Technological innovations in Neurology – 1

Dr Sanjoy Sanyal sanyal.sanjoy8@gmail.com

Professor – Neuroscience

An outline of techno-gadgets used in Neurological disorders

Med 3 Neuroscience students from Summer 2009 to Summer 2010 semesters of Medical University of Americas (MUA), Nevis, St. Kitts-Nevis, W.I., contributed partly to

the material for this presentation

Updated June 2013

• Deep brain stimulation (DBS) (Slides 3 – 23)• Vagus nerve stimulation (VNS) (Slides 23 – 24)• Radiofrequency (RF) ablation – obsolete (Slide 25)• High-intensity focused ultrasound (HIFU) –

ExAblate 4000 (Slides 26 – 37)• Transcranial magnetic stimulation (TMS) –

Neurostar (Slides 38 – 49)• Functional electrical stimulation (FES) (Slide 50)• FES in UL palsy – NESS H200 (Slide 51)• FES in Foot drop – NESS L300 (Slides 52 – 58)• Auditory (Cochlear, Brainstem) implants (59 – 65)• Tinnitus masker – obsolete (Slide 66 – 67)• Wearable sound generator (WSG) (Slides 68 – 69)

Contents

Deep brain stimulation (DBS)Definition: Electrical stimulation of specific deep brain (basal ganglia) structures with implanted electrodes, with the aim of evoking a therapeutic response in motor (and other) dysfunctions.

• DBS is an experimental neurosurgical treatment in which the brain is stimulated with electrical impulses

• Recently out of clinical trials, Medtronics made an electronic stimulation device that stimulates the Globus pallidus (GP) / Subthalamic nucleus (STN)

• DBS uses Activa® Therapy, a brain stimulation technology developed by Medtronic Neurological Therapy Development Group, to deliver carefully controlled electrical pulses to precisely targeted areas of the brain involved in movement control

• The procedure involves placing electrodes, thin flexible wires, through the skull into deep portions of the brain

Deep brain stimulation (DBS)

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Implanted pulse generator (IPG)

DBS components

• Invasive 8-10 hour surgery• Target areas are located by

CT / MRI / Microelectrodes. Latter are used to record the electrical activity of brain cells. When right pattern of activity is noted, surgeon decides on the best location for the electrodes

• Lead is inserted via14mm burr hole in skull, and Electrodes are implanted in Subthalamic nucleus (STN) / Thalamus / Globus pallidus

DBS procedure

• Platinum-iridium Electrode has 4 metal contacts (3 cathodes, 1 anode) that can be used in many different combinations

• Pulse generator (IPG; Neuro-stimulator) in its titanium casing is implanted subcutaneously under left clavicle

• Insulated Extension from IPG is tunneled under skin, runs behind ear, up left side of neck and connects IPG to Lead-Electrodes

DBS procedure

DBS in-situ

>30,000 installed

Cost: $40,000

Advantage: No destruction of brain

Disadvantage: Increased risk of intracranial infection

• Motor control structures – Basal ganglia– Subthalamic nucleus – Globus pallidus– Thalamus

• Memory areas – Limbic– Hippocampus– Amygdala– Hypothalamus– Thalamus

• Motivation, emotion and cognition – Limbic– Cingulate cortex– Ventral striatum

DBS targets

• Experts are still not clear exactly how it works• DBS works much like a pacemaker for the brain • Battery-powered IPG (Neuro-stimulator) delivers

high-frequency, continuous electrical stimulation to brain structures

• Pulses inactivate or modulate the brain’s impulses which helps reduce motor symptoms (dyskinesias)

• The IPG creates electrical stimulation that stops spasmodic contractions at the source

• Electrical impulses to the brain interfere with neural activity of targeted site without destroying the brain

DBS mechanism of action

• After the surgery adjustment has to be made to the frequency and power of the electrical stimulus being presented to the nerve cells through the device

• If the right adjustment is made as to the rate and strength of delivery, remarkable improvement can be seen

• As patient’s response to stimulation changes over time, the impulses can be adjusted from outside by means of an external programming system, w/out the necessity for repeat operation

• Several RCT’s are still going on to provide more evidence of the effectiveness of DBS

DBS mechanism of action

• Apathy; Hallucination• Compulsive gambling • Hyper-sexuality• Cognitive dysfunction• Depression; Déjà vu episodes• Parkinson's patients showed decline in

executive functions, and problems with word

generation, attention and learning• Because brain can shift slightly during surgery, there

is possibility of electrodes becoming displaced or

dislodged. This may cause complications like

personality changes, but electrode displacement is

relatively easy to identify using CT or MRI

DBS side-effects / complications

• Parkinson’s disease (PD): Reduces tremor, rigidity, stiffness (70% patients); Improves speed, dexterity of arm; Blocks involuntary movements, Reduces medication; FDA approved for Rx of Essential tremor and PD

• Dystonias: Chronic, intractable (drug refractory) Primary dystonia, including Generalized and/or Segmental dystonia, Hemi-dystonia and Cervical dystonia (Spasmodic torticollis) in patients >7 years; received FDA approval via Humanitarian Device Exemption process in April 2005

• L-dopa-induced dyskinesia in PD

DBS applications

DBS applications• Tourette’s syndrome• Intractable epilepsy: Stimulation of the anterior

nuclei of thalamus for epilepsy (SANTE); Modulates impulses in Papez circuit

• Obsessive compulsive disorder (OCD): 40% decrease in symptoms

• Learning / Memory-associated disorders• Major depression• Multiple sclerosis: DBS controls tremor• Stroke patients: For rehabilitation, neuropathic pain

and seizure control• Lesch-Nyhan syndrome• Phantom limb pain

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T1 weighted MRI shows position of contacts; 0,1 are w/in STN; 2, 3 are just above STN, where GPi is located.Table summarizes results; Stimulation of STN by cathode 0,1 resulted in decrease in rigidity, tremor and akinesia of PD, but no change in L-dopa-induced dyskinesia; Stimulation of GPi by cathode 2, showed same results, and also a marked decrease in L-dopa induced Dyskinesia

DBS in L-dopa-induced dyskinesia in PD

DBS in Tourette’s syndromeLeft: Plain X-ray of skull AP view, showing position of intracranial lead and electrodes; Right: Axial T1 MRI of brain showing DBS-induced lesion in both thalamus (arrows) in Tourette’s syndrome

• Definition: DBS in conjunction with medications to treat chronic symptoms of Obsessive compulsive disorder (OCD) that are unresponsive to medical and other therapies alone

• OCD: Ventral striatum is involved in the processing of emotional and motivational behavior; These are altered in OCD, due to potential impairment of ventral striatum in these patients

• DBS sites: IPG (under abdomen skin or infraclavicular) sends impulses to (in next slide)– Ventromedial caudate nucleus (bilateral)– Nucleus accumbens (bilateral)– Anterior limb of internal capsule

Reclaim DBS in OCD

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Left: Most ventral axial MRI slice demonstrates Nucleus accumbens (acc) and ventral portion of Putamen (P), which was used to determine ventral striatum targets and trajectories. Targets were defined based on position of the middle of Accumbens. Right: Coronal MRI slice passing through the targets of Caudate nucleus head (C) and Anterior capsule (AC). Dark lines represent trajectories passing through both ventromedial Caudate nucleus head and Accumbens

• High frequency micro-stimulation rather than low frequency result in sustained dopamine release in the striatum

• Animal trials proved performance was significantly better with high frequency rather than low frequency

• Elicits specific autobiographical recollection of precise episodes, TV advertisements, Life events etc

• In some individuals semantic memory is improved as opposed to episodic; This is controlled by Broadmann Area 20 (object recognition)

DBS for learning – memory

DBS in PD

DBS of STN is accepted form of therapy in intractable Parkinson’s disease (PD); It is most commonly performed DBS procedure

Vagus nerve stimulation (VNS)Implanted pulse generator (IPG) is similar to that in DBS; but electrode stimulates left vagus nerve in neck; Uses: Intractable epilepsy, Major depression; MOA is unclear

Radiofrequency ablation

Invasive and destructive procedure; Replaced by HIFU (next)

• Focuses a large number of ultrasound beams onto a small target of a few millimeters inside the body

• Uses high intensity ultrasound beams that are focused into a hotspot where the heating is high enough to induce thermal tissue destruction

• A focal temperature increase can be produced which is sufficient to ablate (surgically remove) the tissue through coagulation

High-intensity focused ultrasound (HIFU) principle

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Magnetic resonance guided high-intensity focused ultrasound (MR-Guided HIFU) has been successfully used in non-invasive surgery in Gynecology and Urology

HIFU in body

Focuses high intensity US waves thro a transducer (like a magnifying glass focusing sunlight) on a deep lesion; Raises local temperature w/out damaging surrounding tissue

• Ultrasound (US) does not go through skull because bone absorbs US waves;

• Transducers: 1,024 (210) Transducers create a helmet-like atmosphere; individually set to beam separately into skull, and calculated to individually meet the targeted focus

• The HIFU beams produced by transducers are transferred through the intact skull into the brain and concentrated on a 3-5 mm focus (‘Hot Spot’)

• This coagulates sharply defined targets deep inside the brain by heating them up to a focal temperature of 60 degrees Celsius

• This non-invasive procedure lasts several hours and is performed without anesthesia; Patients are awake and fully conscious during the intervention

HIFU in brain

• The whole procedure is planned and monitored in real-time by MRI

• The temperature increase during the sequential sonifications, each lasting 10-20 seconds, is continuously displayed and controlled on precise MR temperature distribution maps

• The combination of HIFU and MR imaging allows – Exact planning of the target area– Visualization of the whole procedure – Precise monitoring of temperature development

throughout the procedure• Despite its great potential, MRI exhibits limitations

when information with very high spatial and / or temporal resolution is needed

MR-guided HIFU

MR-guided ExAblate® 4000

• ExAblate is the 1st MR-guided focused ultrasound technology that uses MRI to visualize body anatomy, plan treatment and monitor outcomes in real time; and deliver HIFU to brain tissue non-invasively

ExAblate® 4000

• Benefits: Main advantage is non-invasiveness; Safer than conventional surgery; Avoids risk of complications – infection, hemorrhage and collateral damage to normal brain structures– The whole procedure is performed without

anaesthesia (patient is awake and conscious)– Procedure can be performed on out-patient

basis– Extreme precision and accuracy deep in brain

• Side effects: Vertigo, light headedness, and stinging sensation during procedure

HIFU advantages / side-effects

Patients treated• Neuropathic pain due to functional brain disorders• Post-amputation phantom limb syndrome, Nerve

injury, Stroke, Trigeminal neuralgia, Post-herpetic neuralgia from shingles

Future• Long term effects such as heat-related swelling

and what happens when brain tissue is heated • Paves the way for further research and other

potential clinical applications of treatment; Alzheimer's; Parkinson's disease; Essential tremor; Epilepsy; Brain tumors

HIFU applications present / future

HIFU result• Axial T2 MRI

(with fluid attenuation) of brain

• Showing HIFU-induced lesions in pulvinar region of both thalamus

Transcranial magnetic stimulation (TMS)

TMS principle

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(1) Electric current applied to external coil in anti-clockwise direction; (2) Magnetic field generated around coil (according to Right-hand rule of Physics), with high concentration of magnetic field in center of coil; (3) This induces electric current in brain substance in clockwise direction; (4) Which stimulates nerve cells in the field of induced current

• Electromagnetic coil on the scalp creates very rapid bursts of magnetic energy on the brain surface, which penetrates 2-3 cm deep

• Once inside the brain, the dynamic (rapidly changing) nature of the magnetic pulses induces electrical charges to flow, which activates or inhibits neural activity

• The amount of electricity created in the brain is very small and cannot be felt by the patient

• When in the correct orientation relative to brain neurons, these very small electric charges can cause the neurons to fire or become active

TMS principle

TMS principle • Right-hand rule (Physics): When electric current

flows along a conductor in the direction of pointing thumb of a semi-clenched fist, the resultant magnetic field is generated in the direction of other 4 semi-clenched fingers of the hand

• If the electrical conductor is in form of a coil placed over the brain, a high-intensity magnetic field is generated in the center of the coil in the brain substance, at right angles to the plane of the coil

• The magnetic field, in turn, induces electric current in brain, whose direction of flow is opposite to the original current in the coil

• This induced electric current in the brain stimulates nerve cells, which is the basis of TMS therapy

• rTMS mechanism – Electrostatic energy in a coil produces fast

oscillating magnetic fields– High intensity, multiple impulses in high tempo

(trains) within a short interval produces ‘repetitive’ magnetic field (rTMS), which influence neurons within reach of magnetic field• >1Hz pulses produce neuronal excitation• <1Hz pulses produce neuronal inhibition

–Exact mechanism is uncertain• rTMS uses

– Examine brain behavior relationships – Used on the Pre-frontal cortex (PFC) to treat

Resistant depression

Repetitive TMS (rTMS)

Effects of TMS can be recorded by:

EEG: Electro-encephalogram

PET: Positron Emission Tomogram

fMRI: Functional MRI

NIRS: Near Infra-red Spectroscopy

SPECT: Single Photon Emission Computerized Tomogram

EMG: Electro-myogram

• Advantages– Non- Invasive; Painless– Anesthesia is not required– Economical – Quite effective– Requires a significantly shorter amount of time

to implement – Reduces dependence on medication; Important

for those who do not tolerate medications• Side effects

– Headaches or scalp discomfort– Nausea in some patients

TMS advantages / side-effects

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• Resistant depression: rTMS excites neurons especially in Prefrontal cortex (PFC) to improve symptoms of major depression

• Tinnitus: PET scans look for excessive neuronal activity with increased blood flow in the temporal lobe; This area is then targeted with TMS to decrease neuronal activity and tinnitus

• Stroke• Parkinson’s disease• Epilepsy• Migraine• Obsessive-compulsive disorder (OCD)• Amyotrophic lateral sclerosis (Lou Gehrig’s)• Fibromyalgia

TMS applications – present / future

• FES: Application of neuromuscular electrical stimulation concurrently with training for specific task or functional activity. This application is termed as neuroprosthetics

• FES tries to benefit patients who had a low initial volitional motor control, and who were not expected to recover limb function after stroke

• FES + Exercise is likely to minimize motor loss, but it may not significantly enhance the ability to use the limb after ischemic stroke

• More patients may regain some functional ability after training with FES compared with training without FES. Patients with severe motor loss may require prolonged task-specific FES training

Functional electrical stimulation (FES)

• Improves active range of hand motion and function

• Improves voluntary movement• Re-educates muscles

• Prevents or retards disuse atrophy• Increases local blood circulation• Reduces muscle spasm• Maintains or increases

range of motion• Prevents contractures

FES – NESS H200

• Pathology: Injured Deep Fibular (Peroneal) nerve, which supplies the anterior compartment of leg (especially Tibialis anterior muscle)

• Manifestations: Inability to dorsiflex the foot; Foot hangs inferiorly; hence the term ‘Foot drop’; Patients catch their toes on the ground when walking, making it difficult to walk normally

• Etiology: (Other than Common/Deep Fibular nerve transection) –Multiple Sclerosis (MS)–Traumatic brain injuries– Incomplete s. cord injury–Cerebral palsy–Stroke

Foot drop

• Functional Electrical Stimulation (FES) system to treat Foot drop

• Sends low-level electrical impulses to Deep Fibular nerve in the leg

• Stimulates lifting of foot• FDA approved NESS

L300 in 2008• By 2008, 7/10 major

rehabilitation centers in US had implemented it

FES – NESS L300

FES – NESS L300Gait sensor over ankle detects attempted movement during walking; Stimulator in leg cuff sends impulses to leg dorsiflexors during heel-strike phase of gait

• While walking, the ankle Gait sensor detects gait events and transmits wireless signals to synchronize with electrical impulses emitted by the Stimulator

• Electrical impulses from the leg cuff Stimulator work on the common Fibular nerve and Tibialis anterior at the appropriate time during walking

• The mini Control unit displays real-time information regarding the system’s current status, and allows fine-tuning of adjustments

• Monitoring unit for healthcare professionals logs all information and monitors patient compliance

FES – NESS L300

Benefits• Normal natural walking gait• Prevents muscle atrophy• Increases range of joint motion• Increases local blood flow• Clinical research has shown

–17% immediate increase in mean walking speed–34% increase in mean walking speed after 8 wks–45% improvement in gait asymmetry index after

8 weeks–92% decrease in fall frequency

• Note: NESS L300 cannot function if Common / Deep Fibular nerve itself is cut and / or Tibialis Anterior muscle is atrophied

FES – NESS L300

• The NESS L300 uses wireless communication which eliminates the need for externally worn cumbersome wires

• Stimulation of the Common Fibular nerve and Tibialis Anterior causes dorsiflexion in individuals with Foot drop

• Ness L300 can dramatically improve the lifestyle of these patients by helping them to:–Walk normally–Enjoy everyday activities, which were previously

difficult or impossible to accomplish

NESS L300 summary

Newer generation cochlear implant

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Inset shows a post-operative view

• Microphone: Positioned over external ear; Receives the sound; transmits to Speech processor

• Speech processor: (a) Behind ear; or (b) Body-worn; Receives sound from microphone and decides how the electrodes stimulating cochlear nerve should be activated

• Transmitter coil: Attached by magnet to side of skull; Receives info from Speech processor and transmits radiofrequency (RF) waves to Receiver-Stimulator inside skull; Lack of direct connection thro skull reduces infection and pain

Cochlear implant

• Receiver-Stimulator: Embedded in skull bone behind ear; Receives input from Speech processor via the external Transmitter coil; Receives its power by magnetic induction; Transmits processed sound info, and controls electric current to cochlear electrodes

• Electrode array: Drilled thro mastoid bone into inner ear and implanted on cochlea; Stimulates different areas of cochlea (and CN8c), based on how sound is interpreted by Processor (~to organ of Corti); Several weeks after insertion, cochlear implant is fine-tuned

Cochlear implant

Brainstem implant

• In May 2013 a Brainstem implant was performed in the US for the first time on a 3-year old child. An earlier attempt at Cochlear implant failed because the Cochlear nerve was congenitally absent.

• The components of Brainstem implant are similar to Cochlear implant; but the technique is 4-5 times more challenging because the cable has to go under the Temporal lobe and the Electrode has to be positioned on the Brainstem

• The composite image was created from screenshots of the news video. The labels are self-explanatory. An anatomical error has been highlighted.

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Brainstem implant

Tinnitus masker console

• Tinnitus masker: Tinnitus masking was once thought to be useful because it blocked the sound perceived by the patient

• It proved to be counter-productive because for habituation (one of the effective modes of treatment) to work, the sound needs to be audible

• Habituation cannot occur if perception of the sound is not present; viz. one cannot cure acrophobia simply by avoiding heights

• Tinnitus Retraining Therapy: Goal of this therapy is to adjust the reaction of patient to the tinnitus and the perception of the tinnitus sound itself. This includes counseling and use of Noise generators

Tinnitus masker

• Sound generators: Electronic devices in ear that amplifies hearing and masks tinnitus with ‘white noise’ or static (different sounds at different frequencies that block out the tinnitus sounds)

• Disadvantages: Long time period before patient experiences benefits; High cost related to the prosthesis, High dependence on counseling, Not covered by health insurance

• Wearable sound generator (WSG): New WSGs use many frequencies to stimulate all nerve cells in the auditory pathway, to make allowances for greater plasticity of the nerve cells

Sound generator

• Sound generator produces sound at many different frequencies (a.k.a. ‘white noise’)

• This masks the perception of tinnitus by impedance

Wearable sound generator