Project 1


Title of the project: The Motor Responses Recorded in the Intrinsic Laryngeal Muscles, after Electrical Stimulation of the Brain Cortex, Responsible for Generating Speech. Neurophysiological Mechanism and their Clinical Meanings


  • DETAILS
  • ABSTRACT

Project leader:

Vedran Deletis MD, PhD

Foundation:

The National Foundation for Science, Higher Education and Technological Development of the Republic of Croatia, Program Partnership in Basic Research

Duration:

October 2008. – October 2009.

Total amount awarded:

/

Neurophysiological and anatomical background for producing and understanding speech, unfortunately, even to day, has not been completely understood. Further development of neuroradiological imaging techniques as well as neurophysiological methods measuring evoked potentials elicited from brain areas involved in speech gave us more understanding in their functional organization.

The methodologies for intraoperative identification of different regions of the cerebral cortex involved in speech (Broca area, left inferior frontal gyrus), have not been essentially changed from the original description of W.Penfield in the early fifties. So far this is only precise way to identify this region intraoperatively, and consequently preserve it from injury surgery, preventing so called “motor aphasia” (inability to produce speech). Other neuroradiological techniques such as functional magnetic imaging and positron emission tomography can locate Broca area, but only preoperatively.

In order to use preoperative results of neuroradiological techniques and integrate it in the neuronavigation system, one has to use sophisticated and expansive equipment in order to intraoperatively locate the Broca area. Unfortunately, due to the imperfection of this equipment and slight brain shifting after dura opening, the Penfield technique of electrical stimulation has to be used. Also, patient has to be awake during surgery and cooperate with the surgical team. Furthermore, the Penfield technique can fail in the young and non cooperative patients and in about one third of the patients it elicits intraoperative seizures.

We propose a novel intraoperative neurophysiological technique of eliciting electrical responses in the vocal muscles by using short trains of 3 to 5 stimuli of high frequencies of 250 to 500 Hz applied over the Broca area in order to anatomically identify it.

This novel technique has further advantages:

1. Identification and intraoperative protection of the brain cortex responsible for speech generation resulting in the prevention of motor aphasia.

2. Giving possibilities to operate on patients with pathology around the Broca area and also doing this under general anesthesia.

3. Decrease number of intraoperatively induced seizures after electrical stimulation of the brain.

Preservation of functional integrity of the laryngeal nerves during surgery of the neck, and therefore prevention of surgically induced laryngeal nerve paresis /paralysis.

Project 2


Title of the project: Comprehensive intraoperative monitoring system (CIMS) of neurophysiologic signals


  • DETAILS
  • ABSTRACT

Project leader:

Vedran Deletis MD, PhD

Foundation:

The National Foundation for Science, Higher Education and Technological Development of the Republic of Croatia, Program Partnership in Basic Research

Duration:

October 2008. – October 2011.

Total amount awarded:

/

The basic concept of this apparatus is simultaneous monitoring and recording three categories of signals during surgery on the nervous system.

There are:
1) intraoperative neurophysiologic signals of the functional integrity of the nervous sytem
2) video stream from the operative microscope and
3) anesthesiological parameters (vital signals as a pulls, blood pressure, respiration, electrocardiogram, saturation of blood with oxygen etc.).

Up to day those signals have been separately recorded, or have not been recorded at all. From the practical point of view it was impossible to 'off line' reconstruct and appropriately and comprehensively document important and sometimes critical moments of surgery. Therefore comprehensive documentation for educational purpose it was not possible to gather, and sometimes surgical team was not aware of the exact moment when injury to the nervous tissue occurred.

Furthermore very well established methodologies for the intraoperative monitoring of the functional integrity of the nervous system and prevention of its injury during surgery, has not been documented with parallel events during operative course or anesthesiological regime. Reason for that is non existing machine and electronic media for simultaneously collecting and 'off line' analysis, neurophysiologic and anesthesiological signals as well as video stream from operative microscope.

CIMS machine will be constructed from ‘scratches’, with very original approach and concept for the recording of the neurophysiologic signals, having additional ability to record on DVD media, surgical and anesthesiological course in operating room.

CIMS will be extremely helpful for prevention and documentation of injury to the nervous structure during surgery, which can be used in educational and medico-legal purpose. We plan to commercialize CIMS and obtained CE mark, legal document for use medical equipment within EU countries, while manufacturing it in Croatia.

The simpler version of CIMS can be easily used as a classical neurophysiologic machine in the neurophysiologic lab for recording EEG and evoked potentials (for the purpose of testing patients with auditory, visual, somatosensory and motor evoked potentials)

Project 3


Title of the project: A new insight to the neurophysiology of speech production


  • DETAILS
  • ABSTRACT

Project leader:

M. Sc. Maja Rogić

Foundation:

Unity trough knowledge found, program Gaining experience, 2A

Duration:

September 2009. – April 2010.

Total amount awarded:

/

One of the goals of neurosurgical procedures in the vicinity of eloquent brain regions is to preserve that region from incidental injuries during surgery.

The injuries of critical brain regions that are involved in the speech production may lead to postoperative deficits which cannot be compensated in postoperative period. The exact anatomical, functional and neurophysiological characteristic of speech production are not known yet.

The aim of our study is to define the neurophysiological markers of motor speech production. By finding these neurophysiological markers we would be able to define and recognize the anatomical and functional characteristics of speech production.

The expected outcomes are the following:

1. By finding out the neurophysiological markers of speech production, we would be able to distinguish the anatomical and functional characteristic of speech production.

2. New contribution to the knowledge of the field of neurosurgery. By knowing the neural substrate of speech production, the post-operative deficits in speech production would be lower.

3. Lowering the morbidity of patients and the ability for maximizing surgical resections.

Project 4


Title of the project: Neurophysiologic markers generated by electrical and magnetic stimulation of motor speech related cortical areas


  • DETAILS
  • Introduction
  • Organisations
  • Timetable
  • Dissemination
  • Results




Project leader:

Vedran Deletis MD, PhD

Foundation:

Unity Through Knowledge Fund, Republic of Croatia, Research Cooperability Program 1B

Duration:

15.7.2010 - 15.07.2012

Total amount awarded:

1.296.497,21 HRK




One of the neurosurgical goals when operating within the brain eloquent areas is to preserve their function by avoiding speech and language deficits. A standard neurophysiologic method in achieving this goal is to locate the presumable motor speech related cortical areas by producing speech arrest while electrically stimulating these areas. A prerequisite for inducing speech arrest is having an awake patient or healthy subject actively participating in a speech task (i.e. counting task).

Surgical practice and data published in literature showed that injuries to certain motor speech related cortical areas (primary negative motor area, supplementary negative motor area and primary motor area for laryngeal muscles) do not produce permanent deficits of speech production (expressive aphasia). However, it does not hold for lesions in the phonological part of the Broca’s area (Brodmann’s area 44), which produces permanent expressive aphasia.

The final common organ for speech is the larynx and its muscles. Phylogeneticaly, in speech development, laryngeal muscles are more specialized than other oropharyngeal muscles. Therefore, in this study we will use them as a target organ from which we will record neurophysiologic markers generated by electrical/magnetic stimulation of motor speech related cortical areas.

Our preliminary data, which utilizes novel neurophysiologic methodology, indicates that, while electrically stimulated, most of the motor speech related cortical areas produce distinctive responses in the intrinsic laryngeal muscles. This approach allows us to intraoperatively find neurophysiologic markers (signatures) of the motor speech related areas.

In addition to electrical stimulation of the cerebral cortex through the implanted grid electrodes or during brain surgery of awake patients, we will also conduct parallel experiments using magnetic stimulation on healthy subjects. This approach will significantly contribute to the surgeries of frontal cortex by preserving motor speech related cortical areas and in the future, in the patient having surgery under general anesthesia.

The aims of this study are:

1. To identify the neurophysiologic markers of motor speech related cortical areas of the frontal cortex:

a) in a group of healthy volunteers,
b) patients with implanted subdural electrodes, and
c) patients during awake craniotomy.

2. For the first time using neurophysiologic markers to: preoperatively/intraoperatively localize motor speech related cortical areas (phonological part of Broca’s area, primary motor cortex (M1) for laryngeal muscles and negative motor areas).




Organisation to administer funding

Laboratory for Human and Experimental Neurophysiology (LAHEN)
Department of Neuroscience, School of Medicine, University of Split
Address: Šoltanska 2, 21000, Split, Croatia


Contact person details

Leader of the UKF project:
Prof.dr.sc. Vedran Deletis
Phone: +385 (0) 21 557 875
Mobile phone: +385 (0) 91 754 1385
Email: vdeletis@chpnet.org


Administrative and fnancial issues:
Ana Sedlar. M.A.
Phone1: +385 (0)95 560 40 56
Phone2: +385 (0)21 557 874
Email: ana.sedlar@mefst.hr


Other organisations involved

• Duje Tadin

Department of Brain and Cognitive Sciences University of Rochester Meliora Hall 317 Rochester, NY 14627
Phone: 585 275 8682, Lab: 585 275 7259, Fax: 585 271 3043
Email: duje@cvs.rochester.edu
web address


• PD Dr. med Aurelia Peruad

Ludwig-Maximilians University, Munich, Germany
Marchioninistrasse 15, 81377, Mϋnich, Germany
Phone: 49-089 7095 2699
Email: Aurelia.Peraud@med.uni-muenchen.de


• Prof. Dr.med. Tonn Jörg-Christian

Ludwig-Maximilians University, Munich,
Germany Marchioninistrasse 15, 81377, Mϋnich, Germany
Phone: 49-089 7095 2591
Email: beatrix.tschuran-bilska@med.uni-muenchen.de


• Sedat Ulkatan

Department for Intraoperative Neurophysiology,
Institute for Neurology and Neurosurgery
St Luke’s-Roosevelt Hospital 1000 Tenth Ave, New York, N.Y. 10019
Phone: 212-636 3282
Email: sulkatan@chpnet.org


• Isabel Fernández-Conejero

University Hospital Bellvitge, Barcelona, Spain
Avenida Feixa Llarga, s/n
Phone: +34 600 38 92 10
Email: isabelfernandez@bellvitgehospital.cat


• Karl Kothbauer MD

Division of Neurosurgery,
Dept. of Surgery General and pediatric Neurosurgery,
Luzern Kantonsspital, Switzerland
Phone: 0041-41-2054504
Email: Karl.Kothbauer@ksl.ch


• Mr.sc. Mario Tudor, dr. med

Division of Neurosurgery,
Clinical Hospital Center Split, Croatia
Email: mario.tudor1@st.t-com.hr





The equipment (navigated transcranial magnetic stimulator-nTMS, with special feature) is in the last phase of the construction process by the company (Nexstim, Helsinki, Finland). The construction of this machine was according to the special requirements from our laboratory. We have finished importing procedure for medical devices from foreign country (Finland) to Croatia and we expect that the machine will be imported to our country and settled to our laboratory (LAHEN) by the end of the June 2011. Meanwhile the Nexstim Company installed transcranial magnetic stimulator with 3D navigated brain system as a demo unit to work with in our lab, until we get our full equipment. Delay in the purchasing equipment did not influence to our hodogram activities because demo unit is capable of performing part and first plan of our activities.

Rather complicated set up of equipment has been successfully achieved with obtaining preliminary data. Furthermore, methodology for testing motor speech areas in healthy subjects and patients with subdurally implanted grid electrodes and during awake craniotomy has be established. The methodology of navigated transcranial magnetic stimulation (nTMS) is applied exclusively in the group of healthy volunteers. Ten healthy volunteers underwent brain MRI (magnetic resonance imaging) obtained with 1 mm slices in order to integrate it in the three dimensional navigated brain system. Therefore were able to obtain 3D MRI at KBC, Firule Split, Croatia. Three out of ten healthy subjects have been tested for neurophysiologic markers. A new methodology has been established for facilitation of primary motor cortex for cricothyroid muscle, as well as for phonological part of Broca area. Obtained markers have been recorded from laryngeal muscles after focal stimulation of those two areas using conditionig-test pradigm.

Methodology for electrical stimulation of exposed motor speech related areas has been established and all software and hardware components obtained. In six patients we successfully elicited marker for Broca area primary motor cortex areas for laryngeal muscles.

July 20, 2011 the equipment (custom made navigated transcranial magnetic stimulator (nTMS), Nexstim, Finland) arrived to our laboratory. Installation of the equipment will be made by the technicians from Nexstim company (scheduled on 2-3 of August, 2011). Short training of the LAHEN stuff in using the new equipment is planned for October 2011.




Completed dissemination projects



Policlinic for Hearing and Speech rehabilitation-SUVAG, Zagreb and Section of speech and language pathologists in health- Croatian society for speech and language pathology
Invited talk@Policlinic for hearing and speech rehabilitation-SUVAG, Zagreb
April, 2012.

Invited talk: Maja Rogić, Vedran Deletis


Target audience: 100
Speech and language pathologists (logopedics), psychologists, physicians, physics
Symposium & dinner party on the occasion of the retirement of Johannes Schramm
Symposium@University Clinic Berlin, Germany
November 05, 2011
Vedran Deletis, talk


Target audience:
Neurosurgeons, Neurophysiologist, Neurologist
3rd International Symposium on Navigated Brain Stimulation in Neurosurgery
Poster, Maja Rogic @Berlin, Germany
21-22 October 2011
Poster title: "Functional mapping and distance measurement between primary motor cortex representation of cricothyrod and abductor pollicis brevis muscles with navigated transcranial magnetic stimulation


Target audience: 100
Neurophysiologists, Neurologists
3rd Congress ISIN Barcelona
Congress@Barcelona, Spain
15-17 September, 2011
Invited speaker Vedran Deletis, and his collaborator Maja Rogic abstract and the title of the talk are submitted


Target audience: cca 200 participants
Clinical Neurophysiologists, Neurosurgeons, Neurologist, Anesthesiologists
14 th European Congress on Clinical Neurophysiology - 4 th International conference on
Transcranial Magnetic and Direct Current Stimulation
Congress@Rome, Italy
20-25 June, 2011
Abstract accepted (poster), title of the abstract: Representation of cricothyroid muscles at the primary motor cortex (M1) in healthy subjects, using navigated transcranial magnetic stimulation.


Target audience: cca 200 participants
Clinical Neurophysiologists
2 nd International Workshop on Navigated Brain Stimulation in Neurosurgery
Workshop@Berlin, Germany
October, 8-9. 2010
Invited speaker: Vedran Deletis; Title of talk: Neurophysiologic markers generated by motor speech related cortical areas


Target audience: cca 100 participants
Members of research organizations. Workshop was organized by company members of Nexstim Oy, Finland
Intraoperative Neurophysiologic Monitoring-First Joint Cross-Atlantic Educational Symposium Symposium@Gröningen, Netherlands
November, 4-6. 2010
Invited speaker: Vedran Deletis and Maja Rogić; Title of Vedran Deletis talk: Neurophysiologic markers of motors speech related cortical areas; Title of Maja Rogić talk: Neurophysiology of TMS inducing speech arrest and it's mechanisms


Target audience: cca 200 participants
Intraoperative monitoring professionals, Neurophysiologists, Neurosurgeons, Neurologists, Orthopedists, ENT Surgeons, Anesthesiologists, Nurses, Audiologists, Professionals involved in interventional neuromonitoring of evoked potentials, EMG and EEG during surgical procedures Tumori lubanjske osnovice-sadašnjost i budućnost (eng. Tumors of the cranial base-current and future) Symposium@HAZU, Zagreb, Croatia
November, 23. 2010
Invited speaker: Vedran Deletis; Title of talk: Intraoperativni elektrofiziološki monitoring (eng: Intraoperative electrophysiologic monitoring)


Target audience: cca 100 participants
Specialists involved in diagnoses and treatment of the tumors of the cranial base Simpozij mladih znanstvenika (eng. Symposium of young scientists)
Symposium - competitio between 20 young scientist@School of Medicine, University of Split, Croatia
January, 26. 2011
Participant: Maja Rogić. Title of presentation: Representation of cricothyroid muscles at the primary motor cortex (M1) in healthy subjects, using navigated transcranial magnetic stimulation. Maja Rogić won the 1 st prize on this symposium (grant sum 4000 HRK)


Target audience: cca 50 participants
Young scientist from School of Medicine: scientific novices, post graduated students, research assistants
Course about intraoperative neurophysiologic monitoring
Course, Practice Course@Barcelona, Spain
April, 7-9.2011
Participant: Maja Rogić and Vedran Deletis. Vedran Deletis was invited speaker, Title of the talk: Neurophysiologic markers of motor speech related cortical areas


Target audience: cca 50 participants
Postgraduate students, neurophysiologists, neurosurgeons
Intraoperative Neurophysiologic Monitoring, ASNM Regional Symposium
Symposium@Half Moon Bay, California, San Francisco, USA
February, 19-20.2011
Participant: Vedran Deletis, invited speaker; Title: Intraoperative Neurophysiology


Target audience: cca 200 participants
Neurophysiologist, Anesthesiologist, Neurologist
5. Leipzig Praxiskurs Neuromonitoring
Practice Course@Leipzig, Germany
30. March - 2. April, 2011
Invited speaker: Vedran Deletis; Title of the talk: Intraoperative neurophysiology and neurosurgery


Target audience: cca 50 participants
Neurosurgeons, Neurologist, Anesthesiologist
Cerebral Functions and surgeries: today and tomorrow
Symposium@Udine, Italy
14-15 April, 2011
Round table discussion and chairman: Vedran Deletis


Target audience: cca 100 participants
Neurosurgeons and Neurologists
22 Annual Meeting of America Society for Intraoperative Neurophysiology
Symposium@Buena Vista Palace/Orlando, Florida
13-15 May, 2011
Invited speaker Vedran Deletis; Title of the talk: Monitoring and mapping of the motor cranial nerves;
form the motor cortex to the muscles


Target audience: cca 200 participants
Neurosurgeons, Neurophysiologist, Neurologist
6th Congress of teh Croatian Neurosurgical Society and the Joint Meeting with the Slovenian
Neurosurgical Society
Congress@Opatija, Croatia
25-28. May 2011
Vedran Deletis and Maja Rogic participated with oral presentation, titled:"Neurophysiologic Markers
of motor speech related cortical areas


Target audience: cca 100 participants
Neurosurgeons, Neurophysiologist, Neurologist




Introduction and background

The overall aim of the study supported by UKF grant was: to identify the neurophysiologic markers generated in laryngeal muscles by electrical/magnetic stimulation of motor speech related cortical areas (opercular part of Broca's area and primary motor region (M1) for laryngeal muscles):

a) in a group of healthy volunteers,
b) patients with implanted subdural electrodes, and
c) patients during awake craniotomy.



The specific objectives were:

a) to determine the neurophysiological parameters of stimulation and registration of short latency response (SLR) in the laryngeal muscle with electrical/magnetic stimulation of primary motor region (M1) for the laryngeal muscles of the dominant hemisphere,

b) to determine the neurophysiological parameters of stimulation and registration of the long latency response (LLR) in the laryngeal muscle with electrical/magnetic stimulation of opercular part of Broca's region of the dominant hemisphere,

c) to induce speech arrest during stimulation of opercular part of Broca's region whose stimulation has previously generated the LLR in laryngeal muscle.



Methodology and Results:

a) In all 19 healthy subjects, 6 patients with subdural electrodes, and 33 patients during awake craniotomy, short latency response (SLR) was recorded from laryngeal muscle by magnetic stimulation (in healthy subjects) and electrical stimulation (in patients) of M1 for laryngeal muscles. Single stimulus and train of stimuli were applied for transcranial magnetic stimulation in healthy subject, and train of stimuli for electrical stimulation (transcranial and direct cortical stimulation) in patients.

b) Moving the site of stimulation in front of the localization of M1 for laryngeal muscles toward opercular part of Broca's region of inferior frontal gyrus, long latency response (LLR) was recorded in laryngeal muscle in all 10 healthy subjects in whom we used a new methodology of train of magnetic stimuli during visual object naming (VON) task. LLR was also recorded in laryngeal muscles by stimulation of opercular part of Broca's region with train of electrical stimuli in 27 patients.

c) In 10 subjects in whom opercular part of Boca's region was stimulated generating LLR in laryngeal muscle, the same location was again stimulated with a train of stimuli inducing speech arrest in two subjects during VON task. In three subjects qualitative language disturbances were induced. In 15 patients speech arrest was successfully induced by Penfield technique during speech tasks (counting or VON task) by stimulating the same spot (opercular part of Broca's region) which previously generated LLR in laryngeal muscle.



Conclusion

For the first time neurophysiologic markers of motor speech related cortical areas are identified:

a) neurophysiologic marker for M1 for laryngeal muscle is SLR recorded in laryngeal muscle, and

b) neurophysiologic marker for the opercular part of the Boca's region is LLR recorded in laryngeal muscle.



Significance

The methodology was developed for identification of neurophysiologic markers from laryngeal muscles during stimulation of motor speech related cortical areas in healthy volunteers with transcranial magnetic stimulation, and in patients with transcranial electrical and direct cortical stimulation.

It is expected that this methodology will be used in preoperative mapping of motor speech related cortical areas to facilitate surgical planning, and intraoperatively for mapping of motor speech related cortical areas during neurosurgical operations, in order to preserve these areas from injuries and to prevent postoperative speech deficits. The results of this study will contribute to our understanding of the underlying cognitive mechanisms responsible for the processing and production of speech.

Scientific collaboration and contribution: The project was lead by prof.dr.sc. Vedran Deletis, with coapplicant Duje Tadin, PhD. (Department of Brain and Cognitive Sciences, University of Rochester, USA). Five foreign scientists collaborated on this project (2 from Germany, 1 from USA, 1 from Barcelona, 1 from Switzerland) and 1 national (University Hospital Firule, Split, Croatia).

Significant contribution to project realization goes to the team collaborator (M.Sc. Maja Rogić) from Laboratory for Human and Experimental Neurophysiology (LAHEN), School of Medicine, University of Split), and to foreign collaborators: Sedat Ulkatan MD (St Luke's Roosevelt Hospital, USA) and Isabel Fernandez-Conejero (University Hospital Bellvitge, Barcelona, Spain).