Deep Brain Stimulation

Delivery of electrical current to a specific subcortical grey matter target to stimulate a desired group of nerve cells which results in specific modulation the output of the involved neurocirciut.

1. DEEP BRAIN STIMULATION(DBS) BY DR PARTHA SARATHI MONDAL

2. INTRODUCTION Delivery of electrical current to a specific subcortical grey matter target to stimulate a desired group of nerve cells which results in specific modulation the output of the involved neurocirciut . Targets are predefined, stimulated by predefined dosage of electric current through implanted electrodes. Collateral stimulation is minimal. Electric current delivery can be adjusted depending upon response. Treats a variety of neurological disorders but movement disorders remain the main targets.

3. HISTORY OF DBS Wilder Penfield may be considered as the pioneer of electrical stimulation of brain (while performing epilepsy surgery)- surface stimulation. In1948,J. Lawrence Pool, attempted to treat an elderly woman with anorexia &depression by implanting an electrode in the patient’s caudate nucleus-first deep stimulation. It lacked target specificity. In 1954, Robert Heath attempted to stimulate limbic system to examine the emotional response using Spigel’s system. In 1960,Mazars reported a series of 14 patients treated with intermittent hypothalamic stimulation for painful syndromes . From 1960-1970, main application of DBS was pain. YEAR PERSON TARGET FOR PAIN 1952 HEATH LIMBIC SYSTEM 1962 MAZARS HYPOTHALAMUS 1967 SHEALY DORSAL COLUMN 1973 HOSOBUCHI THALAMUS

4. Modern era of DBS(after 1975) YEAR PERSON TARGET DISEASE 1975 Bechtereva Basal ganglia Movement disorders 1979 Cooper Anterior thalamus Epilepsy 1987 Benabid Vim thalamus Tremor 1994 Benabid Subthalamic nucleus Parkinson’s disease 1994 Siegfried GPi Parkinson’s disease 1999 Nuttin Internal capsule OCD 1999 Vandewalle Thalamus Tourette’s syndrome 2003 Broggi Hypothalamus Cluster headache 2005 Mayberg Brodmann area 25 Dpression

5. Principles of neurostimulation DBS is essentially an extracellular stimulation. Cathodal (-) stimulation results in depolarization-if suprathreshold , can evoke an action potential Anodic(+) stimuli cause hyperpolarization and depolarization of nearby areas which is called virtual cathod -if suprathreshold , can also evoke action potential. Stimulation can be monophasic /biphasic or polyphasic . Electrodes may be monopolar or bipolar. Stimulatory parameters- PARAMETERS EFFECT 1)Amplitude Expressed in voltage or miliApm -controls the intensity of stimulus 2) Pulse width( mS ) Duration of each pulse delivered. 3)Frequency(Hz) Rate of pulse delivered.

6. Stimulation can be along the nerve fiber or across it. Longitudinal stimulation requires less intense stimuli to evoke action potential.

7. When applied to axon, a stimulus evokes two action potentials which propagate in opposite direction. Where orthodromic potential brings the clinical effect, Antidromic (towards cell body) is of littleclinical significance in most of the times .

8. INDICATIONS TARGETS EFFECT 1.Idiopathic Parkinson’s disease STN GPi Vim of Thalamus tremor , rigidity, dyskinesia same as above Tremor 2. Primary dystonias GPi dystonia 3.Essential tremor Vim of Thalamus tremor 4. OCD Medial Thalamus Anterior limb of Int capsule Medial Thalamus Improvement in compulsive behavior. Improvement in depression 5.Epilepsy Hippocampus Anterior Nucleus of the Thalamus Decreased seizure frequency 6.Major depression Nucleus Accumbens 7.Cluster headache Posterior hypothalamus 8.Anorexia nervosa Nucleus Accumbens Subgenual Cortex ( Brodmann area 25) Improved BMI and restoration of menstruation 9.Tardive syndrome Thalamus Posteroventral gpi Internal capsule( ic ) & nucleus accumbens reduction in tic reduction in tic and ocd reduction of ocd >tic 10. Alzheimer’s Disease (AD) Ant fornix

9. DBS In Idiopathic Parkinson’s Disease(IPD) DBS is preferred over pallidotomy or thalamotomy because of adjustability & reversibility of DBS with lower complication rate. Diagnosis - bradykinesia + atleast one of these(resting tremor/rigidity/postural instability). Exclude atypical IPDs(MSA,PSP, Lewy body dementia) Patient selection -duration >5yrs, severe disability (UPDRS score at least 30/108), good(but may be fluctuating) response to levodopa , absence of severe preexisting dementia or psychiatric illness. Expected outcome- Symptoms responsive to DBS -rigidity, tremor, bradykinesia , levodopa induced dyskinesia . Symptoms not responsive to DBS- cognitive decline, hypophonia , postural instability and “on” period gait freezing, autonomic dysfunction.

10. The “Ideal Candidate” Excellent levodopa responder. However response interrupted by troublesome motor fluctuation and dyskinesia . No medication-refractory gait symptoms, mood disorder or cognitive decline-none of these can be improved by DBS. Not too early, nor too late.

11. Mechanism of DBS in IPD Inhibition Hypothesis -1)depolarization block (2) inactivation of voltage-gated currents and (3) activation of inhibitory afferents ( GABAergic ). Excitation Hypothesis -by altering abnormal firing pattern of affected necleus . Disruption hypothesis -DBS activates axon terminals in the stimulated nucleus, inducing extensive release of different neurotransmitters from different axon terminals, such as GABA and glutamate ( Glu ), and dissociates inputs and outputs in the stimulated nucleus, jamming the terminals in effect.

12. TARGETS ADVANTAGE DISADVANTAGE INDICATION SUBTHALAMIC nucleus(STN) Easier surgical target. Treats bradykinesia , tremor and rigidity. Helps in levodopa dose reduction. More chance of cognitive decline. May be more chance of weight gain Most common target for IPD. GLOBUS PALLIDUS internus ( GPi ) Treats bradykinesia , tremor and rigidity. Lower chance of cognitive decline. Difficult surgical target than STN. Doesn’t help in levodopa dose reduction. May be preferred in cases with drug induced dyskinesia , IPD with cognitive decline or mood disorder. Ventral intermediate nucleus of Thalamus Treats only tremor. Other component of IPD are unaffected. Difficult surgical target. May be tried in tremor only IPD. Caudal zona incerta Controls tremor very well. Recently described target. Limited exp. Treats mainly tremor. Affects speech more. May br tried in tremor predominant IPD. Targets for DBS in IPD

13. STN DBS in IPD STN-small, obliquely oriented, biconvex, lens-shaped mass of gray matter, difficult to visualize with conventional clinical 1.5 T and 3.0 T MRI Dimension- 5.9 mm, 3.7 mm, and 5.0 mm in the AP, mediolateral , and dorsoventral dimensions respectively. Dorsolateral STN is associated with sensorimotor functioning while the anteromedial STN is associated with limbic function. Damage to anteromedial part may give rise to mood and cognitive disturbances.

14. STN targeting-direct Ideal as location and morphology of STN may not be symmetrical and may vary from patient to patient. Best done on 7T MRI . Atleast 1.5T MRI is required. SWI and T2 images-better delineation of grey matters. Target should be dorsolateral part of the STN.

15. Red nucleus, particularly anterior border,can be a radiological reference point for indirect targeting. Red nucleus cut taken 4mm below and parallel to commisural plane.A transverse line passed through its anterior border. Target is picked on this line 2mm lateral to medial border of STN(if visible) or atleast 3 mm lateral to lateral border of Red nucleus. AC-PC line as standard reference-fixing target after superimposition on standard radiological atlas ( eg Schaltenbrand Bailey atlas). Target point is picked 3mm posterior, 4mm inferior and 12mm lateral to midcommisural point. STN targeting-Indirect

16. GPi as a target for DBS in IPD Indirect Targeting with AC-PC line=2 mm anterior, 5 mm inferior, and 21 mm lateral to the midcommissural point. Indirect targetting fromPallidocapsular border- on the axial cut through intercommisural plane, target is chosen by drawing a 3- to 4-mm line perpendicular to the pallidocapsular border at the junction of its posterior 1/3 rd and anterior 2/3 rd .

17. Trajectory of electrodes and MER 60 degrees from the AC-PC line in the sagittal plane and 0 to 15 degrees from the vertical in the coronal plane. Avoid cortical veins and entry into ventricular system. Navigation can be used to place the burrhole . Recordings typically begin 10 mm dorsal to the anatomic target in case of STN and from striatum in case of Gpi .

18. ZI- zona incerta H1-H1 field of Forel ( thalamic fasciculus) H2-H2 field of Forel ( lenticular fasciculus) IC-internal capsule OT-optic tract H1

19. Microstimulation ( STN) - assesment of collateral stimulatio n Tip location Effect 1. Corticospinal - corticobulbar tract (anterior/ lateral to STN) Tonic muscle contraction, dysarthria -reposition lead or reduce amplitude 2. Medial lemniscus ( posteromedial to STN) Paresthesia -reposition the tip or decrease amplitude 3. Fascicles of 3 rd nerve ( inferomedial to STN) Diplopia -use upper electrode or change to bipolar electrode. 4. Hypothalamus Flushing, perspiration- usually get habituated. 5. SNr Levodopa blocking effect, depression,worsened akinesia 6.Red nucleus Dysequilibrium and gait ataxia without limb ataxia

20. Microstimulation ( GPi ) - assesment of collateral stimulation 1. Optimum location Usually tremor and dyskinesia Disappear stat. Rigidity also diminishes. 2.Medial shift contractions of the contralateral hand and leg- corticospinal tract ( CST ). 3. Anteromedial shift dysarthria , conjugate eye movement, or tonic facial contraction- corticobulbar tract 4. Posterior shift Numbness on the contralateral face and hand 5. Lateral shift No evoked responses are shown during a high-intensity stimulation.

21. Chronic stimulation Should start after approx 3-4 weeks post surgery to avoid initial lesional improvement. Attempt dose adjustment of levodopa depending on response . Select the electrode with widest stimulation window. Start with lowest possible stimulation to bring desired effect , readjustment can be done depending on response. Stimulation Parameters Values 1.Amplitude 2.4 to 4.4 V 2.Frequency 143 to 173 Hz 3.Pulse 67 to 138  μs

22. Deep Brain Stimulation for Dystonia More effective for primary dystonias . Persistent hypertonia at rest has negative impact on outcome. Patient Selection –correct diagnosis, medically resistant or primary generalized dystonia . Target selection- Gpi which lies 19 to 22 mm lateral, 2 to 3 mm anterior, and 4 to 5 mm inferior to the midcommissural point. Trajectory- 60 to 65 degrees anterior & superior to the intercommissural plane & 0 to 10 degrees lateral to the vertical axis. Electrode should have 3- to 4-mm span of GPe and at least 6 mm of GPi .

23. How does GPi DBS differ in Dystonia from IPD? Usually done B/L in case of dystonias . GA is preferred in dystonias . Stimulation parameters of pallidal DBS higher in dystonias (130–185 Hz, 210–450 μs pulse width, 1.5–5 V) than in PD. Rebound dystonic episodes are common after sudden withdrawal from DBS( eg infected).

24. DBS in secondary dystonia Heterogenous group of disorders. Course of the dystonia dictated by the primary disease. Usually don’t respond consistently and as effectively to DBS as in primary except few(such as tardive dyskinesia ). Alternative targets(STN) than GPi may be utilized who fails to respond to GPi stimulation.

25. DBS for Essential tremor(ET) Patient selection-younger pt, refractory tremor, good cognitive reserve. Targets-usually a B/L procedure. 1)Vim-Most commonly used target. 15 mm lateral to the midline at the level of the intercommissural line (ICL) and 6 mm anterior to the PC. 2)Posterior subthalamic area( PostSTA ) –usually direct targeting 3)STN- 12 mm lateral to the midline, 16 mm posterior to the AC, and 4 mm below the ICL . Stimulation parameters TARGET AMPLITUDE WIDTH FREQUENCY Complication of DBS Vim 145–185 Hz 60–117 μ s 2.0–3.7 V Paresthesia , dysarthria , headache disequilibrium & paresis Post STA 130–170 Hz 60–112.5 μ s 1.9–2.5 V Transient dysphasia ,clumsiness, Hemiparesis , persistent dizziness STN 130–180 Hz 60–90 μ s 1.5–3 V arm dystonia , dysarthria , dizziness, balance disturbances

26. Optimal Target in the Treatment for ET? Post STA DBS showed better tremor control and hand function with the use of lower voltages , which resulted in a reduction of side effects , such as dysarthria and disequilibrium and longer battery life. Tolerance (Habituation )- is a notorious phenomena peculiar to Essential tremor which is not seen in Parkinson’s tremor.May be seen upto 40% cases treated with Vim-DBS. Tolerance doesn’t develop if target is PostSTA . Considering the above, PostSTA DBS probably the optimal target in essential tremor. Axial Coronal Saggital

27. DBS in Epilepsy Target Indication 1)MTLE Head of the hippocampus or the amygdalohippocampal junction. May be tried in dominant lobe epilepsy 2) Myoclonic and focal seizure STN& Substantia Nigra May be tried as a palliative option, particularly in patients with myoclonic epilepsy 3)Lennox- Gastaut syndrome Centromedian Nucleus of the Thalamus May be indicated in other generalized seizures. 4) Medically refractory partial seizures +/-secondary generalization Anterior Nucleus of the Thalamus Decreases seizure frequency and AED requirement. But cant completely abolish seizures without drugs.

28. DBS in psychiatric disorders TARGET OUTCOME 1 ) TARDIVE SYNDROME THALAMUS POSTEROVENTRAL Gpi Internal Capsule(IC) & Nucleus Accumbens Reduction in tic Reduction in tic and OCD Reduction of OCD>tic 2 ) OCD Anterior limb of IC. Ventral Capsule and Ventral Striatum Ventral Capsule and Ventral Striatum. Nucleus Accumbens STN Inferior thalamic peduncle Improvement in compulsive behavior. Improvement in depression as well 3 ) MAJOR DEPRESSION Subgenual cingulate gyrus Nucleus accumbens Anterior Limb of the Internal Capsule Medial Forebrain Bundle Most common target. Treats depression as well as OCD Augments reward effects 3 ) ANOREXIA NERVOSA Nucleus accumbens . Improvement of BMI & restoration of menstruation

29. DBS in obesity TARGETS FUNCTIONS EFFECT OF DBS 1) Lateral Hypothalamus (LH) Controls feeding behaviour . B/L high-frequency (180- to 200-Hz) LH stimulation results in inhibition of LH > deacreased food intake &increased energy expenditure 2) Ventromedial Hypothalamus Satiety center Continuous low-frequency stimulation at 60 -80Hz results in early satiety and thus decreased wt gain 3) Nucleus Accumbens Reward centre for feeding Reduce binge eating DBS for other diseases DISEASES TARGET OUTCOME 1) Alzheimer’s Disease (AD) Ant Fornix Nucleus basalis of meynert Improved memory Transient improvement of neuropsychological status

30. Complications of DBS and avoidance Related to the surgical procedure- hemorrhages, infections, epilepsy, and air embolisms Related to machinery failure- electrode breakage, skin erosion over the IPG or wirings. Related to stimulation itself- psychiatric or cognitive malfunctions and the increased risks for suicide.

31. Related to the surgical procedure or machinery failure COMPLICATION RISK FACTORS AVOIDANCE 1) Intracranial Hemorrhage- incidence 0to 5 % Old age, HTN, Ventricular entry or gyrus breach Multiple electrode passage ? Intraop MER(questionable) Navigation guided entry /passage & avoid cortical vessels. Limit electrode passage to minimum. 2) Mechanical failure (4 to 9.7 %) Acute angulation and/or Lack of fixation at burrhole exit. Subcutaneous placement of wires Avoid sharp angling. Fix electrodes with miniplates at exit point near burr holes. Submuscular implantation of the IPG(except in dystonia ) 3) Infections, Skin Erosions ( 2.9 to 7.7 %) Frontal subcutaneous connector bulk Straight frontal skin incision. Thin scalp skin Age < 58 years or >65yr(*Bhatia et all) Maintance of thorough asepsis Hockey-stick or crescent incisions. Partial drilling of outer table. 4) Epilepsy and Air Embolisms ( 0 to 13 %.) Abnormal postop imaging (hemorrhages, edema, ischemia) Age over 60 Transventricular electrode trajectories Avoid hemorrhagic risks/ venricular penetration. Minimize electrode passage

32. Psychiatric and cognitive disturbance COMPLICATION RISK FACTORS AVOIDANCE 1)Cognitive decline in IPD DBS target is GPi Use STN as target in patients with already impaired cognitive functions 2)Mood changes/depression in IPD Increased incidence when target is STN ( microlesioning of the outer part of the SNr ) Proper lead placement 3) Suicidal tendency Relatively younger age Early onset of IPD. Preoperative major depression or suicide attempt Precise lead placement into dorsolateral part of STN

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