Fri. Kim, Sang Kyong CH.6(1) Deep Brain Stimulation for Pain Management Neural Engineering Special thanks to

Electrical Stimulation of the Brain Since the early 20c Low potential for side effect Potential to affect previously untreatable pain WhoWhenWhereTargetEffects HeathEarly 1950sSeptal area Patients with terminal cancer Pain relief Patient with Schizophrenics Pain relief Pool et al.1956Septal areaPatientsPain relief Ervin1966ThalamusPatientsPain relief Gol1967Septal areaPatientsPain relief

Electrical Stimulation of the Brain 3 6.1

4 WhoWhenWhereTargetEffects Reynolds1969 Periaqueductal gray(PAG) RatDeep analgesia Mayer et al.1971PAGRat SPA in animal (Stimulation produced analgesia) Richardson? During stereotaxic Leisoning procedure (not exactly) 1 Patient with cancer pain Pain relief SPA (Human) Akil, Richardson 1970 PAG Periventricular(P VG) 5 PatientsSPA RichardsonEarly 1970s PVG PAG Patients Chronic pain relief Electrical Stimulation of the Brain

5 6.1 Electrical Stimulation of the Brain

6 6.1 WhoWhenWhereTargetEffects RichardsonEarly 1970s Dorsal Column Peripheral nerve Patients Pain relief Chronic pain relief Marzars et al.1960 Ventral posterior lateralis (VPL) Ventral posterior medialis (VPM) PatientsPain relief Hosobuchi et al. Early 1970s VPM Internal capsule (IC) Patients Relief of Anesthesia dolorosa Young et al1992 Lateral upper brainstem 3 patientsAnalgesia Electrical Stimulation of the Brain

7 6.1 Ventral view Ventral Posterior Lateralis (VPL) Ventral Posterior Medialis (VPM)

8 6.1 Internal capsule v

9 6.1 Brain stem

v Periventricular gray (PVG) (PAG) Internal capsule (IC)

PVG & PAG stimulation PVG or PAG Stimulation  SPA Different effect for each of the sites selected Mechanism Best understood But, most complex Direct effect? NO! By naloxone effect – SPA inhibition More complex mechanism Cell bodies for the central opiate mechanism Mu system Arcuate, infundibular, and periventricular nucleus of the hypothalamus Axons from hypothalamus to raphe nuclei

PVG & PAG stimulation

PVG & PAG Hypothalamus Raphe nucleus

Side effects of DBS Different side effects PAG Osilopsia Epigastric rising syndrome Patients will not allow long stimulation PVG and septal area Mild euphoric Basal forebrain and hypothalamus Elevation of BP

Mechanism Dorsal level Fibers Serotonergic fiber Norepinergic fiber Intermediate opioid interneuron Activated by these tracts Pain inhibition at the first synapse in the dorsal horn PAG, PVG stimulation Activating the same system Pain relief in dorsal level

Mechanism Thalamic level or brainstem level Inhibition of propagation of impulses through the spinoreticular tracts and the spinothalmic tracts Inhibition of input to the spinal cord > central mechanism Activation of this system (Akil et al.) Endogenous opiates release Naloxone Blocking analgesia in animal Reducing analgesia in humans

Mechanism Direct activation of the cells in PAG and PVG (Fessler et al.) Activation of serotonergic and norepinergic mechanisms in the cord Blocking of monoamine mechanisms (Yaksh et al.) SPA reduction PVG stimulation (Young et al.) Release of beta-endorphin Release of methionin enkephlelin PVG and PAG stimulation Opiate fibers activation

PVG & PAG

Thalamus & Internal Capsule Inhibitory mechanism of stimulation Thalamus & Internal capsule Remains Obscure In the cat Sectioning of the dorsal columns below the level of activation  Not completely obliterate the pain-reducing effects Sectioning of the dorsal columns above and below the level of activation  Complete deactivation of pain inhibition

20 6.3

Dorsal column

22 6.3

Dorsal column Single cell recordings in the sensory thalamus On/off mechanism activated by dorsal column stimulation Complex inhibitory mechanism Interaction btw sense fibers and the pain transmission system Sense fibers The proprioception, touch, and position Dorsal column Pain transmission system Dorsal horn Synapses in the brainstem, thalamus, and cortex of the brain Marzars et al. in 1960 Stimulation of the somatosensory pathways in the cord  Pain relief Ervins et al. in 1966 Stimulation of the sensory thalamus  Pain relief

Chronic stimulation Chronic thalamic stimulation (Hosobuchi et al.) For anesthesia dolorosa Lose its effectiveness over time Programmed type of stimulation Ramping or intermittent stimulation  Good pain relief Possibility of parensthesia in the area of the patients’ pain  Accurate placement of the electrodes

Internal capsule Internal capsule stimulation (Hosobuchi et al.) For neospinothalamic stimulation More effective Less likely to produce sensory loss Electrode insertion in the main sensory nucleus Resulting in areas of focal sensory loss Face or Hand  Trouble! Insertion of electrodes into the internal capsule Does not seem to produce sensory loss Unclear reason Probably fibers are less vulnerable than cell bodies to the trauma of electrode insertion

Inhibitory mechanism Stimulation of the dorsal columns Main sensory relay nuclei of the thalamus and internal capsule Activation of touch and proprioception fibers  Inhibition of pain “Gate theory of pain transmission” The effect of VPL/VPM/IC, dorsal column stimulation Multilevel Activation of VPL/VPM/IC More effective for pain relief

Electrode Original electrode Solid silver with silver balls(1mm in diameter) at the tip Last only few weeks due to chloridization Degradation of contact btw electrode balls and the brain tissue 1 st generation chronic electrode Four-contact pull-down electrodes Platinum/iridium Semirigid Electrode Migration 5mm deep to the original placement CSF loss  brain sagged

Electrode Solution to the migration of electrodes Change the electrode wiring material Platinum/iridum wire(semirigid)  Pure platinum wire(flexible) Electrode replacement Possible to scar Intracerebral hemmorrhage Hemiplegia Death Old electrode clipped at the cortex Recent electrode Smooth Prevents glia from infiltrating or adhere to its surface Battery-operated internal pulse generator(IPG) Problem of battery replacement