1. NEUROMODULATION
in Psychiatric Disorders
Giovanni Broggi,
Dept of Neurosurgery
Fond. Istituto Neurologico C.Besta
Milano Italy
A LONG SHADOW OVER THE SOUL
- Fano –March 29-31,2012

2. NEUROMODULATION
in Psychiatric Disorders
• Deep Brain Stimulation –DBS
Different targets
• Vagal Nerve Stimulation-- VNS

3. NEUROMODULATION in Psychiatric Disorders
DBS
Indications:
•OCD
•DISRUPTIVE BEHAVIOUR
•SOMATOFORM DISORDERS
•MAYOR DEPRESSION
•Gilles de la TOURETTE
VNS
Indication:
MAYOR DEPRESSION

4. WHAT IS THE STATE OF ART
of Surgery for Psychiatric Disorders the World?
World Federation Societies Stereo-Functional Neurosurgery
INTERNATIONAL FORUM OF PSYCHIATRIC SURGERY
SHANGHAI, MARCH 9-11, 2011
Neurosurgery for Psychiatric Diseases in Italy
Giovanni Broggi
Dept of Neurosurgery
Fond. Istituto Neurologico C.Besta
Milano, Italy

5. 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

6. Neurosurgery for Psychiatric Diseases
WSSFN ad hoc Committe for Ethical Guidlines
Mood & Mind Supplementum
World Neurosurgery 2012
•Surgery for Psychiatric Disoeders
D.A.J.P.Denys- Amsterdam
•Surgery in Tourette Syndroem
Vaerle Visser-Vandevalle-Maastricht
•DBS for OCD
Stephane Chabardes- Grenoble
•DBS for Alcool dependency
J.Voges- Maagdeburg

7. 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.

9. 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)

10. Deep brain stimulation of the accumbens nucleus
In treatment of obsessive compulsive diseases.
Preliminary experiences

12. 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)

13. Dedicated computational software for detecting Anterior Nucleocapsular region

15. Microrecording on Nucleus Accumbens
70-200ms
μV
Spikess
1
Time (s) 1s
No discharge specific pattern in NA Time (s)
With thw exception of few neurons with discharge frequency of 15Hz
But with some episode of ~200Hz (doublets) frquency

16. Microrecording on Nucleus Accumbens

18. STABLE AT
4 years
Follow-up

20. ?
Follow up In Patient 2: Decrease of YBOCS score from 30 to 12
Increase of GAF score from 41 to 60

24. Results on QoL
BOTH PATIENTS REFRACTORY TO CONSERVATIVE TREATMENT
BOTH 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..”)

25. Hypothalamic neuromodulation
for aggressive behaviour
ANGELO FRANZINI GIUSEPPE MESSINA
CARLO MARRAS GIOVANNI TRINGALI GIOVANNI BROGGI

26. The Problem
Rage attacks , self aggression , and disruptive
behaviour
resistent to conservative treatments
in mentally retarded patients
---------
connatal idiopathic
brain damage ( trauma , encephalitis)
----------
Frequent comorbidity for epilepsy

27. Lesioning of the same target
K. Sano. 1970

28. Sano K. 1970
Franzini et al. 2003
May A. 1999
The Sano graphic reconstruction of electrodes tracks and the fusion
between RM and postoperative CT with electrodes implanted
within the posterior hypothalamus

29. STEREOTACTIC COORDINATES
TO THE AC-PC MIDPOINT:
X = +/- 2 (ventricular wall)
Y = -3 (correction needed)
Z = -5

30. DEACTIVATION during pHyp DBS

31. STEREOTACTIC COORDINATES AND TECHNICAL PROBLEMS
STIMULATION PARAMETERS 180 Hz 90 usec1-2.5 Volt

33. INTRAOPERATIVE
EVOKED
RESPONSE
• -Vertigo, ocular movement disturbances(>3V.)
• -Sense of fear(>4V.)
– Bipolar stimulation at the target

34. Posterior Hypothalamus microrecording
The frequency of single unit action potentials is about 15-16 Hz
No specific neuronal discharge pattern 100
ms

35. THE FIRST CASE Clinical Case : 34 yrs old male
Mental retardation : iQ < 40
Refractory epilepsy
INTRACTABLE 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

36. Posteromedial hypothalamic stimulation for aggressive
and disruptive behaviour in IQ subaverage patients
2004 – 2008
6 patients
patients aetiology age epilepsy neuroimaging
IQ
1 P.G. Idiopathic 26 Not evaluable multifocal no Normal
2 B.A. Perinatal 34 Not evaluable no no Normal
Toxoplasmosis
3 P.M. Idiopathic 21 40 no no Normal
Post-anoxia 64 30 no Insomnia Bilateral frontal cortical
4 C.A. Severe arterial atrophy
hypertension
5 D.C. Post-traumatic 37 Not evaluable no no Bilateral temporal
porencephaly
6 C.C. Idiopathic 20 30 multifocal no Normal
RESPONDERS
NON RESPONDERS

38. 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

40. 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

41. 40 pts

42. 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.

43. Somatoform Disorders
Prognosis
Poor. The course is typically chronic
and persists for years, and often
involves other symptoms such as
depression, anxiety, and drug abuse .

44. Radiosurgycal cyngulotomy for chronic pain

47. Nature Neuroscience 2, 403 - 405 (1999)
doi:10.1038/8065
Pain-related neurons in the human cingulate cortex
W. D. Hutchison1, K. D. Davis, A. M. Lozano
R. R. Tasker1 & J. O. Dostrovsky

48. Stereotact Funct Neurosurg
1992;59:33-38

50. Deep Brain Stimulation of the Anterior Cingulate Cortex (ACC)
Brodman area 24
ATYPICAL FACIAL PAIN

53. 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

54. Deep Brain Stimulation for Treatment-Resistant Depression
Neuron, Volume 45, Issue 5, Pages 651-660
H.Mayberg, A.Lozano, V.Voon, H.McNeely, D.Seminowicz,
C.Hamani, J.Schwalb, S.Kennedy

57. Case 1

58. Case 2
2 years follow up

59. 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
18 months follow-up
Patients and relatives satisfied

60. DBS for Psychiatric Disorders at Besta
Area 25
Area 24
P Hyp
N ACC
www.angelofranzini.com

61. VNS For Depressive Disorder

62. Nucleus Tratctus Solitarus
AFFERENTS
- 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

63. VNS For Depressive Disorder

64. VNS SURGERY

65. VNS:
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

66. VNS
modification of regional functional anatomy
fMRI (Chae et al. , 2002)
•At VNS immediate activation
• Prefrontal gyri, Caudate nuclei,
• temporal and parietal lobes,
Cerebellum
•After 2 weeks of VNS : Frontal and Temporal Lobes
Occipital Lobe and Cerebellum

67. PET STUDIES Blood flow increases: yellow
1
Blood flow decreases: blue
Acute VNS study with PET
images superimposed on
MRI images:
1: High frequency stimulation
group
2
2: Low frequency stimulation
group
(Henry T, 2002)

68. 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

69. 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).

70. From January 2004 to November 2006 fourteen patients with TRD
(age 43 to 80; ten men and four women) underwent VNS
• Baseline scores: ≥ 20 on HDRS21.
• All of them had failed at least four antidepressant trials
in their current major depressive episode
3. They did not benefit from a minimum of 6 months of psychotherapy
and their current episode was lasting for at least two years.

71. 60
Pat 1
50 Pat 2
Pat 3
40 Pat 4
HRSD
Pat 5
Pat 6
30 Pat 7
Pat 8
20 Pat 9
Pat 10
Pat 11
10 Pat 12
Pat 13
Pat 14
0
nt
th
th
th
th
s
s
s
s
yr
yr
yr
yr
a
m
m
m
m
pl
2
4
6
7
12
1
4
8
Im
Time
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 ( HRSD21 < 50 %) : 71%

72. VNS For Depressive Disorder
Results:
:HRSD 21 score ≤ 50 % of baseline score (responsiveness)
HRSD 21 score < 10 as absolute value (remittance)
4 patients did not responde to either criteria
10 Patients responded to the responsiveness criterion
(HRSD 21 score ≤ 50 % of baseline score )
7 out of these 10 patients also met the criterion for remittance
(HRSD 21 score < 10 as absolute value)

73. acknowledgement
• Angelo Franzini
• Giuseppe Messina
• Giovanni Tringali
• Morgan Broggi
• Orsola Gambini
• Carlo Marras
• Vittoria Nazzi

74. THANKS FOR THE ATTENTION

76. Thanks for attention