Functional Neuromarkers for Psychiatry. Applications for Diagnosis and Treatment

452 Pages·2016·61.157 MB·English

by  Juri D. Kropotov

FUNCTIONAL
NEUROMARKERS
FOR PSYCHIATRY
Applications for Diagnosis
and Treatment
Juri D. Kropotov
N.P. Bechtereva Institute of the Human Brain
of the Russian Academy of Sciences
Saint Petersburg, Russia;
Norwegian University of Science and Technology
Trondheim, Norway;
Andrzej Frycz Modrzewski Krakow University
Krakow, Poland
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Acknowledgments
This book is dedicated to those I love. First of all this includes my family:
my parents Anna and Dmitrii, my wife Nelia, my sons Maxim and Vania,
and my stepsons Igor and Anatoly. All of them believed in me and helped
me in different but loving ways.
My early interest in physics was inspired by Victor Kobushkin when
he educated me at the famous Lyceum/school 239 in Leningrad with ad-
vanced teaching in mathematics and physics. My broad view of mathemat-
ics was shaped by Professor Boris Pavlov at Leningrad State University.
In 1972, being a postgraduate student at the university’s Department of
Theoretical Physics, I met Professor Natalia Bechtereva, a granddaughter
of the famous Russian psychiatrist Bechterev. This meeting changed my
life: I became involved in studies of the healthy and diseased human brain.
In my days at the Institute of Experimental Medicine in Leningrad some
severe cases of Parkinson’s disease and epilepsy were treated with deep-
brain stimulation and local lesions by means of implanted electrodes. This
approach provided a unique opportunity of recording the impulse activ-
ity of neurons and other physiological parameters from the human brain.
The main idea was to search for a “neuronal code of human mental activ-
ity” by recording responses of neurons in different behavioral paradigms.
Those were years when sophisticated methods of EEG analysis were still
to be invented and researchers hoped that the recording of neuronal re-
actions in various behavioral tasks would tell them how the brain pro-
cesses information. Unfortunately, these hopes were never completely
satisfied. However, the studies of human neuronal reactions performed
by our group showed that neurons of the basal ganglia were involved not
only in motor actions, but also in sensory and cognitive functions. For this
research in 1985 together with Yury Gogolitsyn and Natalia Bechtereva
I was awarded the highest award in the whole Soviet Union—the State
Prize. Soon after, I created a Laboratory of Neuroinformatics at the Insti-
tute of Experimental Medicine.
In the 1990s, neuroscience horizons were widened by the invention of
new neuroimaging methods: positron emission tomography (PET) and
magnetic resonance imaging (MRI). The Institute of the Human Brain
(director Sviatoslav Medvedev) was the first in the Soviet Union to build
up a PET center. My laboratory moved to this brand new institute in the
naive hope that new imaging methods would answer all our questions.
But again, the initial euphoria was replaced by deep disappointment:
xv
xvi Acknowledgments
no qualitatively new data were obtained and no clinical applications for
psychiatry were found.
All this happened before perestroika, proclaimed by Mikhail Gorbachev,
became a real disaster and the Soviet Union collapsed. The funding of
science ceased as well. To earn a living, people in my laboratory started
bargain tea packages and did a lot of other “business-like” enterprises.
Most of them left the Soviet Union and went to the West for a better
life. Yury Gogolitsyn immigrated to England, Andrey Sevastianov and
Michael Kuznetzov went to the United States, Aleksander Popov to
Australia, Oleg Korzukov and Olga Dubrovskaya to Finland. In 1992–93,
I was working with Peter Kugler, Helen Crowford, and Karl Pribram at
the Brain Research Center at Radford University in Virginia on mathemat-
ical simulation of realistic neural networks. I am very grateful for their
help in those hard years.
However, removal of the iron curtain opened new opportunities for
my laboratory for collaboration with other universities in the West. Here
I want to mention our joint research projects with Nobel Prize winner Ilia
Prigogine and the outstanding Finnish psychologist Risto Naatanen. Risto
introduced me to the field of ERPs. We published with him several papers
on intracranial correlates of mismatch negativity—a small negative fluctu-
ation in response to deviance in repetitive auditory stimulation. It was the
first time I saw a neuronal marker of a psychological operation that could
be potentially used in clinical practice. To continue ERP research in the
laboratory, we needed the corresponding equipment. But where would
we get the funding?
In cooperation with the Institute of Television we set up Potential, a
company, with the aim to manufacture EEG machines for Russian clinics
and for research. At the beginning we were working in collaboration with
Don Tucker, a professor at the University of Oregon and the founder of
EGI, a company. Here I would like to mention Valery Ponomarev, a senior
researcher in my lab, who started writing the software for the EEG ampli-
fiers developed by Potential. Highly talented in mathematics he was able
to introduce into the software a lot of advanced methods for EEG/ERP
analysis. So, instead of buying the equipment for our research, we devel-
oped it ourselves.
We still needed the money to keep people in the lab. So, I decided to
provide services for ADHD children in whom, as Western studies showed,
EEG could be used for diagnostic purposes. However, no medical treatment
existed in Russia because ADHD was not considered by Russian pediatri-
cians as a real disorder and psychostimulants were forbidden. We needed a
new approach and the classical method of operant conditioning provided
the answer. It should be noted that EEG operant conditioning had a long
history in Russia with animal experiments undertaken by Professor Niko-
lai Vasilevskii and with clinical research undertaken by Professor Natalia
Acknowledgments xvii
Chernigovskaya. In the United States, similar studies were being carried
out by Joe Kamia and Barri Sterman. However, the first neurofeedback
protocols for ADHD were suggested to us by Joel Lubar and Siegfried and
Sue Othmer from the United States. The quantitative EEG (QEEG) diag-
nostic procedures were inspired by Roy John, Barry Sterman, and Robert
Thatcher. These new technologies were implemented in my lab by Olga
Dubrovskaya and Vera Grin-Yatzenko. Traditional neurofeedback equip-
ment was developed in our laboratory.
By teaching these technologies at a workshop in Norway, I earned
enough money to buy tickets to the 2001 ISNR conference in Monterey
(USA). ISNR stands for International Society for Neuronal Regulation—one
of the few research communities that were using QEEG/neurofeedback
technologies in clinical practice. At the conference I met Jay Gunkelman,
the president of the society in those days, and I was elected president of the
newly formed European chapter of ISNR. In 2002 the workshop organized
by Jonelle Villar for Jay and me in Portugal inspired Dr. Andreas Mueller
to set up an ERP database. I constructed the tasks and sent my PhD stu-
dent Katja Beliakov to Andy’s practice in Switzerland to collect the data
together with Gian Gadrian. After 4 months they had recorded data from
250 healthy children and after 6 months Valery Ponomarev wrote the soft-
ware for comparing individual QEEG/ERP parameters with the database.
For the first time, group independent component analysis was applied for
extracting ERP functional components. Andy immediately started using
the database in his practice.
It was approximately at this time that Jan Brunner from the Norwe-
gian University of Science and Technology, Trondheim began using the
technology in his clinical practice. He was the first to prove that ERP com-
ponents were reliable and that they selectively correlated with scores in
certain neuropsychological domains. Another approach for applying the
methodology to neuropsychological practice was suggested by Profes-
sor Maria Pachalska from Krakow. She organized a series of lectures and
workshops for me at Krakow Academy in which we tested many patients
with different psychiatric conditions. The results of the work were pub-
lished in a series of papers and the 2014 book Neuropsychologia kliniczna.
It took 10 years of hard work using different approaches to find the
functional neuromarkers of the healthy and diseased brain. Here I would
like to mention Valery Ponomarev, Marina Pronina, Sergei Evdokimov,
Ekaterina Tereschenko, Vera Grin-Yatzenko, Elena Yakovenko, Inna
Nikishena, Olga Dubrovskaya (Kara), Leonid Chutko, Galina Poliakova,
and Yury Poliakov from the Institute of the Human Brain in Saint Peters-
burg (Russia); Andreas Muller, Gian Gadrian and Gian-Marco Baschera
from the Brain and Trauma Foundation in Chur (Switzerland); Bernhard
Wandernorth from BEE Systems in Germany and Switzerland; Jan Ferenc
Brunner, Ida Emilia Aasen, Anne Lise Hoyland, and Knut Hestad from the
xviii Acknowledgments
Norwegian University of Science and Technology in Trondheim; Venke
Arntsberg Grane from the Helgeland Hospital in Norway; Geir Ogrim
from the Østfold Hospital Trust in Norway; Antonio Martins-Mourao
and Tony Steffert from the Open University in England; Beverly Steffert
from the British Psychological Society; Mirjana Askovic from STARTTS in
Sydney (Australia); Nerida Saunders and Rustam Yumash from the Brain
Mind & Memory Centre & Research Institute in Australia; Maria
Pachalska, Anna Rasmus, and Andrzej Mirski from the Andrzej Frycz
Modrzewski Cracow University in Poland. The list of my coworkers is
not complete.
The book I am presenting here is the final result of a lot of hard work
of a multidisciplinary team of extremely dedicated and highly qualified
people, and I am very thankful to all of them. Studies in my laboratory in
Saint Petersburg were supported by grants from different agencies such
as the Soros Foundation, Russian Foundation for Fundamental Research,
Russian Humanitarian Science Foundation, US National Science Foun-
dation, and Austrian Academy of Sciences. The latest grants are Grant
14-06-00937a of RGNF (Russian Humanitarian Science Foundation) and
Grant 16-15-10213 of RSF (Russian Science Foundation).
Juri (Yury) D. Kropotov
April 2016, Saint Petersburg
Introduction
TWO RECENT EVENTS THAT
MAY CHANGE PSYCHIATRY
Two crucial events occurred recently in psychiatry: (1) the appear-
ance of the fifth edition of Diagnostic and Statistical Manual of Mental
Disorders (DSM) published by the American Psychiatric Association
and (2) approval by the US Food and Drug Administration (FDA) of the
first electroencephalogram (EEG)-based biomarker of Attention Deficit
Hyperactivity Disorder (ADHD). DSM-5 was published on May 18,
2013. It was criticized by various authorities for lacking empirical sup-
port and for the influence of the psychiatric drug industry (see the re-
sponse letter of the Coalition for DSM-5 Reform at http://dsm5-reform.
com/). This event evoked feelings of disappointment in psychiatrists
awaiting biomarkers of mental dysfunctions.
The second event happened on Jul. 15, 2013 when the FDA allowed
marketing of the first medical device based on EEG to help assess ADHD
in children and adolescents 6–17 years old. The device, the Neuropsy-
chiatric EEG-Based Assessment Aid (NEBA) System, records EEG for
15–20 min by computing the theta/beta ratio, which has been shown
to be higher in children and adolescents with ADHD than in children
without it.
MENTAL ILLNESS AS A CHALLENGE
TO HEALTHCARE SYSTEMS
Mental disorders are a global problem and represent one of the biggest
challenges for healthcare systems. Worldwide there are some 500 million
people suffering from mental disorders. In the European Union, mental
disorders are considered one of the leading causes of the disease burden.
What makes the situation worse is that the prevalence of mental disorders
is expected to grow for a variety of reasons including aging of the whole
population and increasing economic problems such as reduced job secu-
rity, work intensification, and enhancement of stress.
xix
xx IntroductIon
DSM AND ICD AS DICTIONARIES
OF PSYCHOPATHOLOGY
Although the book is titled Functional Neuromarkers for Psychiatry, its
main goal is to introduce neuroscience methodology into psychiatric
practice. So, historically this book can be considered as a reflection of a
neuroscience age of psychiatry.
In the past, mental disorders were defined by the absence of organic
lesions. Mental disorders became neurological disorders at the moment
a brain lesion was found. Because no obvious brain damage was usually
found in mental disorders by the conventional clinical methods of the 19th
and 20th centuries, the psychiatry of the past did not rely on brain damage
markers and was confined by description of symptoms and signs.
In this description approach, DSM and the International Classification of
Disorders (ICD) in the corresponding chapters of mental and behavioral dis-
orders were a clear step forward. Psychopathology was decomposed into
separate disorders. DSM-5 is supposed to serve (at least in the United States)
as a universal authority, a “bible” for psychiatric diagnosis. It has practical
importance in that psychiatric diagnosis determines treatment recommen-
dations for clinicians and the payment strategy for healthcare providers.
However, in contrast with other fields of the advanced medical science
such as heart or cancer diseases, these manuals are based not on objective
laboratory measures but rather on some vague consensus about clusters
of clinical symptoms. But, as we learn from other medical fields, symp-
toms alone rarely indicate the best choice of treatment, only knowing the
cause of the symptoms on the basis of laboratory measures provides
the optimal treatment.
THE HURDLES TO OVERCOME
If a cardiologist sees a patient with chest pain symptoms he or she
would ask for an electrocardiogram (ECG) recording the heart’s electrical
conduction system. An ECG picks up electrical impulses generated by the
polarization and depolarization of cardiac tissue in the form of specific
waves. This information is used to measure directly the rate and regular-
ity of heartbeats, and indirectly the size and position of the chambers and
the presence of any damage to the heart. The ECG may provide a clue as
to whether a patient is having an ischemic event.
However, a psychiatrist seeing a patient with, say, schizophrenia
symptoms would not ask for an EEG recording and assessment as the
first choice. This is despite the solid fact that an EEG registers electrical
signals of the brain and theoretically could tell us much about the course
of the symptoms. This begs the question: why do we use recordings of
IntroductIon xxi
electrical signals for diagnosis in heart disease but do not use recordings
of electrical signals in psychiatry? There are several reasons for that.
First, there is the difference in complexity. The brain is much more
complex than the heart. Heart physiology provides a relatively limited
number of ECG parameters that can be used for diagnosis. ECG param-
eters include only five waveforms which are easily identified in each sub-
ject and have a clear functional meaning in the heart cycle. In contrast,
the number of parameters provided by multichannel EEG in the resting
state is enormous. If event-related potentials (ERPs) are included in the
analysis, the amount and quality of information increases tremendously.
Second, ECG waveforms do not show big intraindividual differences and
have clear diagnostic value. In contrast, EEG and especially ERP parameters
show large interindividual variation. Moreover, EEG/ERP parameters
are very sensitive to fluctuations in the state of subjects. It appears that the
healthy population is not homogeneous in terms of brain functioning. If we
take into account the heterogeneity of a given diagnostic category of mental
illness, the difficulties in separating patients with the given diagnosis from
healthy controls by means of a biomarker becomes evident.
Third, the recording and measuring procedures in ECG are fully stan-
dardized. In contrast, in EEG only electrode placement is standardized.
The other parameters, especially conditions of ERP recordings, are not
standardized. As a consequence, setting up databases in clinical practice
is limited in the EEG field and practically absent in the ERP field.
Fourth, the heart is a relatively simple organ of the body (a pump)
whereas the brain is the most sophisticated system in the world, one that
is intended not only to self-regulate but also to process external and in-
ternal information unconsciously and consciously. A cardiologist in his or
her clinical practice relies on the well-established theory of the heart. No
theory of brain functioning has so far been built up.
Similar reasons can explain why other functional neuromarkers such as
magnetoencephalography (MEG), functional magnetic resonance imag-
ing (fMRI), and positron emission tomography (PET) have not been used
in clinical practice so far.
FROM SYMPTOMS TO NEURONAL CIRCUITS
The diagnostic categories of mental illness described in the DSM and
ICD are not organized according to impairment of brain systems. How-
ever, as neuropsychology shows, similar symptoms can be induced by
local damage in different parts of a given widely distributed neuronal
circuit of the brain or even in functionally different systems. This state-
ment is supported by studies of functional brain activity (such as ERP,
fMRI, PET) recorded under various psychiatric conditions in comparison
xxii IntroductIon
with functional brain activity in healthy controls. More and more studies
clearly demonstrate that the patterns of brain activation during particu-
lar functional tests may be diagnostic, just as cardiac imaging during a
stress test is now used to diagnose coronary artery disease. A promising
approach for “biomarker” discovery has been based on pattern-recognition
methods applied to neuroimaging data. In a 2015 paper Thomas Wolfers
from Radboud University, the Netherlands, and coworkers reviewed the lit-
erature on MRI-based pattern recognition for making diagnostic predictions
in psychiatric disorders and evaluated the recent progress made in translat-
ing such findings toward clinical application. In 2014, Gra´inne McLoughlin,
Scott Makeig, and Ming Tsuang from University of California, San Diego
showed convincing evidence that new computational approaches in EEG
research such as independent component analysis provided powerful tools
for identifying distinct cortical source activities that are sensitive and specific
to the pathophysiology of psychiatric disorders.
FROM “DECADE OF THE BRAIN” TO
“DECADE OF TRANSLATION”
The 1990s were called the “decade of the brain” in which new concepts
of brain functioning were formulated on the basis of accumulated data
(Fig. I.1). This was also when new methodological approaches were devel-
oped such as blind source separation techniques for separating local sources
of brain activity. The early part of this century (2000–2010) may be recog-
nized as the “decade of discovery” during which brain circuits of normal
and abnormal brain functioning have been identified. This is the time when
new nonpharmacological methods of treatment such as transcranial direct
current stimulation, transcranial magnetic stimulation, and other forms
of neuromodulation have been tested in clinical practice. The “decade of
FIGURE I.1 Developing neuroscience of mental illness.