NEUROMODULATION in Psychiatric Disorders

Giovanni Broggi,

Dept of NeurosurgeryFond. Istituto Neurologico C.Besta

Milano Italy

A LONG SHADOW OVER THE SOUL- Fano –March 29-31,2012

NEUROMODULATION in Psychiatric Disorders

• Deep Brain Stimulation –DBS

Different targets

• Vagal Nerve Stimulation-- VNS

Indications:•OCD•DISRUPTIVE BEHAVIOUR•SOMATOFORM DISORDERS•MAYOR DEPRESSION•Gilles de la TOURETTE

NEUROMODULATION in Psychiatric Disorders

DBS

VNSIndication:MAYOR DEPRESSION

Neurosurgery for Psychiatric Diseases in Italy

Giovanni BroggiDept of Neurosurgery

Fond. Istituto Neurologico C.BestaMilano, Italy

World Federation Societies Stereo-Functional NeurosurgeryINTERNATIONAL FORUM OF PSYCHIATRIC SURGERY

SHANGHAI, MARCH 9-11, 2011

WHAT IS THE STATE OF ART of Surgery for Psychiatric Disorders the World?

DBS • Milano Besta

– 7 cases for aggressive behavior (post Hyp)– 5 cases of OCD ( ACC)– 1 case somatoform disease, pain ( B.A.24)– 3 cases of major depression ( B.A. 25)– 5 case of Gilles Tourette ( GPi // cortex B.A.9-46)

• Milano Galeazzi– 32 case of Gilles Tourette (Vop-CM // Gpi)

VNS for Major Depression

Milano Besta 21 cases

Torino Univ 11 cases

Udine Hospital 6 cases 2011

Neurosurgery for Psychiatric Diseases

Mood & Mind SupplementumWorld Neurosurgery 2012

•Surgery for Psychiatric DisoedersD.A.J.P.Denys- Amsterdam

•Surgery in Tourette SyndroemVaerle Visser-Vandevalle-Maastricht

•DBS for OCDStephane Chabardes- Grenoble

•DBS for Alcool dependencyJ.Voges- Maagdeburg

WSSFN ad hoc Committe for Ethical Guidlines

DELGADO, M. R., H. HAMLIN and W. P. CHAPMAN. Technique of intracranial electrode implacement for recording and stimulation and its possible therapeutic value in psychotic patients. Conf. neurol., 12:315-319, 1952.

INCB Criteria of Patiens selection

• Diagnosis by the referral psychiatrist• Control and agreement on the diagnosis

by two indipendent psychiatrist

• Neuroradiological studies

• Team ( psychiatrist, neurologist, neurosurgeons) discussion and agreement

• Informed consensus to surgery ( patient , family or legal tutor)

Deep brain stimulation of the accumbens nucleusIn treatment of obsessive compulsive diseases.

Preliminary experiences

Coordinates of Nucleus Accumbens:

2.5 mm rostral anterior border of

AC (Z)

6.5 mm lateral of midline (X)

- 4.5 mm ventral AC (Y)

Dedicated computational software for detecting Anterior Nucleocapsular regionDedicated computational software for detecting Anterior Nucleocapsular region

No discharge specific pattern in NAWith thw exception of few neurons with discharge frequency of 15Hz But with some episode of ~200Hz (doublets) frquency

Microrecording on Nucleus Accumbens

70-200ms

Time (s) 1 s

μV

1

Time (s)S

pike

s\s

Microrecording on Nucleus Accumbens

STABLE AT 4 years

Follow-up

Follow up In Patient 2: Decrease of YBOCS score from 30 to 12Decrease of YBOCS score from 30 to 12

Increase of GAF score from 41 to 60Increase of GAF score from 41 to 60

?

BOTH PATIENTS REFRACTORY TO CONSERVATIVE TREATMENTBOTH PATIENTS SELECTED BY TWO INDEPENDENT PSYCHIATRIC TEAMS

BOTH PATIENTS OBTAINED SIGNIFICANT IMPROVEMENT BY DBS

BOTH PATIENTS REGAINED SOCIAL LIFE(work , friends , hobbies…)

~~~~~~~~~~~

ONE PATIENTS IS REALLY SATISFIED(“I have been cured”)

ONE PATIENTS IS NOT SATISFIED(“still I feel me unhappy , sick..”)

Results on QoL

ANGELO FRANZINI GIUSEPPE MESSINA CARLO MARRAS GIOVANNI TRINGALI GIOVANNI BROGGI

Hypothalamic neuromodulationfor aggressive behaviour

The ProblemRage attacks , self aggression , and disruptive

behaviour

resistent to conservative treatments

in mentally retarded patients

---------

connatal idiopathic

brain damage ( trauma , encephalitis)

----------

Frequent comorbidity for epilepsy

Lesioning of the same target K. Sano. 1970

The Sano graphic reconstruction of electrodes tracks and the fusion between RM and postoperative CT with electrodes implanted

within the posterior hypothalamus

Sano K. 1970

May A. 1999

Franzini et al. 2003

STEREOTACTIC COORDINATES TO THE AC-PC MIDPOINT:

X = +/- 2 (ventricular wall)Y = -3 (correction needed)Z = -5

DEACTIVATION during pHyp DBS

STEREOTACTIC COORDINATES AND TECHNICAL PROBLEMS

STIMULATION PARAMETERS 180 Hz 90 usec1-2.5 Volt

INTRAOPERATIVE EVOKED

RESPONSE

• -Vertigo, ocular movement disturbances(>3V.)

• -Sense of fear(>4V.)

– Bipolar stimulation at the target

100 ms

The frequency of single unit action potentials is about 15-16 Hz

Posterior Hypothalamus microrecording

No specific neuronal discharge pattern

THE FIRST CASE Clinical Case : 34 yrs old maleMental retardation : iQ < 40

Refractory epilepsyINTRACTABLE DISRUPTIVE BEHAVIOUR isolation (4 years)

Neuroleptics drowsisness – epilepsy – tardive dystonia

Withdrawald of neuroleptics Two weeks after surgery

Recover of social activities two months after surgery

Decrease of seizures rate 50% (neuroleptics ?)

no more isolation

four years follow-up

Normalnomultifocal3020Idiopathic6 C.C.

Bilateral temporal porencephaly

nonoNot evaluable37Post-traumatic5 D.C.

Bilateral frontal cortical atrophy

InsomniaSevere arterial hypertension

no3064Post-anoxia4 C.A.

Normalnono4021Idiopathic3 P.M.

NormalnonoNot evaluable34Perinatal Toxoplasmosis

2 B.A.

NormalnomultifocalNot evaluable26Idiopathic1 P.G.

neuroimaging epilepsy IQage aetiology patients

2004 – 2008 6 patients

Posteromedial hypothalamic stimulation for aggressive and disruptive behaviour in IQ subaverage patients

RESPONDERS

NON RESPONDERS

LONG TERM RESPONDERS (67%)

-Neuroleptics dosage decrease > 50%-No more Hospitalization-No more contentive measures-Family or therapeutic community stay-Improvement of cognitive functions-Marked reduction of epileptic seizures (2 epileptics)

-Adverse effects--Slight worsening of neck dystonia (2 patients) when stimulating with the most caudal contact--Impairement of ocular movements when the current amplitude > 3 Volts

DISAPPEARANCE OF SELF-AGGRESSIVE BEHAVIOR IN A BRAIN-INJURED PATIENT AFTER DEEP BRAIN STIMULATION OF THE HYPOTHALAMUS:TECHNICAL CASE REPORT.

Neurosurgery. 62(5):E1182, May 2008.

Kuhn, Jens M.D.; Lenartz, Doris M.D.; Mai, Jurgen K. M.D.; Huff, Wolfgang M.D.; Klosterkoetter, Joachim M.D.; Sturm, Volker M.D

40 pts

Somatoform Disorders Common Characteristics

Disorders in this category include those where the symptoms suggest

a medical condition but where no medical condition can be found by a physician.

In other words, a person with a somatoform disorder might experience significant pain without

a medical or biological cause, or they may constantly experience minor aches

and pains without any reason for these pains to exist.

Somatoform Disorders

PrognosisPoor. The course is typically chronic and persists for years, and often involves other symptoms such as depression, anxiety, and drug abuse.

Radiosurgycal cyngulotomy for chronic pain

Nature Neuroscience 2, 403 - 405 (1999) doi:10.1038/8065

Pain-related neurons in the human cingulate cortexW. D. Hutchison1, K. D. Davis, A. M. Lozano

R. R. Tasker1 & J. O. Dostrovsky

Stereotact Funct Neurosurg 1992;59:33-38

Deep Brain Stimulation of the Anterior Cingulate Cortex (ACC)Brodman area 24

ATYPICAL FACIAL PAIN

60 years female patient

More than 10 years of chronic pain of the face perioral area

Refractory to any kind of drugs treatment including opioids ,neuroleptics ,antiepileptics etc..

No social life , completely invalidated

After four months of high frequency stimulation of the Cingulate cortex (Brodman area 24) the patient became

pain free

At 3 year, follow-up still control of pain, that became episodic instaed of continous

Deep Brain Stimulation for Treatment-Resistant Depression

Neuron, Volume 45, Issue 5, Pages 651-660H.Mayberg, A.Lozano, V.Voon, H.McNeely, D.Seminowicz, C.Hamani, J.Schwalb, S.Kennedy

Case 1

2 years follow up

Case 2

Case 1 46 years old , male

Diagnosis of bipolar depression 22 years old (one maniac episode)

Psychoterapy

Drug therapy

ECT (6 times)

VNS (2 years)

HRDS 1 = 32

HRDS 1 = 5

Patients and relatives satisfied 18 months follow-up

www.angelofranzini.com

DBS for Psychiatric Disorders at Besta

Area 25 Area 24

N ACC

P Hyp

VNS For Depressive Disorder

Nucleus Tratctus Solitarus

AFFERENTSAFFERENTS

- Vagal nerve

- Carotid sinus nerve

- Aortic depressor nerve

- Cranial nerves V, VII e IX

- Grey substace of spinal cord (through the “spinosolitary tract”)

- Area postrema

- Rostro-ventro-lateral portion of medulla

- Parabrachialis nucleus

- Dorsal tegmental nucleus of mesencephalus

- Paraventricular nucleus of hypothalamus

- Posterior portions of lateral hypothalamic nuclei

- Central nucleus of amygdala

VNS For Depressive Disorder

VNS SURGERY

VNS:VNS:

Modification of regional functional anatomy Modification of regional functional anatomy

Main conceptual benchmarks in the genesis of depression:

- imbalance in the prefrontal-limbic circuit

-VNS could modify such balance

Functional Magnetic Resonance (fMRI) may evidence the immediate effects of VNS

SPECT and PET may evidence long-term effects

VNS VNS modification of regional functional anatomymodification of regional functional anatomy

fMRI fMRI (Chae et al. , 2002)(Chae et al. , 2002)

•At VNS immediate activationAt VNS immediate activation

• Prefrontal gyri, Caudate nuclei, Prefrontal gyri, Caudate nuclei, • temporal and parietal lobes, temporal and parietal lobes,

CerebellumCerebellum

•After 2 weeks of VNS : After 2 weeks of VNS : Frontal and Temporal LobesFrontal and Temporal Lobes

OccipitalOccipital Lobe and Cerebellum Lobe and Cerebellum

Blood flow increases: yellow

Blood flow decreases: blue

Acute VNS study with PET images superimposed on MRI images:

1: High frequency stimulation group

2: Low frequency stimulation group

1

2

(Henry T, 2002)

PET STUDIES

74 European patients with therapy-resistant major depressive disorder. Psychometric measures were obtained after 3, 12, and 24 months of VNS.

Journal of Clinical Psychopharmacology & Volume 30, Number 3, June 2010

Mixed-model repeated-measures analysis of variance revealed a significant reduction (P ≤ 0.05) at all the 3 time points in the 28-item Hamilton Rating Scale for Depression (HRSD28) score

•53.1% (26/49) of the patients fulfilled the response criteria (Q50% reduction in the HRSD28 scores from baseline)

• 38.9% (19/49) fulfilled the remission criteria(HRSD28 scores e 10).

From January 2004 to November 2006 fourteen patients with TRD From January 2004 to November 2006 fourteen patients with TRD (age 43 to 80; ten men and four women) underwent VNS(age 43 to 80; ten men and four women) underwent VNS

• Baseline scores: ≥ 20≥ 20 on HDRS21.

• All of them had failed at least four antidepressant trialsfour antidepressant trials in their current major depressive episode

3. They did not benefit from a minimum of 6 months6 months of psychotherapy and their current episode was lasting for at least two years.at least two years.

0

10

20

30

40

50

60

Impl

ant

1 m

th

4 m

th

8 m

th

12 m

th2

yrs

4 yr

s6

yrs

7 yr

s

Time

HR

SD

Pat 1Pat 2Pat 3Pat 4Pat 5Pat 6Pat 7Pat 8Pat 9Pat 10Pat 11Pat 12Pat 13Pat 14

Diagram of ongoing of HDRS21 score in 14 patients with a follow-up of at least 1 year, as a function of time.

Arrow indicates the clinical worsening of patient 2 which occurred after IPG’s Battery Depletion

Responders ( HRSDResponders ( HRSD21 21 < 50 %) : 71%< 50 %) : 71%

Results:Results::HRSD 21 score ≤ 50 % of baseline score (responsiveness)

HRSD 21 score < 10 as absolute value (remittance)

4 patients4 patients did not responde to either criteria

10 Patients10 Patients responded to the responsiveness criterion

(HRSD 21 score ≤ 50 % of baseline score )

7 out of these 10 patients7 out of these 10 patients also met the criterion for remittanceremittance

(HRSD 21 score < 10 as absolute value)

VNS For Depressive Disorder

acknowledgement

• Angelo Franzini

• Giuseppe Messina

• Giovanni Tringali• Morgan Broggi

• Orsola Gambini

• Carlo Marras

• Vittoria Nazzi

THANKS FOR THE ATTENTION

Thanks for attention