and in traumatic brain injury, we currently focus many on the lesion side.

00:17:38: In cerebral stroke, it will be predominantly the motor cortex.

00:17:42: We stimulate the lesion side with mentioned protocols intending to induce the long-term potentiation.

00:17:48: Interestingly, common approach is also to stimulate the contralesional motor cortex, to induce the long-term depression.

00:17:56: It means with low frequencies, such as one hertz, or with the continuous tether bird stimulation, or with the cathodol stimulation in case of TDCS.

00:18:06: Such stimulation of the contralesional hemisphere is performed to harness its inhibiting influence on the recovery of the lesion hemisphere.

00:18:15: Another interesting approach is the stimulation to induce analgesic effect in neuropathic pain.

00:18:22: The protocol most commonly used is magnetic stimulation over the primary motor cortex with high frequency or a nodal electric stimulation of the primary motor cortex.

00:18:35: The putative mechanism of action in case of the magnetic stimulation is the anti-deramic excitation of thalamocortical pathways and does to modulate the function of thalamose, a key structure in pain processing.

00:18:50: Notwithstanding this, Protocols in neurological disorders are still being optimized.

00:18:56: An example is recently raised the role of cerebral stimulation for cognitive impairment in neurodegenerative diseases.

00:19:05: How about accelerated protocols?

00:19:07: What do they mean and do they change the clinical impact?

00:19:13: They changed dramatically the clinical impact in psychiatry where stimulation with up to ten sessions a day instead of just one traditionally reduced the total time to achieve remission in drug-resistant depression and apparently increased efficacy.

00:19:30: In the area of neurologic diseases, results are conflicting.

00:19:34: In our lab, we tried accelerated RTMS to bring relief in neuropathic pain with inconsistent effect.

00:19:42: After acquired brain injury, can we non-invasively improve cognition, for example, after TBI?

00:19:50: What's realistic today?

00:19:53: I think in general we don't know it yet.

00:19:56: The results of studies and meta-analyses are conflicting.

00:19:59: In contrast to neurodegenerative diseases, cognitive deficits after brain injury are often associated with delineated brain lesion, often in subcortical areas, for example within the limbic system, if we only could reach with our stimulation deeper.

00:20:16: It will be probably possible with newer emerging neurostimulation modalities we mentioned.

00:20:21: Yet we have to wait.

00:20:25: I would like to ask for Parkinson's disease because a pharmacotherapy and deep brain stimulation seems to be a well-established option for PD.

00:20:36: Does non-invasive stimulation fit in Parkinson's disease and if yes, where?

00:20:44: There might be some efficacy and not only regarding the motor assist symptoms.

00:20:49: The results are however conflicting so far.

00:20:52: Neurostimulation generally does not modify neurodegenerative process and the TDCS and RTMS do not reach to the basal ganglia, so the effects are rather transient and not huge.

00:21:06: Indication in which may have a chance to become an established option is the treatment of Parkinson related depression, which otherwise is difficult to treat with drugs.

00:21:16: Regarding motor, cognitive and other symptoms, maybe we can expect better efficacy from the newer stimulation methods.

00:21:23: which are able to reach subcortivized structures.

00:21:28: Let's move to stroke rehabilitation.

00:21:30: Many people think, stimulate motor cortex and recovery bruise.

00:21:35: How does it work?

00:21:37: Is it really that simple?

00:21:39: It is not only the motor cortex.

00:21:41: We can stimulate, for example, the right inferior frontal gurus to rehabilitate the post-stroke aphasia.

00:21:49: In contrast to neurodegenerative diseases, the stroke is a non-progressive process.

00:21:54: So the functions which are gained with the neurostimulation may not be lost.

00:21:59: Overall results from meta-analysis suggest that patients benefit from neurostimulation, albeit with higher variability between subjects.

00:22:08: In my opinion, neurostimulation should be tried in every stroke survivor, suffering from substantial motor cognitive or language deficit.

00:22:18: Although it's not sure if our patient will benefit, There is a significant hope he will.

00:22:22: Therefore, we should try.

00:22:25: Across these conditions we discussed, how important is pairing stimulation with therapy or training?

00:22:35: It is always advisable to stimulate along with routine rehabilitation, which will help to maintain the gain function.

00:22:42: The good example is a neural other device, which is a set manufactured to perform TMS and cognitive training at once in patients with Alzheimer's disease.

00:22:52: and all other dimensions.

00:22:55: So it's always advisable to combine rehabilitation and new low modulation.

00:23:01: TMS and TES mainly affect the cortex.

00:23:05: We already established that.

00:23:07: Are we getting closer to modulating deeper targets non-invasively?

00:23:12: Two ideas that come up are temporal interference dilulation and low intensity focus ultrasound.

00:23:19: In one sentence each, what's the basic idea?

00:23:25: The transcribe focused ultrasound uses a low-intensity ultrasound waves, which converge in the chosen brain structure.

00:23:35: The intensity of waves is strong enough to exert mechanical pressure on cell membranes and on their ion channels, which in turn, deplorizes the neurons in a safe and reversible manner.

00:23:47: This method is characterized by an excellent spatial resolution.

00:23:53: The second one is a transcranial temporal interference stimulation which uses two or sometimes more high frequency over thousand hertz electric fields which differ slightly regarding their frequency.

00:24:11: One of them can be for example thousand hertz and another and the other thousand five hertz.

00:24:17: The difference will be then five hertz.

00:24:20: As the fields interfere within a given brain area, the difference produces a low frequency field of five hertz, which is safe and suitable to influence the neural excitability.

00:24:34: What do you think about the next five to ten years?

00:24:39: Is the future mainly about personalization, better targeting, better timing and dosing?

00:24:46: We hope personalization in terms of determining the imaging, neurophysiological, and laboratory data will enhance the efficacy.

00:24:56: Better targeting with multifocal stimulation, modifying systematically significant hubs of dysfunctional networks, may further contribute to the outcomes.

00:25:06: Finally, we should not forget the closed loop paradigms, with stimulation continuously being adjusted to the monitored biological stigmas, for example electroencephalography.

00:25:19: Let's be practical, outside scientific setting.

00:25:23: What feels ready for careful clinical application and what should stay research-only for now?

00:25:31: Transcranial magnetic stimulation and transcranial electrical stimulation are safely used in clinical settings across the world.

00:25:40: Transcranial focused ultrasound, transcranial temporal interference stimulation and other more esoteric techniques still await recommendations of expert societies regarding safety indications and parameters of stimulation, as well as guidelines of training and certifications.

00:25:58: Final message to the listener.

00:26:00: What's the one thing you want people to remember?

00:26:04: Please remember.

00:26:04: there is such a therapeutic option as neuromodulation with neurological indications we talked about.

00:26:13: These are the main post-stroke deficits, neuropathic pain and also neurodegenerated dementia sometimes also migraine and drug resistant migraine and several others.

00:26:27: maybe one conditions emerging and very important is the are the neurological diseases in pediatric population especially cerebral palsy.

00:26:37: please do not forget also about depression especially drug resistant one as it co-exists often with severe neurologic diseases.

00:26:45: Thank you professor Andrak for joining us today.

00:26:49: Thank you very much.

00:26:50: It was pleasure.

00:26:52: And thank you for listening to EANcast Weekly Neurology.

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