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NEUROMODULATION IN
PSYCHIATRY
DR.VIDHYA.S,
MD POSTGRADUATE
MADURAI MEDICAL COLLEGE
Overview
 Brain stimulation
 Therapies
INTRODUCTION
 Brain stimulation includes delivery of electric
or magnetic field transcranially or by direct
placement of electrodes into the brain
thereby delivering electric current into a
cranial nerve or brain itself.
 Also called as non pharmacological somatic
therapies.
objective
 Neuromodulation therapies
 allow focused delivery of modifying agents
e.g., electrical, optical or chemical signals –
 to targeted areas of the nervous system in
order to improve neural function.
 range from non-invasive techniques to
techniques involving the surgical implantation
of devices
 to alter activity in discrete areas of the
nervous system.
 Neuromodulation therapies are:
 • Highly targeted to specific areas of the
brain or spinal cord, rather than systemic
throughout the body such as pharmaceutical
treatments
 • Highly reversible, allowing physicians to
immediately cease treatment with the removal of
the stimulating device
 • Continuous, improving therapeutic
compliance over techniques that rely on fixed
intermittent dosing.
HISTORY AND EVOLUTION
 STARTED WITH NEUROLOGY
 NEUROSURGEON DR.NORMAN SHEALY
USED ELECTRIC STIMULATION FOR PAIN
RELEIF
 EXPANDED TO SPINAL CORD
STIMULATION AND THEN LATER TO
CORTICAL STIMULATION FOR STROKE AND
APHASIA
 BRAIN STIMULATION IN PSYCHIATRY
STARTED WITH ECCT-1983
 WITH A 50 YEARS OF GAP-TMS IN 1980s
Classification
Convulsive/nonconvulsive
Direct/indirect
Invasive/non invasive
Techniques on the horizon:
 1. Focussed ultrasound(FUS)
 2. Optogenetic stimulation
 3. Near Infra red therapy
 4. low field magnetic stimulation
Mechanism of action
ELECTRICAL
STIMULATION OF THE
BRAIN
FINAL COMMON
PATHWAY
 MODE OF STIMULATION-
ELECTRICAL/MAGNETIC
 SITE OF STIMULATION
TRANSCRANIAL
EPIDURAL
INTRACEREBRAL
 ACUTE EFFECTS
 Phasic activation of neural circuits
 Observable motor responses (e.g., twitch)
 Temporary disruption (e.g., speech arrest) or
facilitation of ongoing processing (e.g., speeds
reaction time)
 PROLONGED EFFECTS
 NEUROPLASTICITY
 • Change in synaptic efficacy, akin to long-term
potentiation or depression
 • Alterations in neurotropic factors
 • Modulation of cortical excitability
 • Modulation of functional connectivity
Cortico-striato-thalamocortical loop
 In 1986, Alexander and Delong described a series
of 5 loops of information, from cortex to basal
ganglia and back to cortex.
 Each loop activity courses through the basal
ganglia in parallel direct and indirect pathways.
 movement disorders, the motor loop is of
importance.
 For psychiatric disease, the dorsolateral,
orbitofrontal, and anterior cingulate loops are
important.
Relevant anatomy
 HPA circuit
 7 targets
 for neuromodulation surgery have been
published: Cg25, the anterior internal capsule
(AIC), the nucleus accumbens (NA), the
ventral striatum (VS), the inferior thalamic
peduncle (ITP), the subthalamic nucleus (StN)
and the left vagus nerve
 Single electrical pulses, delivered at sufficient
intensity, can induce neuronal depolarization and
trigger trans-synaptic action, resulting in the
activation of a function circuit.
 Repeating pulses at regular intervals can exert
even more powerful acute effects on brain
function.
 intermittent stimulation, which presumably
requires the induction of some form of
neuroplasticity, which persists beyond the period
of stimulation.
 Neuroplasticity is thought to occur through
dynamic alterations in synaptic efficacy.
 For example, repeatedly electrically
stimulating the perforant pathway at
 high frequency - Long-term potentiation
 low frequencies depress it - long-term
depression (LTD).
Focality and Invasiveness
 FOCAL
LESS FOCAL-LESS INVASIVE
▪MORE INVASIVE
MORE FOCAL
tDCS- polarises the system.
Brain stimulation vs
psychopharmacology
FEATURES BRAIN STIMULATION PHARMACOLOGICAL
METHODS
MECHANISM induce Action potentials via
electrical depolarization of
axons in a manner that is
independent of receptor
binding.
Molecular action at receptors
and intracellular signalling
SIDE EFFECTS Systemic side effects are
absent
Systemic side effects are
common
PHARMACODYNAMIC
EFFECTS
no drug interactions or other
pharmacodynamic
interactions
significant metabolism and
drug interactions present
DURATION Phasic application effects
lasting for short time( pulses
last for less than a minute)
lasting effects seen
depending on the drug half
life and duration
 Brain stimulation modalities have contributed
in multiple parallel ways:
 as tools of discovery to examine normal brain
function,
 as tools to examine the pathophysiology of
psychiatric disorders, and
 as novel therapeutic agents.
Brain stimulation methods
ELECTRO
CONVULSIVE
THERAPY
DEFINITION
 electric current is passed through the brain via
electrodes placed against the head to
produce a seizure
HISTORY
 PARACELSUS- CAMPHOR METHOD
 VON MEDUNA- IM CAMPHOR/
PENTYLENETETRAZOL
 CERLETTI/BINI-FIRST ELECTRICAL
INDUCTION OF SEIZURES IN CATATONIC
SCHIZOPHRENIA
 1958-FIRST CONTROLLED STUDY OF ECT
 1970-POSITION OF ELECTODE
 1980S-FDA APPROVAL
MECHANIS OF ACTION
 FUNCTIONAL BRAIN ACTIVATION-CBF,CMR inc.
 NEUROTRANSMITTER SYSTEMS
Downregulate b receptors
Enhance 5HT transmission
Dopaminergic action
GABA,Adenosine
Glutamine and cognitive effects-underway
 HPA AXIS
 NEUROPLASTICITY
 ANTICONVULSANT EFFECT
INDICATIONS
 Major diagnostic indications
 Major depression, both unipolar and bipolar
 Psychotic depression in particular
 Mania, including mixed episodes
 Schizophrenia with acute exacerbation
 Catatonic subtype particularly
 Schizoaffective disorder
 Other diagnostic indications
 Parkinson's disease
 Neuroleptic malignant disorder
Clinical indications
 Primary use
 Rapid definitive response required on medical or
psychiatric grounds
 Risks of alternative treatments outweigh benefits
 Past history of poor response to psychotropics or good
response to ECT
 Patient preference
 Secondary use
 Failure to respond to pharmacotherapy in the current
episode
 Intolerance of pharmacotherapy in the current episode
 Rapid definitive response necessitated by deterioration
of the patient's condition
 PROCEDURE
 SIDE EFFECTS-MEMORY IMPAIRMENT
 MORTALITY
 CONTRAINDICATIONS
TMS
DEFINITION
 TMS refers to the induction of small electrical
currents in the superficial layers of the
cerebral cortex by applying rapidly alternating
magnetic fields to the head.
BASIC PRINCIPLES
 FARADAY’S LAW
 MAXWELL EQUATION
When there is a primary circuit
where time varying current
flowing, there was an induction
of current in a secondary circuit
which was at close proximity;
quantified by Maxwell’s
equation for electromagnetism
PROCEDURE:
 TMS devices deliver strong magnetic pulses via a
coil that is held on the scalp. Because magnetic
fields are unaffected by the electrical impedance
of the scalp and skull, this method of stimulation
enables the focal stimulation of smaller areas of
the brain.
 TMS has been referred to as “electrodeless”
electrical stimulation because it uses magnetic
fields to induce electrical pulses indirectly.
 As such, it represents a noninvasive means of
stimulating focal regions of the brain.
 NO ANAESTHESIA NEEED.
TYPES OF rTMS
 SINGLE-PULSE- one pulse at a time without regular
rhythm and at low rates of delivery.
 REPETITIVE PULSE-repeated at regular rhythmic
intervals ( 1 to 25 Hz)
 “low-frequency Rtms”frequency is 1 Hz or less and
 “high-frequency rTMS” usually 5 to 20 Hz.
 PAIRED PULSE
 REPEATED PAIRED PULSE
 Theta burst stimulation (TBS) -high-frequency bursts
(e.g., 3 pulses at 50 Hz) at regular frequency.
 continuously (cTBS) or intermittently (iTBS).
 cTBS -induce inhibitory effects
 iTBS is reported to exert excitatory effects
History
 Barker, Jalinous, and Freeston -The first human use of pulsed
magnetic fields
 Initially -very low frequencies of TMS were applied in
exploratory studies on the treatment of depression and
schizophrenia.
 mid-1990s, repetitive stimulators capable of higher
repetition rates (up to 20 Hz) became available.
 Higher frequency stimulation was able to influence higher
brain functions such as language, mood, and memory.
 Early studies with high-frequency rTMS suggested that it
might have antidepressant properties when applied to the
dorsolateral prefrontal cortex (DLPFC) (George et al., 1995;
Pascual- Leone et al., 1996).
Mechanism of action
 Alternating magnetic fields- induce electrical currents
in the superficial cortex .
 electrical currents are called “eddy currents” because
they are circular in shape, and are oriented in the plane
perpendicular to the plane of the TMS coil.
 At sufficient intensity, electrical currents will
stimulate neuronal depolarization, which can result in
an action potential.
 Two types of pulses-monophasic and biphasic.
Magnetic pulse frequency is 1 to 50 Hz.
 Low frequency stimulation for 15 mins induces
transient inhibition of cortical activity while high
frequency stimulation induces cortical activity.
SIDE EFFECTS :
The most serious known risk of TMS is unintended
seizure.
 Factors contributing are :
 the form of TMS (single-pulse(minimal risk) versus
rTMS(induce seizure without any predisposing
factor),
 the dosage (intensity, frequency, train duration,
inter-train interval), and
 subject factors that may place the individual at
increased risk (such as the presence of a
neurological disorder or seizure- lowering
medications).
 Precautions to be taken:
 1.Safety Guidelines-duration in seconds that could be
administered at each combination of frequency and intensity
prior to the emergency of spread of excitation, a warning sign
of seizure.
 2.subjects should always be advised of this potential.
 3.It is also recommended that rTMS be administered
under medical supervision, and that procedures be in place to
screen and monitor patients medically for changes in clinical
status that could affect seizure risk.
 4.The treating clinician should have the proper training
and equipment to manage a seizure should one occur
 B.The most common side effects of TMS are
scalp discomfort and headache. These effects
are attributable to scalp muscle stimulation
and stimulation of the facial nerve. Earplugs
are worn by the patient and administrator to
protect hearing.
 C.The risks of TMS during pregnancy have not
been thoroughly studied. Since TMS is
experimental, it may carry as yet unknown
risks.
Advantages
 Noninvasive, can study normal subjects
 Effects reversible
 Focal stimulation
 good spatial resolution
 Excellent temporal resolution
 Selective frequency dependent
neurophysiological effects—effects akin to
LTP and LTD
 Complement to functional imaging
Clinical studies
 Major depression-most thoroughly studied
with TMS to date.
 Significant antidepressant effects of rTMS
when given to the DLPFC evidenced by
number of randomized controlled trials and
by several meta-analyses.
 The average effect size in depression is
moderate – less than that seen with ECT but
close to that seen with antidepressant
medications.
 Schizophrenia - low-frequency rTMS to inhibit
temporal–parietal regions of the cortex reported
to be hyperactive during hallucinations.
 A recent meta-analysis of prospective studies
including both low- and high-frequency rTMS on
negative symptoms found a moderate effect size.
Poor outcome was associated with length of
illness.
 Although less studied, TMS has shown some
promising early results in anxiety disorders.
Current Status in Treatment
Algorithms
 TMS is not currently FDA approved, and
therefore is not included in treatment
algorithms.
 Should it ultimately be found safe and
effective for depression, it would likely be
most useful positioned between medications
and ECT.
Dosing
 Scalp position,target localisation
 Coil shape- commonly used “shape of 8”
 Iron coils cost effective
 The delivered intensity of rTMS is related to the
distance of the coil from the target cortex.
 Increasing the distance decreases the intensity of
the stimulation reaching the brain-negatively
correlated with antidepressant response and with
the degree of stimulation- induced brain
activation.
 rTMS is carried out while the patient is awake and
reclining in a specially equipped chair. Sessions
usually last 20-40 minutes, five days a week,
typically for six weeks.
 In open-label clinical trials, after 4-6 weeks of
treatment, one out of two patients treated with
rTMS for depression experienced a reduction in
symptoms of 50% or more, and one out of three
experienced remission. The effect was lower in
patients who had exhibited resistance to more
 Train-freq,duration,intensity
 Intertrain interval
 No.of sessions/day/course
 treatment-related factors include variation in coil
and stimulator type, waveform shape and polarity,
and coil position and orientation relative to target
cortex.
 Even when these factors are held constant,
considerable within-subject variability in
physiological response to TMS in the motor
system has been reported.
Repetitive transcranial magnetic
stimulation (rTMS)
non-invasive treatment
delivers repetitive pulses of an MRI-strength magnetic
field from a coil placed over the scalp.
The FDA approved rTMS in 2008-treatment to alleviate
symptoms of mildly treatment-resistant depression
studied as a possible treatment for-schizophrenia, pain,
stroke, and amyotrophic lateral sclerosis (ALS).
 antidepressants.
 For patients with treatment-resistant depression,
rTMS has been approved in Canada, Australia, New
Zealand, the European Union, and Israel in addition to
in the United States.
Future Directions
It will be important to replicate key findings, identify optimal dosing
parameters to maximize efficacy,examine dose–response
relationships, determine patient characteristics that predict
response, and explore the impact of concomitant medications and
psychotherapy on TMS effects.
 post-TMS relapse prevention is an area yet to be definitively
addressed.
 Future work may develop coils optimized for deeper penetration
and pulse shapes that are more physiologically optimized to
human neurophysiology.
 example is control- lable pulse-shape TMS (cTMS), which can
induce pulses that are rectangular in shape (like ECT pulses).
 The role of high-frequency rTMS in augmenting antidepressants
warrants further investigation. Traditional TMS devices induce
pulses that are sinusoidal, a waveform that was abandoned with
ECT owing to its inefficiency and excessive side effects.
DIRECT BRAIN STIMULATION
DEFINITION
 Deep brain stimulation (DBS) is a technique
that consists of a surgically implanted lead
that provides focal electrical neural-network
modulation within a brain circuit or circuits of
interest.
 With DBS, intracranial electrodes are
implanted and chronically stimulate targeted
brain areas. Unlike lesioning procedures, DBS
is believed to be reversible, and the intensity
of stimulation can be adjusted according to
the acute effect on symptoms.
 The US FDA issued an approval for the use of DBS in
essential tremor in 1997 and
 PARKINSON DISEASE in 2002.
 A humanitarian device exemption (HDE) was granted
for motoric symptoms of dystonia in 2003.
 obsessive-compulsive disorder (OCD), depression, and
Tourette syndrome (TS), have proven more difficult to
study.
 The US FDA issued a HDE for obsessive compulsive
disorder in 2009.
 TS and depression both remain unapproved uses of
DBS technology;
 So far, patients worldwide have received DBS
for depressive disorder, with varying
stimulation sites: white matter underlying
cingulate area 25 internal capsule/nucleus
accumbens , the inferior thalamic peduncle,
subthalamic nucleus and the lateral habenula
 The list of potential complications and side
effects is lengthy and includes
anxiety/agitation, headache, lead
dislodgement, and infection.
Neuropsychiatric effects from DBS of “motoric targets.”
 Positive :
 implantation in the Gpi for PD and tardive dyskinesiahave reported
improvements in mood and
 STN DBS -patients with comorbid PD and OCD have also had
improvements in anxiety .
 Some TS patients implanted in the CM thalamus unexpectedl reductions in
OCD and depression symptoms.
 Negative
 STN DBS may adversely affect cognitive and limbic circuitry in some
 De novo impulse control disorder, mania, increased anger, worsening
apathy, fatigue, cognitive decline, binge eating, worsening depression, de
novo psychosis, and suicidality all appear to be uncommon, but possible
effects.
 side effects are reversible and may be stimulation related, resolving when
the DBS is turned off .
 Some related to lead position and stimulation parameters. Some effects
(e.g. verbal fluency) may be related to the surgery itself (i.e., microlesion
effect).
Limbic targets
 Positive
 The NAc target-antianxiety effect, improvements in OCD, it was hypothesized to
have an independent antidepressant effect.
 Acute changes in memory were associated with unintended stimulation of the fornix
 NAc DBS has also resulted in weight loss,
 The NAc is also a potential target for the treatment of addiction( alcohol intake,
nicotine dependence, and opiate use.)
 Negative
 Mania is one of the most concerning
 paradoxical worsening of anxiety and depression has also been reported.
 Feelings of suicidality can emerge;
 Feelings of irritability and anger .
 Cognitive dysfunction at high amplitudes has been observed with Broadmann Area 25
DBS along with the occurrence of paradoxical worsening of depressive symptoms.
 Limbic STN DBS for OCD has been associated with hypomania, anxiety,
impulsiveness, depression symptoms, and obsessive-compulsive thoughts.
VNS-VAGAL NERVE
STIMULATION
 Direct, intermittent electrical stimulation of the left cervical vagus
nerve via a pulse generator implanted in the left chest wall.
 The electrode is wrapped around the left vagus nerve in the neck
and is connected to the generator subcutaneously.
 Intermittent left vagal nerve stimulation sends afferent signals to
the nucleus tractus solitarius and connected limbic and cortical
areas.
 Implantation surgery involves two incisions – one for the
generator in the chest and another in the neck for the electrode.
Surgery is usually performed under brief general anesthesia.
 Stimulation parameters are adjusted with a programming wand
that communicates with the generator. Patients may turn off the
stimulation when needed by holding a magnet over the generator.
 VNS was originally approved by the FDA for
the treatment of resistant epilepsy, and in
2005 was approved for the adjunctive
treatment of chronic, treatment-resistant
depression.
Mechanisms of Action
 The left vagus nerve contains 80% afferent fibers,
hence stimulating it activates predominantly vagal
afferents.
 Chronic stimulation of the vagal afferents changes
activity in brain-stem nuclei (such as the nucleus of
the solitary tract), and from there neighboring
nuclei (e.g., Raphe) that alter sero- tonergic
activity in cortical and limbic structures.
 Chronic stimulation of the vagal afferents is
anticonvulsant, and this effect appears to be
dependent upon the locus ceruleus.
 Side Effects
 VNS is generally well tolerated.
 Voice alteration, dyspnea, and neck pain are the most frequently
reported adverse events.
 The surgical implantation carries the risks of infection, vocal cord
paralysis, and bradycardia or asystole. VNS does not cause
apparent cognitive side effects. In fact, neurocognitive
performance was significantly improved with VNS – apparently
due to the improvement in depression.
 Contraindications :history of bi-lateral or left cervical vagotomy
and use of short-wave diathermy, microwave diathermy, or
therapeutic ultrasound diathermy. Patients with VNS implanted
cannot receive magnetic resonance imaging (MRI) scans, but can
receive MRI with a special “send/receive” coil.
 VNS is approved by the FDA for the
 adjunctive long-term treatment for chronic or recurrent depressive
episodes in adults with a major depressive episode who have not
had an adequate response to four or more adequate
antidepressant trials.
 Chronically depressed, able to tolerate slow onset of action and
 those who had had ECT before, but always relapses quickly despite
adequate medication an
 Cannot be tapered off maintenance ECT, and it is not even working
that well.
 Success rates with VNS are considerably lower than with ECT
and onset of action is comparatively slow (e.g., approximately 30%
response rate after 1 year). Therefore, VNS may be worth
considering when patients have failed to respond to less invasive
treatments, ECT was ineffective, or post-ECT relapse cannot be
prevented with less invasive means.
 In a systematic review done by Cimpianu et al on
Vagal nerve stimulation in psychiatry concluded that
from 1292 publications, studies focused on VNS as
treatment of unipolar or bipolar major depressive
disorder and the neurocognitive improvement after
VNS in major depressive disorder, on the
improvement of cognitive function in Alzheimer´s
disease, improvement of schizophrenia symptoms,
treatment of obsessive compulsive disorder (OCD),
panic disorder (PD) and post-traumatic stress disorder
(PTSD), treatment resistant rapid-cycling bipolar
disorder, treatment of fibromyalgia, and Prader-Willi
syndrome
 Dosing
 The optimal dose of VNS is unknown. The
published studies were not designed to identify
optimal dosing parameters (time on, time off,
frequency, current, pulse width). The epilepsy
literature suggests that there is a threshold current for
efficacy. However, given our present knowledge of
VNS dosing, current is typically increased up to >1mA
and clinical benefit are assessed over several months.
The side effects of VNS are known to be dose
dependent (e.g., lowering the pulse width reduces
neck pain, allowing patients to tolerate higher
currents).
MAGNETIC SEIZURE THERAPY
Definition
uses an alternating magnetic field to cross the
scalp and the calvarium and induce a more
localized electric current in targeted regions of
the cerebral cortex.
The aim is to produce a seizure whose focus
and patterns of spread may be controlled. Like
ECT, MST is performed under general
anesthesia.
 MST is given using a modified TMS device
that can administer higher output than
conventional TMS devices. The MST
procedure is also performed with a muscle
relaxant and requires very similar staffing and
infrastructure resources to those of ECT.
 MST is at the stage of clinical trials, and is not
currently FDA approved.
History
 The first MST-induced seizures, induced in rhesus
monkeys, were performed in 1998 using a custom-
modified TMS device.
 The first human case of a 20-year-old inpatient
with a medication-resistant major depressive
episode treated in Berne, Switzerland, was
published in 2001 (Lisanby et al., 2001a).
 The first trial of MST in the United States,
performed at Columbia University and published
in 2003, reported fewer acute cognitive side
effects
Mechanisms of Action:
 A focal means of seizure induction. Seizures
induced by MST are distinct from those
induced by ECT.
 MST-induced seizures show
 less impact on parasympathetic outflow,
 less generalization to hippocampus and
deeper brain structures(differential cognitive
profile),
 Results in less serum prolactin surge.
Side Effects
 Similar to those with ECT and connected to the risks associated
with anesthesia and generalized seizure.
 the MST coil produces a clicking noise that may potentially affect
hearing and, to prevent any cumulative damage, earplugs should
be worn by both the patient and members of the treating team.
 With respect to memory, studies have suggested that MST results
in less retrograde amnesia than ECT.
 MST seizures are less well generalized and tend to produce less
robust motor convulsions. For this reason, it has been noted that
the dosage requirement for the muscle paralytic agent
succinylcholine is lower than with conventional ECT. Shortening
the period of paralysis could reduce the risks of the procedure by
reducing the period of respiratory suppression.
Current Status in Treatment
Algorithms
 MST is not FDA approved.
 If the hypothesis that MST can approach the
efficacy of ECT but with fewer side effects
proves valid, then it might in future play a role
prior to referral to ECT.
 As general anesthesia is part of the MST
procedure, it will still likely be reserved for
medication treatment-resistant patients after
medications have been tried.
TRANSCRANIAL DIRECT
CURRENT STIMULATION
Definition
 A noninvasive form of treatment that uses very
weak (1 to 3 mA) direct electrical current applied to the
scalp. Because direct current polarizes rather than
stimulates with discrete pulses, its action does not
appear directly to result in action potential firing in
cortical neurons.
 This direct current (DC) form of electrical stimulation
that distinguishes it from devices that use alternating
currents (AC)[CES, ECT, VNS, and DBS] which
produce discrete pulse stimulation.
 The small device is very portable and usually operated
by readily available DC batteries.
HISTORY:
 tDCS was initially investigated in the 1960s
and has experienced a recent resurgence of
interest. Reports from Britain in the 1960s de-
tailing dramatic recovery from even ECT-
resistant depression, from catatonic and
manic states, and, in one case, of a
schizophrenic man with mutism have not
been replicated.
SIDE EFFECTS
 tDCS appears well tolerated, with no known
serious adverse effects. Common side effects
include a slight tingling at the site of
stimulation and some cases of skin irritation.
Some patients may also experience
headache, fatigue, and/or nausea
Mechanisms of Action
 Little is known
 DC polarizes tissue. Polarization can change
the firing rate of neurons.
 tDCS appears to act via an NMDA-mediated
alteration of neuronal membrane polarization
which might lower the threshold for
activation, facilitating neurotransmission.
 Depending on the direction of current flow,
this polarization can either inhibit (cathodal)
or facilitate (anodal) function.
CLINICAL STUDIES
 Preliminary research suggests that tDCS
may enhance certain brain functions
independent of mood;
 Research is focusing on its potential
effectiveness in facilitating recovery from
stroke and from certain forms of dementia.
 Several studies have suggested significant
antidepressant effect after anodal
polarization over the dorsolateral prefrontal
cortex (DLPF).
Current Status in Treatment
Algorithms
 tDCS is not approved by the FDA for psychiatric
treatments and is thus considered an experimental research
technology with much work needed to demonstrate its
efficacy
 inexpensive and relatively safe alternative form of treatment
to medications, prior to the more invasive stimulation
methods like ECT or VNS.
 Stimulation is non-invasive, requires no anesthesia and is
very well tolerated.
 Treatments are provided about five times per week over
several weeks (similar to transcranial magnetic stimulation).
Response and remission rates have not been consistently
reported in the literature. Relapse rate following successful
treatment has not been reported.
IMPLANTED CORTICAL
STIMULATION
 Cortical brain stimulation is a novel neurosurgical
approach in which electrodes are implanted over the
surface of the cortex to provide electrical brain
stimulation in a targeted superficial region.
 Being studied for treatment of conditions like stroke,
tinnitus, and treatment-resistant depression.
 Other names-implanted cortical stimulation (ICS),
cortical stimulation system, cortical brain stimulation.
 The stimulating electrode can be implanted relatively
superficially in either epidural or subdural layers, but
the specific topographic placement of the stimulator
varies depending on the condition being treated
 8.Cranial Electrical Stimulation
 Definition
 CES uses a weak (1 to 4 mA) current. However,
with CES the current is alternating. It is
traditionally applied via saline-soaked, felt-
covered electrodes clipped onto the earlobes. The
current of CES is in a similar range to that of tDCS,
with the major difference being that the current is
alternating, creating either sinusoidal or modified
square waves with a frequency range of 0.5 to
15,000 Hz, depending on the type of stimulator
 History
 CES was originally developed in 1949 in the former Soviet Union and
used as an aid in inducing sleep. It was thus called “Electrosleep.” In
addition to the treatment for insomnia, it was also used as an aid in
anesthesia, based on the observation that even when the current was
reduced to a point of not causing excessive sleepiness, some patients
seemed to benefit from the anesthetic effect of the stimulation. Research
on the device in the United States dates to the 1960s. It was
grandfathered-in by the FDA as a neurological therapeutic device for the
treatment of insomnia, anxiety, depression, and stress, and the name
CES, for cranial electrotherapy stimulator, was suggested. In the 1970s,
CES was used by many U.S. clinicians to treat substance abuse and
substance abstinence syndrome in the belief that patients with a history
of abuse were more susceptible to cross-addiction to psychotropic
medications and because they were thought to be more resistant to the
effects of such medications when compared to nonaddicted persons
 .
 Mechanism of Action
 The exact mechanism of action has not been elicited, Previous
hypotheses proposed that the stimulation with the alternating
microcurrent affects the thalamic and hypothalamic brain tissue
and facilitates the release of neurotransmitters. Claims have been
made that through interaction with cell membranes, the
stimulation produces changes in signal transduction associated
with classical second-messenger pathways, including calcium
channels and cyclic AMP. There are summary reports that CES
causes increases in plasma serotonin, norepinephrine, dopamine,
and monoamine oxidase type B (MAOB) in blood platelets and
cerebrospinal fluid (CSF), as well as release of 5-hydroxy-indol-
acetic acid (DHEA) and enkephalins and reduction of cortisol and
tryptophan.
Side Effects
 is not harmful, primarily due to its low
voltage power supply (9-V battery) and lack of
any reported adverse event by the FDA.
 Local skin effects,
 general feeling of dizziness,
 the use of the device during pregnancy, in
those with low blood pressure, or in people
who have arrhythmias or pacemakers is not
advised by device manufacturers.
OTHER STIMULATION TECHNIQUES
 1• low-field magnetic stimulation-LFMS-
employs application of a weak magnetic and
electric field uniformly resulting in
bidirectional pulse train of alternating
polarity.
optogenetic stimulation through DBS
 Optical Light Stimulation
 Researchers are looking into the therapeutic potential of
stimulating neurons using light instead of electrical or
magnetic fields. In the laboratory, neurons respond to pulses
of infrared light, which can be supplied by a compact light-
emitting diode (LED). Unlike electrical stimulation, which
spreads through tissue and cannot be focused, light
stimulation offers the advantage of being able to be
pinpointed. Medical devices that might use light stimulation
in the future include cochlear implants, deep brain
stimulation implants, functional restoration treatments for
paralysis or movement disorders, and retinal prosthesis.

Optogenetic Neuromodulation
 select cells can be tagged to respond to differently
colored “stop” and “go” lights delivered through fiber
optics.
 researchers introduce a gene for a light-sensitive
molecule, channel rhodopsin 2, into a specific subset
of neurons.
 Exposing the cells to blue light causes them to fire.
 Adding another light-sensitive protein, halorhodopsin,
silences the neurons in response to yellow light.
 Researchers are using the tools to study animal
models of Parkinson's disease, blindness, spinal injury,
depression, narcolepsy, addiction, and memory.
 3.Focused ultrasound
 4• near-infrared light therapy
CONCLUSION
Well established in neurology
Application in psychiatry is under research
International neuromodulation society- psychiatric
disorders under research
 interventional psychiatry (Williams et al., 2014)
 The broader goals of this new area of
subspecialization include the establishment and
provision of evidence-based safe practices and
implementation of a nationally recognized
credentialing policy for those clinicians providing
brain stimulation.
THANK
YOU

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Neuromodulation in psychiatry.

  • 3. INTRODUCTION  Brain stimulation includes delivery of electric or magnetic field transcranially or by direct placement of electrodes into the brain thereby delivering electric current into a cranial nerve or brain itself.  Also called as non pharmacological somatic therapies.
  • 4. objective  Neuromodulation therapies  allow focused delivery of modifying agents e.g., electrical, optical or chemical signals –  to targeted areas of the nervous system in order to improve neural function.  range from non-invasive techniques to techniques involving the surgical implantation of devices  to alter activity in discrete areas of the nervous system.
  • 5.  Neuromodulation therapies are:  • Highly targeted to specific areas of the brain or spinal cord, rather than systemic throughout the body such as pharmaceutical treatments  • Highly reversible, allowing physicians to immediately cease treatment with the removal of the stimulating device  • Continuous, improving therapeutic compliance over techniques that rely on fixed intermittent dosing.
  • 6.
  • 7. HISTORY AND EVOLUTION  STARTED WITH NEUROLOGY  NEUROSURGEON DR.NORMAN SHEALY USED ELECTRIC STIMULATION FOR PAIN RELEIF  EXPANDED TO SPINAL CORD STIMULATION AND THEN LATER TO CORTICAL STIMULATION FOR STROKE AND APHASIA
  • 8.  BRAIN STIMULATION IN PSYCHIATRY STARTED WITH ECCT-1983  WITH A 50 YEARS OF GAP-TMS IN 1980s
  • 9.
  • 10.
  • 11.
  • 13. Techniques on the horizon:  1. Focussed ultrasound(FUS)  2. Optogenetic stimulation  3. Near Infra red therapy  4. low field magnetic stimulation
  • 16.  MODE OF STIMULATION- ELECTRICAL/MAGNETIC  SITE OF STIMULATION TRANSCRANIAL EPIDURAL INTRACEREBRAL
  • 17.
  • 18.  ACUTE EFFECTS  Phasic activation of neural circuits  Observable motor responses (e.g., twitch)  Temporary disruption (e.g., speech arrest) or facilitation of ongoing processing (e.g., speeds reaction time)  PROLONGED EFFECTS  NEUROPLASTICITY  • Change in synaptic efficacy, akin to long-term potentiation or depression  • Alterations in neurotropic factors  • Modulation of cortical excitability  • Modulation of functional connectivity
  • 19. Cortico-striato-thalamocortical loop  In 1986, Alexander and Delong described a series of 5 loops of information, from cortex to basal ganglia and back to cortex.  Each loop activity courses through the basal ganglia in parallel direct and indirect pathways.  movement disorders, the motor loop is of importance.  For psychiatric disease, the dorsolateral, orbitofrontal, and anterior cingulate loops are important.
  • 22.  7 targets  for neuromodulation surgery have been published: Cg25, the anterior internal capsule (AIC), the nucleus accumbens (NA), the ventral striatum (VS), the inferior thalamic peduncle (ITP), the subthalamic nucleus (StN) and the left vagus nerve
  • 23.  Single electrical pulses, delivered at sufficient intensity, can induce neuronal depolarization and trigger trans-synaptic action, resulting in the activation of a function circuit.  Repeating pulses at regular intervals can exert even more powerful acute effects on brain function.  intermittent stimulation, which presumably requires the induction of some form of neuroplasticity, which persists beyond the period of stimulation.
  • 24.  Neuroplasticity is thought to occur through dynamic alterations in synaptic efficacy.  For example, repeatedly electrically stimulating the perforant pathway at  high frequency - Long-term potentiation  low frequencies depress it - long-term depression (LTD).
  • 25. Focality and Invasiveness  FOCAL LESS FOCAL-LESS INVASIVE ▪MORE INVASIVE MORE FOCAL tDCS- polarises the system.
  • 26. Brain stimulation vs psychopharmacology FEATURES BRAIN STIMULATION PHARMACOLOGICAL METHODS MECHANISM induce Action potentials via electrical depolarization of axons in a manner that is independent of receptor binding. Molecular action at receptors and intracellular signalling SIDE EFFECTS Systemic side effects are absent Systemic side effects are common PHARMACODYNAMIC EFFECTS no drug interactions or other pharmacodynamic interactions significant metabolism and drug interactions present DURATION Phasic application effects lasting for short time( pulses last for less than a minute) lasting effects seen depending on the drug half life and duration
  • 27.  Brain stimulation modalities have contributed in multiple parallel ways:  as tools of discovery to examine normal brain function,  as tools to examine the pathophysiology of psychiatric disorders, and  as novel therapeutic agents.
  • 30. DEFINITION  electric current is passed through the brain via electrodes placed against the head to produce a seizure
  • 31. HISTORY  PARACELSUS- CAMPHOR METHOD  VON MEDUNA- IM CAMPHOR/ PENTYLENETETRAZOL  CERLETTI/BINI-FIRST ELECTRICAL INDUCTION OF SEIZURES IN CATATONIC SCHIZOPHRENIA  1958-FIRST CONTROLLED STUDY OF ECT  1970-POSITION OF ELECTODE  1980S-FDA APPROVAL
  • 32. MECHANIS OF ACTION  FUNCTIONAL BRAIN ACTIVATION-CBF,CMR inc.  NEUROTRANSMITTER SYSTEMS Downregulate b receptors Enhance 5HT transmission Dopaminergic action GABA,Adenosine Glutamine and cognitive effects-underway  HPA AXIS  NEUROPLASTICITY  ANTICONVULSANT EFFECT
  • 33. INDICATIONS  Major diagnostic indications  Major depression, both unipolar and bipolar  Psychotic depression in particular  Mania, including mixed episodes  Schizophrenia with acute exacerbation  Catatonic subtype particularly  Schizoaffective disorder  Other diagnostic indications  Parkinson's disease  Neuroleptic malignant disorder
  • 34. Clinical indications  Primary use  Rapid definitive response required on medical or psychiatric grounds  Risks of alternative treatments outweigh benefits  Past history of poor response to psychotropics or good response to ECT  Patient preference  Secondary use  Failure to respond to pharmacotherapy in the current episode  Intolerance of pharmacotherapy in the current episode  Rapid definitive response necessitated by deterioration of the patient's condition
  • 35.  PROCEDURE  SIDE EFFECTS-MEMORY IMPAIRMENT  MORTALITY  CONTRAINDICATIONS
  • 36. TMS
  • 37. DEFINITION  TMS refers to the induction of small electrical currents in the superficial layers of the cerebral cortex by applying rapidly alternating magnetic fields to the head.
  • 38. BASIC PRINCIPLES  FARADAY’S LAW  MAXWELL EQUATION
  • 39. When there is a primary circuit where time varying current flowing, there was an induction of current in a secondary circuit which was at close proximity; quantified by Maxwell’s equation for electromagnetism
  • 40.
  • 41. PROCEDURE:  TMS devices deliver strong magnetic pulses via a coil that is held on the scalp. Because magnetic fields are unaffected by the electrical impedance of the scalp and skull, this method of stimulation enables the focal stimulation of smaller areas of the brain.  TMS has been referred to as “electrodeless” electrical stimulation because it uses magnetic fields to induce electrical pulses indirectly.  As such, it represents a noninvasive means of stimulating focal regions of the brain.  NO ANAESTHESIA NEEED.
  • 42. TYPES OF rTMS  SINGLE-PULSE- one pulse at a time without regular rhythm and at low rates of delivery.  REPETITIVE PULSE-repeated at regular rhythmic intervals ( 1 to 25 Hz)  “low-frequency Rtms”frequency is 1 Hz or less and  “high-frequency rTMS” usually 5 to 20 Hz.  PAIRED PULSE  REPEATED PAIRED PULSE  Theta burst stimulation (TBS) -high-frequency bursts (e.g., 3 pulses at 50 Hz) at regular frequency.  continuously (cTBS) or intermittently (iTBS).  cTBS -induce inhibitory effects  iTBS is reported to exert excitatory effects
  • 43. History  Barker, Jalinous, and Freeston -The first human use of pulsed magnetic fields  Initially -very low frequencies of TMS were applied in exploratory studies on the treatment of depression and schizophrenia.  mid-1990s, repetitive stimulators capable of higher repetition rates (up to 20 Hz) became available.  Higher frequency stimulation was able to influence higher brain functions such as language, mood, and memory.  Early studies with high-frequency rTMS suggested that it might have antidepressant properties when applied to the dorsolateral prefrontal cortex (DLPFC) (George et al., 1995; Pascual- Leone et al., 1996).
  • 44. Mechanism of action  Alternating magnetic fields- induce electrical currents in the superficial cortex .  electrical currents are called “eddy currents” because they are circular in shape, and are oriented in the plane perpendicular to the plane of the TMS coil.  At sufficient intensity, electrical currents will stimulate neuronal depolarization, which can result in an action potential.  Two types of pulses-monophasic and biphasic. Magnetic pulse frequency is 1 to 50 Hz.  Low frequency stimulation for 15 mins induces transient inhibition of cortical activity while high frequency stimulation induces cortical activity.
  • 45.
  • 46.
  • 47.
  • 48. SIDE EFFECTS : The most serious known risk of TMS is unintended seizure.  Factors contributing are :  the form of TMS (single-pulse(minimal risk) versus rTMS(induce seizure without any predisposing factor),  the dosage (intensity, frequency, train duration, inter-train interval), and  subject factors that may place the individual at increased risk (such as the presence of a neurological disorder or seizure- lowering medications).
  • 49.  Precautions to be taken:  1.Safety Guidelines-duration in seconds that could be administered at each combination of frequency and intensity prior to the emergency of spread of excitation, a warning sign of seizure.  2.subjects should always be advised of this potential.  3.It is also recommended that rTMS be administered under medical supervision, and that procedures be in place to screen and monitor patients medically for changes in clinical status that could affect seizure risk.  4.The treating clinician should have the proper training and equipment to manage a seizure should one occur
  • 50.  B.The most common side effects of TMS are scalp discomfort and headache. These effects are attributable to scalp muscle stimulation and stimulation of the facial nerve. Earplugs are worn by the patient and administrator to protect hearing.  C.The risks of TMS during pregnancy have not been thoroughly studied. Since TMS is experimental, it may carry as yet unknown risks.
  • 51. Advantages  Noninvasive, can study normal subjects  Effects reversible  Focal stimulation  good spatial resolution  Excellent temporal resolution  Selective frequency dependent neurophysiological effects—effects akin to LTP and LTD  Complement to functional imaging
  • 52. Clinical studies  Major depression-most thoroughly studied with TMS to date.  Significant antidepressant effects of rTMS when given to the DLPFC evidenced by number of randomized controlled trials and by several meta-analyses.  The average effect size in depression is moderate – less than that seen with ECT but close to that seen with antidepressant medications.
  • 53.
  • 54.  Schizophrenia - low-frequency rTMS to inhibit temporal–parietal regions of the cortex reported to be hyperactive during hallucinations.  A recent meta-analysis of prospective studies including both low- and high-frequency rTMS on negative symptoms found a moderate effect size. Poor outcome was associated with length of illness.  Although less studied, TMS has shown some promising early results in anxiety disorders.
  • 55. Current Status in Treatment Algorithms  TMS is not currently FDA approved, and therefore is not included in treatment algorithms.  Should it ultimately be found safe and effective for depression, it would likely be most useful positioned between medications and ECT.
  • 56. Dosing  Scalp position,target localisation  Coil shape- commonly used “shape of 8”  Iron coils cost effective  The delivered intensity of rTMS is related to the distance of the coil from the target cortex.  Increasing the distance decreases the intensity of the stimulation reaching the brain-negatively correlated with antidepressant response and with the degree of stimulation- induced brain activation.
  • 57.
  • 58.  rTMS is carried out while the patient is awake and reclining in a specially equipped chair. Sessions usually last 20-40 minutes, five days a week, typically for six weeks.  In open-label clinical trials, after 4-6 weeks of treatment, one out of two patients treated with rTMS for depression experienced a reduction in symptoms of 50% or more, and one out of three experienced remission. The effect was lower in patients who had exhibited resistance to more
  • 59.  Train-freq,duration,intensity  Intertrain interval  No.of sessions/day/course  treatment-related factors include variation in coil and stimulator type, waveform shape and polarity, and coil position and orientation relative to target cortex.  Even when these factors are held constant, considerable within-subject variability in physiological response to TMS in the motor system has been reported.
  • 60. Repetitive transcranial magnetic stimulation (rTMS) non-invasive treatment delivers repetitive pulses of an MRI-strength magnetic field from a coil placed over the scalp. The FDA approved rTMS in 2008-treatment to alleviate symptoms of mildly treatment-resistant depression studied as a possible treatment for-schizophrenia, pain, stroke, and amyotrophic lateral sclerosis (ALS).  antidepressants.  For patients with treatment-resistant depression, rTMS has been approved in Canada, Australia, New Zealand, the European Union, and Israel in addition to in the United States.
  • 61. Future Directions It will be important to replicate key findings, identify optimal dosing parameters to maximize efficacy,examine dose–response relationships, determine patient characteristics that predict response, and explore the impact of concomitant medications and psychotherapy on TMS effects.  post-TMS relapse prevention is an area yet to be definitively addressed.  Future work may develop coils optimized for deeper penetration and pulse shapes that are more physiologically optimized to human neurophysiology.  example is control- lable pulse-shape TMS (cTMS), which can induce pulses that are rectangular in shape (like ECT pulses).  The role of high-frequency rTMS in augmenting antidepressants warrants further investigation. Traditional TMS devices induce pulses that are sinusoidal, a waveform that was abandoned with ECT owing to its inefficiency and excessive side effects.
  • 63. DEFINITION  Deep brain stimulation (DBS) is a technique that consists of a surgically implanted lead that provides focal electrical neural-network modulation within a brain circuit or circuits of interest.
  • 64.
  • 65.
  • 66.  With DBS, intracranial electrodes are implanted and chronically stimulate targeted brain areas. Unlike lesioning procedures, DBS is believed to be reversible, and the intensity of stimulation can be adjusted according to the acute effect on symptoms.
  • 67.  The US FDA issued an approval for the use of DBS in essential tremor in 1997 and  PARKINSON DISEASE in 2002.  A humanitarian device exemption (HDE) was granted for motoric symptoms of dystonia in 2003.  obsessive-compulsive disorder (OCD), depression, and Tourette syndrome (TS), have proven more difficult to study.  The US FDA issued a HDE for obsessive compulsive disorder in 2009.  TS and depression both remain unapproved uses of DBS technology;
  • 68.
  • 69.  So far, patients worldwide have received DBS for depressive disorder, with varying stimulation sites: white matter underlying cingulate area 25 internal capsule/nucleus accumbens , the inferior thalamic peduncle, subthalamic nucleus and the lateral habenula
  • 70.  The list of potential complications and side effects is lengthy and includes anxiety/agitation, headache, lead dislodgement, and infection.
  • 71. Neuropsychiatric effects from DBS of “motoric targets.”  Positive :  implantation in the Gpi for PD and tardive dyskinesiahave reported improvements in mood and  STN DBS -patients with comorbid PD and OCD have also had improvements in anxiety .  Some TS patients implanted in the CM thalamus unexpectedl reductions in OCD and depression symptoms.  Negative  STN DBS may adversely affect cognitive and limbic circuitry in some  De novo impulse control disorder, mania, increased anger, worsening apathy, fatigue, cognitive decline, binge eating, worsening depression, de novo psychosis, and suicidality all appear to be uncommon, but possible effects.  side effects are reversible and may be stimulation related, resolving when the DBS is turned off .  Some related to lead position and stimulation parameters. Some effects (e.g. verbal fluency) may be related to the surgery itself (i.e., microlesion effect).
  • 72. Limbic targets  Positive  The NAc target-antianxiety effect, improvements in OCD, it was hypothesized to have an independent antidepressant effect.  Acute changes in memory were associated with unintended stimulation of the fornix  NAc DBS has also resulted in weight loss,  The NAc is also a potential target for the treatment of addiction( alcohol intake, nicotine dependence, and opiate use.)  Negative  Mania is one of the most concerning  paradoxical worsening of anxiety and depression has also been reported.  Feelings of suicidality can emerge;  Feelings of irritability and anger .  Cognitive dysfunction at high amplitudes has been observed with Broadmann Area 25 DBS along with the occurrence of paradoxical worsening of depressive symptoms.  Limbic STN DBS for OCD has been associated with hypomania, anxiety, impulsiveness, depression symptoms, and obsessive-compulsive thoughts.
  • 73.
  • 74.
  • 76.  Direct, intermittent electrical stimulation of the left cervical vagus nerve via a pulse generator implanted in the left chest wall.  The electrode is wrapped around the left vagus nerve in the neck and is connected to the generator subcutaneously.  Intermittent left vagal nerve stimulation sends afferent signals to the nucleus tractus solitarius and connected limbic and cortical areas.  Implantation surgery involves two incisions – one for the generator in the chest and another in the neck for the electrode. Surgery is usually performed under brief general anesthesia.  Stimulation parameters are adjusted with a programming wand that communicates with the generator. Patients may turn off the stimulation when needed by holding a magnet over the generator.
  • 77.
  • 78.  VNS was originally approved by the FDA for the treatment of resistant epilepsy, and in 2005 was approved for the adjunctive treatment of chronic, treatment-resistant depression.
  • 79. Mechanisms of Action  The left vagus nerve contains 80% afferent fibers, hence stimulating it activates predominantly vagal afferents.  Chronic stimulation of the vagal afferents changes activity in brain-stem nuclei (such as the nucleus of the solitary tract), and from there neighboring nuclei (e.g., Raphe) that alter sero- tonergic activity in cortical and limbic structures.  Chronic stimulation of the vagal afferents is anticonvulsant, and this effect appears to be dependent upon the locus ceruleus.
  • 80.  Side Effects  VNS is generally well tolerated.  Voice alteration, dyspnea, and neck pain are the most frequently reported adverse events.  The surgical implantation carries the risks of infection, vocal cord paralysis, and bradycardia or asystole. VNS does not cause apparent cognitive side effects. In fact, neurocognitive performance was significantly improved with VNS – apparently due to the improvement in depression.  Contraindications :history of bi-lateral or left cervical vagotomy and use of short-wave diathermy, microwave diathermy, or therapeutic ultrasound diathermy. Patients with VNS implanted cannot receive magnetic resonance imaging (MRI) scans, but can receive MRI with a special “send/receive” coil.
  • 81.  VNS is approved by the FDA for the  adjunctive long-term treatment for chronic or recurrent depressive episodes in adults with a major depressive episode who have not had an adequate response to four or more adequate antidepressant trials.  Chronically depressed, able to tolerate slow onset of action and  those who had had ECT before, but always relapses quickly despite adequate medication an  Cannot be tapered off maintenance ECT, and it is not even working that well.  Success rates with VNS are considerably lower than with ECT and onset of action is comparatively slow (e.g., approximately 30% response rate after 1 year). Therefore, VNS may be worth considering when patients have failed to respond to less invasive treatments, ECT was ineffective, or post-ECT relapse cannot be prevented with less invasive means.
  • 82.  In a systematic review done by Cimpianu et al on Vagal nerve stimulation in psychiatry concluded that from 1292 publications, studies focused on VNS as treatment of unipolar or bipolar major depressive disorder and the neurocognitive improvement after VNS in major depressive disorder, on the improvement of cognitive function in Alzheimer´s disease, improvement of schizophrenia symptoms, treatment of obsessive compulsive disorder (OCD), panic disorder (PD) and post-traumatic stress disorder (PTSD), treatment resistant rapid-cycling bipolar disorder, treatment of fibromyalgia, and Prader-Willi syndrome
  • 83.  Dosing  The optimal dose of VNS is unknown. The published studies were not designed to identify optimal dosing parameters (time on, time off, frequency, current, pulse width). The epilepsy literature suggests that there is a threshold current for efficacy. However, given our present knowledge of VNS dosing, current is typically increased up to >1mA and clinical benefit are assessed over several months. The side effects of VNS are known to be dose dependent (e.g., lowering the pulse width reduces neck pain, allowing patients to tolerate higher currents).
  • 85. Definition uses an alternating magnetic field to cross the scalp and the calvarium and induce a more localized electric current in targeted regions of the cerebral cortex. The aim is to produce a seizure whose focus and patterns of spread may be controlled. Like ECT, MST is performed under general anesthesia.
  • 86.  MST is given using a modified TMS device that can administer higher output than conventional TMS devices. The MST procedure is also performed with a muscle relaxant and requires very similar staffing and infrastructure resources to those of ECT.  MST is at the stage of clinical trials, and is not currently FDA approved.
  • 87. History  The first MST-induced seizures, induced in rhesus monkeys, were performed in 1998 using a custom- modified TMS device.  The first human case of a 20-year-old inpatient with a medication-resistant major depressive episode treated in Berne, Switzerland, was published in 2001 (Lisanby et al., 2001a).  The first trial of MST in the United States, performed at Columbia University and published in 2003, reported fewer acute cognitive side effects
  • 88. Mechanisms of Action:  A focal means of seizure induction. Seizures induced by MST are distinct from those induced by ECT.  MST-induced seizures show  less impact on parasympathetic outflow,  less generalization to hippocampus and deeper brain structures(differential cognitive profile),  Results in less serum prolactin surge.
  • 89. Side Effects  Similar to those with ECT and connected to the risks associated with anesthesia and generalized seizure.  the MST coil produces a clicking noise that may potentially affect hearing and, to prevent any cumulative damage, earplugs should be worn by both the patient and members of the treating team.  With respect to memory, studies have suggested that MST results in less retrograde amnesia than ECT.  MST seizures are less well generalized and tend to produce less robust motor convulsions. For this reason, it has been noted that the dosage requirement for the muscle paralytic agent succinylcholine is lower than with conventional ECT. Shortening the period of paralysis could reduce the risks of the procedure by reducing the period of respiratory suppression.
  • 90. Current Status in Treatment Algorithms  MST is not FDA approved.  If the hypothesis that MST can approach the efficacy of ECT but with fewer side effects proves valid, then it might in future play a role prior to referral to ECT.  As general anesthesia is part of the MST procedure, it will still likely be reserved for medication treatment-resistant patients after medications have been tried.
  • 92. Definition  A noninvasive form of treatment that uses very weak (1 to 3 mA) direct electrical current applied to the scalp. Because direct current polarizes rather than stimulates with discrete pulses, its action does not appear directly to result in action potential firing in cortical neurons.  This direct current (DC) form of electrical stimulation that distinguishes it from devices that use alternating currents (AC)[CES, ECT, VNS, and DBS] which produce discrete pulse stimulation.  The small device is very portable and usually operated by readily available DC batteries.
  • 93. HISTORY:  tDCS was initially investigated in the 1960s and has experienced a recent resurgence of interest. Reports from Britain in the 1960s de- tailing dramatic recovery from even ECT- resistant depression, from catatonic and manic states, and, in one case, of a schizophrenic man with mutism have not been replicated.
  • 94. SIDE EFFECTS  tDCS appears well tolerated, with no known serious adverse effects. Common side effects include a slight tingling at the site of stimulation and some cases of skin irritation. Some patients may also experience headache, fatigue, and/or nausea
  • 95. Mechanisms of Action  Little is known  DC polarizes tissue. Polarization can change the firing rate of neurons.  tDCS appears to act via an NMDA-mediated alteration of neuronal membrane polarization which might lower the threshold for activation, facilitating neurotransmission.  Depending on the direction of current flow, this polarization can either inhibit (cathodal) or facilitate (anodal) function.
  • 96. CLINICAL STUDIES  Preliminary research suggests that tDCS may enhance certain brain functions independent of mood;  Research is focusing on its potential effectiveness in facilitating recovery from stroke and from certain forms of dementia.  Several studies have suggested significant antidepressant effect after anodal polarization over the dorsolateral prefrontal cortex (DLPF).
  • 97.
  • 98. Current Status in Treatment Algorithms  tDCS is not approved by the FDA for psychiatric treatments and is thus considered an experimental research technology with much work needed to demonstrate its efficacy  inexpensive and relatively safe alternative form of treatment to medications, prior to the more invasive stimulation methods like ECT or VNS.  Stimulation is non-invasive, requires no anesthesia and is very well tolerated.  Treatments are provided about five times per week over several weeks (similar to transcranial magnetic stimulation). Response and remission rates have not been consistently reported in the literature. Relapse rate following successful treatment has not been reported.
  • 99. IMPLANTED CORTICAL STIMULATION  Cortical brain stimulation is a novel neurosurgical approach in which electrodes are implanted over the surface of the cortex to provide electrical brain stimulation in a targeted superficial region.  Being studied for treatment of conditions like stroke, tinnitus, and treatment-resistant depression.  Other names-implanted cortical stimulation (ICS), cortical stimulation system, cortical brain stimulation.  The stimulating electrode can be implanted relatively superficially in either epidural or subdural layers, but the specific topographic placement of the stimulator varies depending on the condition being treated
  • 100.  8.Cranial Electrical Stimulation  Definition  CES uses a weak (1 to 4 mA) current. However, with CES the current is alternating. It is traditionally applied via saline-soaked, felt- covered electrodes clipped onto the earlobes. The current of CES is in a similar range to that of tDCS, with the major difference being that the current is alternating, creating either sinusoidal or modified square waves with a frequency range of 0.5 to 15,000 Hz, depending on the type of stimulator
  • 101.  History  CES was originally developed in 1949 in the former Soviet Union and used as an aid in inducing sleep. It was thus called “Electrosleep.” In addition to the treatment for insomnia, it was also used as an aid in anesthesia, based on the observation that even when the current was reduced to a point of not causing excessive sleepiness, some patients seemed to benefit from the anesthetic effect of the stimulation. Research on the device in the United States dates to the 1960s. It was grandfathered-in by the FDA as a neurological therapeutic device for the treatment of insomnia, anxiety, depression, and stress, and the name CES, for cranial electrotherapy stimulator, was suggested. In the 1970s, CES was used by many U.S. clinicians to treat substance abuse and substance abstinence syndrome in the belief that patients with a history of abuse were more susceptible to cross-addiction to psychotropic medications and because they were thought to be more resistant to the effects of such medications when compared to nonaddicted persons
  • 102.  .  Mechanism of Action  The exact mechanism of action has not been elicited, Previous hypotheses proposed that the stimulation with the alternating microcurrent affects the thalamic and hypothalamic brain tissue and facilitates the release of neurotransmitters. Claims have been made that through interaction with cell membranes, the stimulation produces changes in signal transduction associated with classical second-messenger pathways, including calcium channels and cyclic AMP. There are summary reports that CES causes increases in plasma serotonin, norepinephrine, dopamine, and monoamine oxidase type B (MAOB) in blood platelets and cerebrospinal fluid (CSF), as well as release of 5-hydroxy-indol- acetic acid (DHEA) and enkephalins and reduction of cortisol and tryptophan.
  • 103. Side Effects  is not harmful, primarily due to its low voltage power supply (9-V battery) and lack of any reported adverse event by the FDA.  Local skin effects,  general feeling of dizziness,  the use of the device during pregnancy, in those with low blood pressure, or in people who have arrhythmias or pacemakers is not advised by device manufacturers.
  • 104. OTHER STIMULATION TECHNIQUES  1• low-field magnetic stimulation-LFMS- employs application of a weak magnetic and electric field uniformly resulting in bidirectional pulse train of alternating polarity.
  • 105. optogenetic stimulation through DBS  Optical Light Stimulation  Researchers are looking into the therapeutic potential of stimulating neurons using light instead of electrical or magnetic fields. In the laboratory, neurons respond to pulses of infrared light, which can be supplied by a compact light- emitting diode (LED). Unlike electrical stimulation, which spreads through tissue and cannot be focused, light stimulation offers the advantage of being able to be pinpointed. Medical devices that might use light stimulation in the future include cochlear implants, deep brain stimulation implants, functional restoration treatments for paralysis or movement disorders, and retinal prosthesis. 
  • 106. Optogenetic Neuromodulation  select cells can be tagged to respond to differently colored “stop” and “go” lights delivered through fiber optics.  researchers introduce a gene for a light-sensitive molecule, channel rhodopsin 2, into a specific subset of neurons.  Exposing the cells to blue light causes them to fire.  Adding another light-sensitive protein, halorhodopsin, silences the neurons in response to yellow light.  Researchers are using the tools to study animal models of Parkinson's disease, blindness, spinal injury, depression, narcolepsy, addiction, and memory.
  • 107.  3.Focused ultrasound  4• near-infrared light therapy
  • 108. CONCLUSION Well established in neurology Application in psychiatry is under research International neuromodulation society- psychiatric disorders under research  interventional psychiatry (Williams et al., 2014)  The broader goals of this new area of subspecialization include the establishment and provision of evidence-based safe practices and implementation of a nationally recognized credentialing policy for those clinicians providing brain stimulation.

Editor's Notes

  1. In the case of movement disorders, the motor loop is of importance. For psychiatric disease, the dorsolateral, orbitofrontal, and anterior cingulate loops are important. Each loop has a direct and indirect component   The primary cortical association of the associative loop is the dorsal compartment. Most of the information in the dorsal compartment flows through central striatal regions, such as the head of the caudate and portions of the NA core. The primary cortical association of the limbic loop is the ventral compartment. Most of the information in the ventral compartment flows through ventromedial striatal regions, such as the NA core and the NA shell. Like other cortico-striato-pallido-thalamocortical (CSPTC) loops, information travels through parallel indirect and direct pathways, with the output structures being the globus pallidus pars interna (GPi) and substantia nigra pars reticularis (SNr).