Optical Stimulators in Headache

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Optical Stimulators in Headache

• (or, it's going to be a great century)

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BrainGate

• BrainGate is a brain implant system developed by
  the bio-tech company Cyberkinetics in 2003 in
  conjunction with the Department of Neuroscience
  at Brown University.
• Currently the chip uses 96 hair-thin electrodes th
  at sense the  neurons firing in specific areas of
  the brain, for example, the area that controls
  arm movement. The activity is translated into
  electrically charged signals and are then sent
  and decoded using a program, which can move a
  robotic arm, a computer cursor, or even a
  wheelchair.  Three patients have been implanted
  with the BrainGate system. 

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ECT

•  

Electroconvulsive therapy (ECT), also known
as electroshock, is a well established, albeit
controversial, psychiatric treatment in
which seizures are electrically induced in
anesthetized patients for therapeutic effect.
Today, ECT is most often used as a treatment for
severe major depression which has not responded
to other treatment, and is also used in the
treatment of mania (often in bipolar
disorder), catatonia and schizophrenia. It was
first introduced in the 1930s and gained
widespread use as a form of treatment in the
1940s and 1950s today, an estimated 1 million
people worldwide receive ECT every year, usually
in a course of 612 treatments administered 2 or
3 times a week.
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Transcranial magnetic stimulation

• Transcranial magnetic stimulation (TMS) is a
  noninvasive method to excite neurons in
  the brain weak electric currents are induced in
  the tissue by rapidly changing magnetic
  fields (electromagnetic induction). This way,
  brain activity can be triggered with minimal
  discomfort, and the functionality of the
  circuitry and connectivity of the brain can be
  studied.
• Repetitive transcranial magnetic stimulation is
  known as rTMS and can produce longer lasting
  changes. Numerous small-scale pilot studies have
  shown it could be a treatment tool for various
  neurological conditions (e.g. migraine, stroke, Pa
  rkinson's disease, dystonia, tinnitus) and
  psychiatric conditions (e.g. major depression,
  auditory hallucinations) and dandruff.

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   rTMS Brain Effects

• Repetitive TMS (rTMS) produces effects which last
  longer than the period of stimulation. rTMS can
  increase or decrease the excitability
  of corticospinal or corticocortical pathways
  depending on the intensity of stimulation, coil
  orientation and frequency of stimulation. The
  mechanism of these effects is not clear although
  it is widely believed to reflect changes in
  synaptic efficacy akin to long-term
  potentiation (LTP) and long-term
  depression (LTD). 

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rTMS RISKS

• As it induces an electrical current in the
  human brain, TMS and rTMS can produce
  a seizure. The risk is very low with TMS except
  in patients with epilepsy and patients on
  medications. The risk is significantly higher,
  but still very low, in rTMS especially when given
  at rates gt5Hz at high intensity.The only other
  effects of TMS which are reported in most
  subjects are
• Discomfort or pain from the stimulation of the
  scalp and associated nerves and muscles on the
  overlying skin
• Hearing the loud click made by the TMS pulse
• rTMS in the presence of EEG electrodes can result
  in electrode heating and, in severe cases, skin
  burns

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TMS Clinical Uses

• A large number of studies with TMS and rTMS have
  been conducted for a variety of neurological and
  psychiatric conditions but few have been
  confirmed and most show very modest effects, if
  any. Multiple controlled studies support the use
  of this method in treatment-resistant depression
  it has been approved for this indication in
  Europe, Canada, Australia, and the US. Some
  conditions which have been reported to be
  responsive to TMS-based therapy are chronic pain,
  epilepsy, fibromyalgia,major depression,
  migraine, OCD, Parkinson's 
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FDA and rTMS

• As of October 8, 2008, a TMS device, NeuroStar,
  manufactured by Neuronetics Inc. has been
  approved for use by the Food and Drug
  Administration (FDA) in the United States for use
  in adult patients with major depression who have
  previously tried medication and not improved
  satisfactorily.
• .

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TMS uses induction of electric current

•  A coil of wire, encased in plastic, is held to
  the head. When the coil is energized by the rapid
  discharge of a large capacitor, a rapidly
  changing current flows in its windings. This
  produces a magnetic field oriented orthogonally to
  the plane of the coil, inducing an oppositely
  directed current in the brain that flows
  tangentially with respect to skull.  These
  magnetic fields do not directly affect the whole
  brain they only reach about 2-3 centimeters into
  the brain directly beneath the treatment
  coil. With stereotactic MRI-based control, the
  precision of targeting TMS can be approximated to
  a few millimeters.

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rTMS typical data

•  
• magnetic field often about 2 teslas on the coil
  surface and 0.5 T in the cortex
• current rise time zero to peak, often around
  70-100 microseconds
• wave form monophasic or biphasic
• repetition rate for rTMS below 1 Hz (slow TMS),
  above 1 Hz (rapid-rate TMS)

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Multielectrode arrays

• Multielectrode arrays (MEAs) or microelectrode
  arrays are devices that contain multiple plates
  or shanks through which neural signals are
  obtained or delivered, essentially serving as
  neural interfaces that connect neurons to electron
  ic circuitry. 

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MEA theory

• Neurons and muscle cells create ion currents
  through their membranes when excited, causing a
  change in voltage both inside and outside the
  cell. When recording, the electrodes on an
  MEA transduce the change in voltage from the
  environment carried by ions into currents carried
  by electrons (electronic currents). When
  stimulating, electrodes transduce electronic
  currents into ionic currents through the media.
  This triggers the voltage-gated ion channels on
  the membranes of the excitable cells, causing the
  cell to depolarize and trigger an action
  potential if it is a neuron or a twitch if it is
  a muscle cell.

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MEA applications

• There are several implantable interfaces that are
  currently available for consumer use
  including deep brain stimulators, cochlear
  implants, and cardiac pacemakers. Deep brain
  stimulation (DBS) has been effective at treating
  movement disorders such as Parkinsons
  disease, and cochlear implants have helped many
  to improve their hearing by assisting stimulation
  of the auditory nerve.

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DBS

•  Deep brain stimulation (DBS) is
  a surgical treatment involving the implantation
  of a medical device called a brain pacemaker,
  which sends electrical impulses to specific parts
  of the brain. DBS in select brain regions has
  provided remarkable therapeutic benefits for
  otherwise treatment-resistant movement and
  affective disorders such as chronic
  pain, Parkinsons disease, tremor and dystonia,
  and major depression.

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The FDA and DBS

• The Food and Drug Administration (FDA) approved
  DBS as a treatment for essential tremor in 1997,
  for Parkinson's disease in 2002,3 and dystonia i
  n 2003.4 DBS is also routinely used to
  treat chronic pain and has been used to treat
  various affective disorders, including major
  depression. While DBS has proven helpful for some
  patients, there is potential for serious
  complications and side effects

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DBS placement
DBS leads are placed in the brain according to
the type of symptoms to be addressed. For
non-Parkinsonian essential tremor the lead is
placed in the ventrointermedial nucleus (VIM) of
the thalamus. For dystonia and symptoms
associated with Parkinson's disease (rigidity, bra
dykinesia/akinesia and tremor), the lead may be
placed in either the globus pallidus or subthalami
c nucleus. All three components are surgically
implanted inside the body.

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Surgical implantation of DBS
 Under local anesthesia, a hole about 14 mm in
diameter is drilled in the skull and the
electrode is inserted, with feedback from the
patient for optimal placement. The installation
of the IPG and lead occurs under general
anesthesia. The right side of the brain is
stimulated to address symptoms on the left side
of the body and vice versa.

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DBS biochemistry

• It has been shown in thalamic slices from
  mice that DBS causes nearby astrocytes to
  release adenosine triphosphate (ATP), a precursor
  to adenosine (through a catabolic process). In
  turn, adenosine A1 receptor activation depresses
  excitatory transmission in the thalamus, thus
  causing an inhibitory effect that
  mimicks ablation or "lesioning".

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DBS side effects/risks

• Neuropsychiatric side effects.  Apathy, hallucinat
  ions,compulsive gambling, hypersexuality, cognitiv
  e dysfunction, and depression. However, these may
  be temporary and related to correct placement and
  calibration of the stimulator and so are
  potentially reversible. A recent trial of 99
  Parkinson's patients who had undergone DBS 9 of
  patients had "psychiatric events", which ranged
  in severity from a relapse in voyeurism to
  a suicide attempt. Most patients in this trial
  reported an improvement in their quality of life
  following DBS.

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Charles Matthews M.D. Director, N.C.
Comprehensive Headache Clinic Raleigh N.C.
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• Neurology  The specialty concerned with medical
  disorders of the central and peripheral nervous
  system and muscle.
• Board Certification  Diplomate of the American
  Academy of Psychiatry and Neurology, with Special
  Competence in Adult Neurology
• Typically three years after a four year medical
  program
• Subspecialty Headache, Neurophysiology,
  Neuroimaging

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• The North Carolina Comprehensive Headache Clinic
• Established 1993
• Average 25 patients/day
• Over 30,000 outpatient visits 
• There are 10 million people in the US who are
  dissatisfied with their headache treatment

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Headache types

• Migraine
• Muscle contraction
• Cluster
• Hypnic
• Menstrual
• Toxic  Carbon monoxide
• Traction (mass lesion)
• Inflammation   Infection  

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Migraine 

• Migraine is a neurological syndrome characterized
  by altered bodily perceptions, headaches,
  and nausea.
•  More common in women than in men. 
• The word migraine was borrowed from Old
  French migraigne(originally as "megrim", but
  respelled in 1777 on a contemporary French
  model). The French term derived from
  a vulgar pronunciation of the Late
  Latin word hemicrania, itself based
  on Greek hemikrania, from Greek roots for "half"
  and "skull".
•  The typical migraineheadache is unilateral and
  pulsating, lasting from 4 to 72 hours
•  Symptoms include nausea, vomiting, photophobia (i
  ncreased sensitivity to bright light),
  and hyperacusis (increased sensitivity to sound).
• One third of people who suffer migraineheadache
  perceive an aura  unusual visual, olfactory, or
  other sensory experiences that are a sign that
  the migraine will soon occur.

 
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Migraine prodrome

• Prodrome phase
• Prodromal symptoms occur in 4060 of
  migraineurs 
• Altered mood, irritability, depression or euphoria
  , fatigue, yawning, excessive sleepiness, craving
  for certain food (e.g. chocolate), stiff muscles
  (especially in the neck), constipation or
  diarrhea, increased urination, and other visceral
  symptoms.
• Precedes the headache phase of the migraine attack
  by several hours or days.

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Migraine aura

• Focal neurological phenomena that precede or
  accompany the attack. 
• Appear gradually over 5 to 20 minutes and
  generally last fewer than 60 minutes. The
  headache phase of the migraine attack usually
  begins within 60 minutes of the end of the aura
  phase, but it is sometimes delayed up to several
  hours, and it can be missing entirely. 
• Symptoms can be visual, sensory, or motor.

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Migraine pain phase

•       Unilateral, throbbing, and moderate to
  severe 
•       Can be aggravated by physical activity. 
•        May be bilateral 
•        Onset usually gradual. 
•        Peaks and then subsides and usually lasts
  4 to 72 hours 
•        Frequencyvariable, a few in a lifetime to
  several a week
•        Average migraineur experiences one to
  three/month. 
•        Photophobia, phonophobia, and osmophobia,
  cognitive         

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Postdrome phase

• Tired or "hungover" 
• Cognitive difficulties, gastrointestinal
  symptoms, mood changes, and weakness.
• Some people feel unusually refreshed or euphoric
  after an attack, whereas others note depression
  and malaise. 
• Loss of appetite, photophobia, and
  lightheadedness. 
• For some patients, a 5- to 6-hour nap may reduce
  the pain,

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Diagnosis of Migraine

• Migraines are underdiagnosed and
  misdiagnosed. The diagnosis of migraine without
  aura, according to the International Headache
  Society, can be made according to the following
  criteria, the "5, 4, 3, 2, 1 criteria"
• 5 or more attacks
• 4 hours to 3 days in duration
• 2 or more of - unilateral location, pulsating
  quality, moderate to severe pain, aggravation by
  or avoidance of routine physical activity
• 1 or more accompanying symptoms - nausea and/or
  vomiting, photophobia, phonophobia
• For migraine with aura, only two attacks are
  required to justify the diagnosis.
• The presence of either disability, nausea or
  sensitivity, can diagnose migraine with
• sensitivity of 81
• specificity of 75
• Migraine should be differentiated from other
  causes of headaches such as cluster headaches.
  These are extremely painful, unilateral headaches
  of a piercing quality. The duration of the common
  attack is 15 minutes to three hours. Onset of an
  attack is rapid, and most often without the
  preliminary signs that are characteristic of
  a migraine.

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Spreading Cortical Depression of Leao
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Rami BursteinCutaneous allodyniaTrigeminal
sensitization

•  

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Medications for migraineAntidepressantsAnticonv
ulsantsBeta blockersSignificant doesn't mean
it's significant!

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Le Chatelier's Principle

•      -If a chemical system at equilibrium
  experiences a change in concentration,
  temperature, volume, or partial pressure, then
  the equilibrium shifts to counter-act the imposed
  change.
•       -It is common to take Le Ch?telier's
  principle to be a more general observation,
  roughly stated
•      -Any change in status quo prompts an
  opposing reaction in the responding system.

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Prediction for students

• Most of you will have a neurostimulator implanted
  during your lifetime
• Artificial sensory system
• Data reception
• Precise treatment of neurological disease
• Memory assistance and enhancement
• -Sitting with my grandmother during the moon
  landing-
• People overestimate change in the short term and
  underestimate in the long term
• Comparative optical and electrical stimulators

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Read/write optical stimulators?

• file///Users/charlesmatthews/Desktop/090722-body-
  glow-01.jpg
• ESchematic illustration of experimental setup
  that found the human body, especially the face,
  emits visible light in small quantities that vary
  during the day. B is one fo the test subjects.
  The other images show the weak emissions of
  visible light during totally dark conditions. The
  chart corresponds to the images and shows how the
  emissions varied during the day. The last image
  (I) is an infrared image of the subject showing
  heat emissions. Credit Kyoto University Tohoku
  Institute of Technology PLoS ONE

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Mitochondrial origin as algal symbiont

• Endosymbiotic theory
• Electron micrograph of amitochondrion showing its
  mitochondrial matrix and membranes.
• The endosymbiotic theory concerns the origins
  of mitochondria and plastids (e.g. chloroplasts),
  which are organelles of eukaryotic cells.
  According to this theory, these organelles
  originated as separate prokaryotic organisms
  which were taken inside the cell
  as endosymbionts. Mitochondria developed
  from proteobacteria (in particular, Rickettsiales 
  or close relatives) and chloroplasts
  from cyanobacteria.

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What is the brain?

• -McCulloch-Pitts logical engine operating with
  Boolean algebra.  A heat engine that performs
  mathematical work.
•      -Any logical sentence can be formed. 
•      -Hubel and Weisel- the visual system
•      -the Grandmother cell
•  
•      Problem- where is it?  "Binding" problem

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What else might the brain be?

• -the pupil and spatial relations
• -somatotopic organization
• Key point!  Analog data preserves space relations
• -crossings and decussations- 
• Neuromas heal like pupillary functions
• Crossings are neuromas/pupils?
• the brain as a camera obscura
• Efficient nonlinear information search
• von Neumann- brain is both digital and analog
• Key question- how do the computer and the camera
  obscura interact?
• Brouwer's fixed point theorem! (you heard it here
  first)

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Brouwer's fixed point theorem

• Single and finite dimensional cases
• Retinal "surface" images can be
• stirred into the volume of the cortex
• Retains space-like relations
• Efficient search due to orientation
•      of surfaces through detection of
•      fixed points by specific neurons
• ?Direct analog brain broadcasting
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              Argus NeuroOptics

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