changes of motor control in central nervous system … · central nervous system in schizophrenia...

Department of Psychiatry, University of HelsinkiHelsinki, Finland

CHANGES OF MOTOR CONTROL IN CENTRAL NERVOUS SYSTEM

IN SCHIZOPHRENIA AND RESTLESS LEGS SYNDROME

Aulikki Ahlgrén-Rimpiläinen

ACADEMIC DISSERTATION

To be presented with the permission of the Medical Faculty of the University of Helsinki for public examination in the Auditorium of the Department of Psychiatry

17th January 2014

Supervisors: Research Professor Hannu Lauerma, MD, PhD National Institute of Health and Welfare and Docent Seppo Kähkönen, MD, PhD University of Helsinki

Reviewers: Professor Hannu Eskola, PhD (Tech) Tampere University of Technology and Docent Pekka Tani, MD, PhD University of Helsinki

Opponent: Professor Jarmo Hietala, MD, PhD University of Turku

ISBN 978-952-10-9680-8 (paperback)Also available in electronic formatISBN 978-952-10-9681-5 (PDF)Helsinki University PressHelsinki 2014

To my family

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LIST OF ORIGINAL PUBLICATIONS

This thesis is based on the following original articles referred by their Roman numerals I-IV in the text.

I. Ahlgrén-Rimpiläinen A, Lauerma, H, Kähkönen S, Aalto H, Pyykkö I, Palmgren K, Rimpiläinen I. Effect of visual information on postural control in subjects with schizophrenia. Journal of Nervous and Mental Disease, 2010; 198 (8):601-603.

II. Ahlgrén-Rimpiläinen A, Lauerma, H, Kähkönen S, Markkula J, Rimpiläinen I. Recurrent CSPs after transcranial magnetic stimulation of motor cortex in Restless Legs Syndrome. Neurology Research International, Volume 2012, Article ID 628949, 7 pages doi:10.1155/2012/628949

III. Ahlgrén-Rimpiläinen A, Kähkönen S, Lauerma, H, Rimpiläinen I. Disrupted central inhibition after transcranial magnetic stimulation of motor cortex in schizophrenia with long-term antipsychotic treatment. ISRN Psychiatry, Volume 2013, Article ID 876171, 9 pages. doi:10.1155/2013/876171.

IV. Ahlgrén-Rimpiläinen A, Lauerma H, Kähkönen S, Tuisku K, Holi M, Aalto H, Pyykkö I, Rimpiläinen I. Postural control in Restless Legs Syndrome with medication intervention using pramipexole. Neurological Sciences, doi: 10.1007/s10072-013-1478-6. Accepted 11 June 2013, published online 21 June 2013.

These articles are reproduced with the kind permission of their copyright holders.

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ABBREVIATIONS

Ach acetylcholineADM abductor digiti minimi muscleAIMS abnormal involuntary movement scaleANL atypical neuroleptic AP anterior-posteriorBAS Barnes Akathisia Rating ScaleCFPP computerized force platform posturographyCL con� dence limitCMCT central motor conduction timeCNL conventional neurolepticCNS central nervous systemCPF center point of forceCPFV center point of force velocityCSP central silent periodCT computerized tomogramDA dopamineDRSIS dopamine receptor speci� c individual sensitivityDSM Diagnostic and Statistical Manual of Mental DisordersEEG electroencephalographyEMG electromyographyEP extrapyramidalGABA gamma-aminobuturic acid5-HT serotoninHUCH Helsinki University Central HospitalICD-10 International Statistical Classi� cation of Diseases and Related Health ProblemsIRLSSG International Restless Legs Syndrome Study GroupLICI long-interval cortical inhibitionMCT motor conduction timeMS millisecondNE norepinephrinePANSS positive and negative syndrome scalePET positron emission tomographyPLM periodic limb movementPLMD periodic limb movement disorderPNS peripheral nerve systemRLS Restless Legs Syndrome

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SAI short latency afferent inhibitionSANS scale for the assessment of negative symptomsSAS Simpson-Angus scaleSICI short-interval intracortical inhibitionSCID structured clinical interview for diagnosisSD standard deviationSPECT single-photon emission computed tomography TA tibialis anterior muscleTD tardive dyskinesiaTMS transcranial magnetic stimulationVAS visual analogue scale

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CONTENTS

LIST OF ORIGINAL PUBLICATIONS ................................................................................... 5

ABBREVIATIONS..................................................................................................................... 7

CONTENTS ................................................................................................................................ 9

ABSTRACT ............................................................................................................................... 13

1. INTRODUCTION .................................................................................................................. 15

2. REVIEW OF THE LITERATURE ...................................................................................... 17

2.1. Schizophrenia ............................................................................................................ 17

2.2. Restless Legs Syndrome ......................................................................................19

2.3. Medication aspects ............................................................................................... 22

2.3.1. Neurotransmitters of clinical relevance in schizophrenia

and RLS ................................................................................................................... 22

2.3.2. Antipsychotic medication: conventional neuroleptics and

atypical neuroleptics .......................................................................................... 22

2.3.3. Pharmacotherapy of RLS ....................................................................... 23

2.4. The human motor control system and its integration to the central

nervous system ............................................................................................................... 23

2.4.1. Motor control .............................................................................................. 23

2.4.2. Visual processing .....................................................................................24

2.4.3. Postural control system .......................................................................... 25

2.5. Transcranial magnetic stimulation .....................................................................26

2.5.1. Introduction ..................................................................................................26

2.5.2. TMS parameters: motor conduction and motor threshold ...........26

2.5.3. TMS measures of inhibition: central silent period .......................... 27

2.5.4. Other TMS methods for measuring inhibition: measures of

paired pulses TMS ................................................................................................28

2.5.5. Transcallosal inhibition ...........................................................................28

2.6. Computerized force platform posturography (CFPP) ...............................29

2.7. Review of the earlier TMS studies .....................................................................30

2.7.1. Schizophrenia ..............................................................................................30

2.7.2. Restless Legs Syndrome ......................................................................... 32

2.7.3. Medication effects of clinical relevance in schizophrenia and

in RLS ...................................................................................................................... 33

2.8. Postural control in schizophrenia and in RLS ............................................... 33

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ABSTRACT

3. THE AIMS OF THE STUDY (I–IV) ................................................................................. 35

3.1. CFPP In schizophrenia (Study I) ......................................................................... 35

3.2. TMS in RLS and schizophrenia (studies II–III) ................................................ 35

3.3. CFPP in RLS (study IV) .........................................................................................36

4. SUBJECTS AND METHODS (STUDIES I–IV) ............................................................. 37

4.1. General aspects regarding subjects (I–IV) ....................................................... 37

4.1.1. Subjects with schizophrenia and controls (study I) .......................... 37

4.1.2. Subjects with RLS and controls (study II) ..........................................39

4.1.3. Subjects with schizophrenia and controls (Study III) ..................... 40

4.1.4. Subjects with RLS and controls (Study IV) .......................................42

4.2. Methods ....................................................................................................................43

4.2.1. TMS studies II and III .................................................................................43

4.2.2. The methods in CFPP studies I and IV ..............................................45

4.2.3 The procedure of the study IV with pramipexole intervention ...47

4.3. Statistical methods ...............................................................................................47

4.3.1. TMS studies II and III .................................................................................47

4.3.2. CFPP studies I and IV ...............................................................................48

4.4. Ethical considerations ...........................................................................................48

5. RESULTS ..............................................................................................................................51

5.1. CFPP and schizophrenia (Study I) .......................................................................51

5.2. TMS AND RLS (STUDY II) ..................................................................................... 52

5.3. TMS and schizophrenia (study III) .....................................................................54

5.4. CFPP and RLS (study IV) .....................................................................................54

6. DISCUSSION ......................................................................................................................59

6.1. General aspects (I–IV) ............................................................................................59

6.2. Material and methodological questions ......................................................... 60

6.2.1. Special questions concerning subjects (studies I–IV) .................... 60

6.2.2. Transcranial magnetic stimulation (Studies II–III) ............................61

6.2.3. Computerized force platform posturography (CFPP) ...................62

6.3. Results of TMS studies II and III .........................................................................62

6.3.1. Special considerations in regard with study III and dopamine

interactions .............................................................................................................63

6.4. Results of the CFPP studies ................................................................................65

6.5. Limitations of the study (I–1V) ...........................................................................66

6.5.1. Study I ...........................................................................................................66

6.5.2. Study II .........................................................................................................66

6.5.3. Study III ........................................................................................................67

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6.5.4. Study IV .......................................................................................................67

6.6. Summary: the aims and the results of the study (I–IV) ..............................67

6.6.1. Study I ...........................................................................................................67

6.6.2. Studies II and III .........................................................................................68

6.6.3. Study IV .......................................................................................................68

7. CONCLUSIONS ..................................................................................................................69

8. FUTURE CONSIDERATIONS ...........................................................................................71

9. ACKNOWLEDGEMENTS ................................................................................................. 73

10. REFERENCES ................................................................................................................... 75

11. ORIGINAL PUBLICATIONS ............................................................................................89

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ABSTRACT

Aims and background: The purpose of this study was to investigate movement disturbances in schizophrenia and Restless Legs Syndrome (RLS). Schizophrenia is associated with impaired cognitive, attentional and perceptive symptoms, but also with motor control abnormalities, such as akathisia. Akathisia resembles cardinal symptoms of RLS, like restlessness in legs. Motor and postural controls are supported by central regulation of dopamine transmission. Dysregulation of dopamine is considered to be one of the background factors in schizophrenia and RLS. Antidopaminergic agents alleviate symptoms in schizophrenia, whereas dopaminergic agents are effective in RLS.

Methods: Transcranial magnetic stimulation (TMS) allows investigation of the functions of central motor pathways and inhibition in the central nervous system (CNS). After a single pulse TMS on the dominant and non-dominant motor cortex areas motor evoked potentials (MEP), motor conduction time (MCT), central conduction time (CMCT) and central silent periods (CSP) were elicited in the respective Abductor digiti minimi (ADM) and Tibialis anterior (TA) muscles. Intramuscular electrodes were applied as a precise recording technique.

Computerized force platform posturography (CFPP) allows investigation of the sensorimotor neural and attentional mechanisms in the CNS needed to maintain postural stability. Center point of pressure forces (CPPF) and the center point of force velocity (CPFV) were measured during the subject`s stance eyes open and eyes closed on a stable computerized platform. Identical TMS and CFPP study procedures were performed in volunteers with schizophrenia on long-term antipsychotic medication and in volunteers with RLS in comparison to healthy controls. The CFPP was repeated in subjects with RLS after a single day intervention with a dopaminergic agent.

Findings: Consistent with earlier TMS research, no signi� cant differences or side-to-side differences in the function of corticospinal motor pathways between or within the study groups were observed. Interestingly, in our study central inhibition was found to be disrupted into multiple separate CSPs. The number of CSPs was signi� cantly higher in the dominant ADM in subjects with schizophrenia and in subjects with RLS compared to the controls. Atypical antipsychotics tended to prolong, while conventional antipsychotics tended to shorten CSP in schizophrenia. The CFPP studies demonstrated that in schizophrenia, closing the eyes had less impact on the CPFV than in controls. Contrary to that � nding, subjects with RLS demonstrated lower sway velocity eyes open compared to controls. Pramipexole intervention balanced the CPFV differences.

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ABSTRACT

Conclusions: Motor inhibitory control was changed in RLS and schizophrenia, appearing as repeated suppression of muscle activity preferably in the dominant ADM. The ability of controlling the upright stance was not impaired per se in schizophrenia or in RLS. However, it was discovered a defect of visual compensation in schizophrenia, and in turn, a hyper compensatory effect of vision on postural control in RLS. Schizophrenia and RLS may share the subcortical CNS origin involved in the pathophysiology of the motor control and related dopamine dysregulation. Conversely, the observed different interaction patterns in handling the visual component during the postural stance refer to different feedback mechanisms in concern of motor and postural control in schizophrenia compared to RLS.

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1. INTRODUCTION

Most medical disorders consist of a continuum with two extreme endings, where most cases can be located somewhere in the middle of the continuum. Minor mental or neurological signs often precede major clinical somatic, neurological or psychiatric symptoms. Even though schizophrenia is included in psychiatric disorders, persons with schizophrenia also exhibit minor neurological signs indicating slight cerebral dysfunction, particularly regarding the motor coordination, sensory integration, developmental re� exes and patterns of lateralization. These “soft neurological signs” often precede the outbreak of illness and may be present in � rst-episode schizophrenia (Dazzan et al., 2002).

Restless Legs Syndrome (RLS) is considered to be a neurological and a sensorimotor disorder, mainly manifesting as forced movements and indescribable sensations in the legs. RLS is also classi� ed as a sleep disorder due to sleep interfering symptoms. RLS is often followed by clinical manifestations of anxiety, depression and unspeci� c inner discomfort. The burden of the somatic symptoms can be considerable but they cannot explain all “soft mental signs” experienced by persons with RLS (Phillips et al., 2000, Hornyak, 2010).

Applicable investigation tools, transcranial magnetic stimulation and computerized force platform, made the primary purpose of this study possible: the closer inspection of the central motor control in these two distinct, but similar kinds of movement disturbances exhibiting disorders. The secondary purpose was to diminish the gap between psychiatry and neurophysiology.

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2. REVIEW OF THE LITERATURE

2.1. Schizophrenia

“Outspread � ngers often show � ne tremor... The expression of the face, vacant, immobile, like a mask, astonished, is sometimes reminiscent of the rigid smile of the Aeginetans... Simple movements are stiff, slow, forced.” (Emil Kraepelin, 1919)

Since the days of Kraepelin and Bleuler it has been known that minor signs of motor abnormalities emerge in a signi� cant proportion of persons suffering from schizophrenia. An early sign of incipient schizophrenia can be a loss of the natural gracefulness of body movements. It is estimated that 10 to 25 percent of persons with schizophrenia have such visible abnormal body movements unrelated to antipsychotic drug treatment. Neuroleptic agents may cause similar phenomena (Grebb and Cancro, 1989).

It is well known that many persons with schizophrenia do not differ from healthy people or persons with other psychiatric disorders in appearance, but sometimes persons with schizophrenia can be recognized without seeing the person’s face, but by paying attention to the gait or � gure of the subject’s walk. The impression is based on a slight abnormality of motor activity typical for schizophrenia. The expression “Praecox Gefühl” was created by a Dutch psychiatrist, Rümke who claimed that the diagnosis of schizophrenia was sometimes made more or less through intuition. The term “praecox feeling” precedes the neuroleptic era. It is an outdated term, but important when efforts are made to understand and describe the clinical core of schizophrenia (Parnas et al., 2011).

Impairment of motor development and � ne motor coordination can predict schizophrenia spectrum disorders in adulthood and may relate to a genetically determined higher risk to develop schizophrenia (Crow et al., 1995). Neurological soft signs are minor “soft” neurological abnormalities in sensory and motor performance that can be detected during clinical examination. Neurological soft signs can be categorized as de� cits in 1) integrative sensory function (possible origin in the parietal lobe dysfunction), 2) de� cits in motor coordination identi� ed by testing general co-ordination, intention tremor, � nger-thumb opposition, balance and gait and 3) de� cits in performing complex motor task (possible origin in frontal-basal ganglia circuitry). Vestibular responses of schizophrenic patients have been studied,

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but without consistent results (Levy et al., 1978). Abnormalities have been reported in eye movements, pursuit and saccadic movements and developmental re� exes (Stevens et al., 1982, Grif� ths et al., 1998, Boks et al., 2000). Abnormal rapid eye movements, saccades, during attempts to follow a moving subject smoothly are seen in approximately 50 to 80 percent of individuals with schizophrenia, in 40 percent of their � rst-degree relatives and eight percent of non-mentally ill persons, which makes these movement abnormalities perhaps the most important physiological marker of schizophrenia. It has been hypothesized that the site of pathology may be the frontal lobe input to the basal ganglia and superior colliculus (Grebb and Cancro 1989, Buchsbaum, 1990). Smooth pursuit velocity gain seems to be impaired early in the course of schizophrenia and may be worsened by long-term (years) treatment with antipsychotics. Other indices of smooth pursuit, catch-up saccades and ability to predict target movement are adversely in� uenced by illness chronicity rather than medication (Hutton et al., 2001).

Several studies have demonstrated a lateralized impairment of attention in schizophrenia. The most essential � nding is a subclinical right hemineglect which has been demonstrated in several studies with blindfolded patients (Harvey et al., 1993), however, a major confounding factor is the possibility that neuroleptic medication may reverse either normal or deviant asymmetry (Early et al., 1989). A lateralized reaction time abnormality with a longer reaction time to targets in the right visual � eld as opposed to the left visual � eld was observed among drug-free but not among drug-treated schizophrenics (Wigal et al., 1997). Furthermore, lateralization may be affected either by eye closure, state of vigilance or both (Lauerma et al., 1994). Lateralized sensorimotor deviances associated with schizotypal features and levodopa have been replicated in some studies (Mohr et al., 2005).

The mechanical structure of the human skeleton is unstable. To maintain balance, continuous postural corrections must be made with muscle activity. Corrections are based on the information from several sensory systems and require motor coordination. Abnormalities in the postural control system such as degradation or defectiveness of a sensory system or reduced capability to make decisions, have unstabilizing effects on posture. Reduction of motor coordination has similar effects given that the optimal timing, strength or duration of muscle correction is lost, greater correction is needed to maintain postural stability (Koles and Castelain, 1980).

According to traditional psychiatric conception, schizophrenic symptoms mainly consist of changes and disturbances in perception, thinking and mood, which promote to secondary changes in social behaviour and relationships. Although most patients suffer from serious motor disturbances, the symptoms have frequently been contributed to side effects of psychiatric medications affecting the motor control mechanisms in the extrapyramidal system of the brain. However, some

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clinical studies demonstrate the opposite and additionally neuroprotective effect of antipsychotics have been discussed (Grif� ths et al., 1998, Madsen et al., 1999). It has been reported that about 36–53% of non-medicated persons with schizophrenia have motor symptoms (Owens et al., 1982, Woerner et al., 1992, Caligiuri et al., 1993). Schizophrenia related abnormal motor function, disturbances in coordination, involuntary movements and impaired � ne motor skills are not completely related to antipsychotic medication. Motor disturbances or dyskinesias consist of varying degrees of rigidity, bradykinesia, tremor, akathisia and catatonic signs, detected in approximately 80% of schizophrenic patients (Yager, 2000).

Neuroleptic induced akathisia (NIA), a side effect of dopamine antagonists, is clinically one of the most relevant movement disturbances to be compared to the symptoms of RLS (Walters et al., 1991). Individuals suffering from NIA can sense subjective muscular discomfort that makes one feel agitated, impatient and restless. In most serious stages of NIA one may alternately sit and stand in rapid tact, move constantly one´s legs or go around without being able to stand or sit still. These symptoms are primary motor and involuntary. Their underlying mechanism is not completely understood, but imbalance between noradrenergic and dopaminergic system is discussed (Kaplan & Saddock, 1998).

Various brain structure related abnormal � ndings, such as reduced number of GABA-interneurons and reduced gene-expression for GABA-synthesis in the prefrontal cortex (Benes et al., 1991, 1999, Akbarian et al., 1995), elevated striatal and changed caudal dopamine synthesis and release (Hirvonen et al., 2008, Fusar-Poli et al., 2013) favour the concept that schizophrenia is not “just a mental disease”, but rather a brain disease, whereby mental and motor symptoms are signs of complex interneuronal conduction disturbances and dysregulation of neurotransmitters in the central nervous system (Hirvonen et al., 2005, Marsman et al., 2013). Current drug treatments, which primarily act at D (2/3) receptors, fail to target all currently known schizophrenia related abnormalities. For these reasons, future drug development should focus on the control of presynaptic dopamine synthesis and release capacity (Howes et al., 2012).

2.2. Restless Legs Syndrome

Idiopathic Restless Legs Syndrome (RLS) is a common sensorimotor and sleep-related disorder and a growing � eld of clinical research interest. The International Restless Syndrome Study Group has proposed four minimal clinical diagnostic criteria (Walters et al., 1995), later revised (Allen et al., 2003). They include: 1) An urge to move the legs accompanied by or because of experienced unpleasant sensations in the legs or sometimes in the arms. 2) The symptoms get typically worse

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at rest or during inactivity. 3) In order to partially or totally relieve the symptoms one has to move the legs, body or arms including but not limited to stretching or walking until the unpleasant sensations cease. 4) The symptoms get worse at night rather than daytime or only occur in the evening or at night.

Clinicians may misdiagnose or dismiss this treatable and sometimes serious disorder or associate it anxiety or depression related. Sometimes there are depressive manifestations. Patients may seek the doctor due to inability to sleep. The prevalence of idiopathic RLS has been estimated to be around 1–15% in general population (Chokroverty et al., 1999, Allen et al., 2003). Nonetheless, the prevalence is thought to be approximately 2–8% higher, when factoring in the severity and frequency of the symptoms (Ohayon et al., 2012).

RLS shares many features with neuroleptic-induced akathisia (NIA) although there is no evidence supporting association between antipsychotics -induced restless legs symptoms and polymorphisms of dopamine (D1, D2, D3 and D4) receptor genes in schizophrenia (Kang et al., 2008). In a polysomnographic study sleep disturbances were milder in NIA than idiopathic RLS. The latter was characterized by more violent leg movements (Becker, 1993). A positive response to dopaminergic therapy is a common feature of RLS (Montplaisir et al., 1999, Tuisku et al., 2002, Schapira et al., 2006, IV). About 80% of RLS sufferers have periodic leg movements during sleep, which can interrupt sleep and result in daytime drowsiness. Five major diagnostic features of augmentation are identi� ed for RLS patients: usual time of RLS symptom onset each day, number of body parts with RLS symptoms, latency to symptoms at rest, severity of the symptoms as they occur and effects of dopaminergic medication on symptoms (Garcia-Borreguero et al., 2007, IRLSSG).

RLS can occur as a primary disorder or as a secondary condition. Two subtypes of RLS have been identi� ed based on age at onset of symptoms. Individuals, who experience symptoms of RLS before age of 45 years, are more likely to have a family history of RLS and a possible genetic predisposition. The progression of this subtype disorder is slower, compared to those RLS patients with later onset of symptoms. The secondary RLS phenotype is mostly linked to iron de� ciency, pregnancy or end-stage renal disease (Schapira et al., 2006, Allen et al., 2007). Antidepressants such as miancerin and mirtazapine (5-HT2 blockade) may provide protection against acute akathisia but stimulate restless legs symptoms (Markkula et al., 1997, 1998).

The pathophysiology of RLS is still unknown, but dopaminergic de� ciency and genetic causes have been proposed. Lack of movement-related potentials in myoclonus during the daytime in RLS was considered to be compatible with an involuntary mechanism of induction and points towards a subcortical or spinal origin of RLS (Trenkwalder et al., 1993). Opioids may also provide a marked relief on symptoms of RLS. A question of placebo responds of medication has been raised regarding RLS and pharmacotherapy in general (Fulda et al., 2008). In functional

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and magnetic resonance imaging studies morphologic changes have been found in the somatosensory cortex, motor cortex and thalamic gray matter and low iron concentration in substantia nigra, especially in the early-onset RLS (Wetter et al., 2004, Earley et al., 2006). Changes in the brain iron metabolism are probably connected to changes in central regulation of dopamine transmission (Allen et al., 2007).

Dopaminergic hypoactivity, increased availability of D(2)–receptors, involvement of D(3)- receptors and dysregulation of spinal dopamine are also strongly suggested (Cervenka et al., 2006, Clemens et al., 2006). A gait analysis study revealed subclinical abnormal electromyographic activation of the gastrocnemius muscles in subjects with RLS, referring to impaired dopaminergic control of supraspinal, but also spinal structures in the CNS, affecting the spinal control of gait (Paci et al., 2009).

In familial cases a gene at chromosomal location 9p-24-22 is linked to RLS and the expressed mutation is dopamine receptor speci� c individual sensitivity (DRSIS). The symptoms are triggered during changes in alertness, at sleep hours, resulting in insuf� cient dopamine transmission. The sensated sensorimotor experiences are characterized as typical urge to move the limbs with or without paresthesias. This phenomenon leads to motor signs such as periodic limb movements and motor restlessness and can temporary be presented as loss of extensor motor system dominance over the � exor motor system of the upright position. In Uner Tan syndrome, the nonsense mutation in the same gene leads to underdevelopment of the neural substrates of upright posture. The defects inclusive dopamine receptor de� ciency result clinically in severe cognitive dysfunctions, complete loss of extensor dominance in extremities, abrupt speech, cerebellar symptoms, and strabismus. Both RLS and Uner tan Syndrome seem to be linked to different mutations in the same dopaminergic receptor gene, that affects the diencephalons dopaminergic system and the neural networks involved in upright position (Akpinar et al., 2009).

Despite the wide-spread interest of research towards RLS, the pathophysiology is still unclear and no speci� c lesions have been identi� ed for RLS. Low iron concentration in the central nervous system together with the factors described in hypodopamine theory are considered to be crucial etiological issues involved in the pathophysiology of RLS (Allen et al., 2007, Miyamoto et al., 2009).

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2.3. Medication aspects

2.3.1. NEUROTRANSMITTERS OF CLINICAL RELEVANCE IN SCHIZOPHRENIA AND RLS

Some neurotransmitters have excitatory effects, while others have inhibitory effects. However, it is the receptor type that modi� es the � nal effect of the neurotransmitter. Acetylcholine (Ach) is released at all neuromuscular junctions involving skeletal muscle � bers, at many synapses in the CNS, at all neuron to neuron synapses in the peripheral nerve system (PNS) and at all neuromuscular and neuroglandular junctions within the parasympathetic division of CNS.

Norepinephrine (NE) is widely distributed in the brain and in the parts of CNS. It has typically an excitatory effect. Dopamine is released in many areas of the brain and has either excitatory or inhibitory effects, which play an important role in precise control of movements. If the neurons that produce dopamine are damaged, it may result a Parkinsonism like state, with stiffness and rigidity of the muscles. Serotonin is an important CNS neurotransmitter for attention and emotional regulation, even for mood regulation. Gamma-aminobutyric acid (GABA) has generally an inhibitory effect, but its function is not completely understood. In the CNS GABA appears to reduce anxiety (Martini, 2007). Dysregulation of dopamine interactions and interactions between GABAergic and dopaminergic neurotransmitter systems may play an important role in producing diverse symptoms of schizophrenia (Stahl, 2010).

2.3.2. ANTIPSYCHOTIC MEDICATION: CONVENTIONAL NEUROLEPTICS AND ATYPICAL NEUROLEPTICS

There are four main dopamine pathways relevant to antipsychotics pharmacology. The mesolimbic to cortical tract projection (mesolimbic and mesocortical pathways) is hypothesized to be responsible for the antipsychotic effects and the substantia nigra to striatum projection (nigrostriatal pathway) for the Parkinsonisms side effects. Tuberoinfundibular pathway transmits dopamine from the hypothalamus to the pituitary gland. Dopamine release in the tuberoinfundibular pathway inhibits prolactin release (Stahl, 2010).

Antipsychotics can be divided into two main categories: conventional antipsychotics and atypical antipsychotics. The potency of dopamine receptor antagonists (for example chlorpromazine, haloperidol, sulpiride) correlates with their af� nity with dopamine 2 receptors. They prevent endogenous dopamine from activating the receptors.

Atypical antipsychotics of clozapine-type are effective especially through serotonin-dopamine antagonism. Clozapine is chemically related to serotonin-

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dopamine antagonists, olanzapine and quetiapine. Clozapine has a high potency of binding dopamine type 1, type 3, type 4 and serotonin type 2 (5HT-2) and noradrenergic alpha (1) receptors. It also has antagonist activity at muscarinic and histamine type (1) receptors. Clozapine is indicated in treatment –resistant schizophrenia and in prevention of tardive dyskinesias. Zotepine has a chemical structure similar to clozapine. Zotepine acts by blocking both dopamine 1 and 2 receptors and blocks four serotonin subtype receptors and histamine H 1 –receptor. It is a potent inhibitor of noradrenaline reuptake (Fleischhacker et al., 1997, Stahl, 2010).

2.3.3. PHARMACOTHERAPY OF RLS

Symptoms of RLS have been treated by dopaminergic agents, benzodiazepines, anticonvulsants and opiates, but dopamine agonists are considered � rst-line therapy (Kushida et al., 2006, Trenkwalder et al., 2009). For primary RLS ropinirole and pergolide may be the most effective dopamine agonists to relieve paraesthesia and motor restlessness. Gabergoline and levodopa are also effective, as well as antiepileptic drugs like gabapentin (Vignatelli et al., 2006). Also other dopamine agonists like pramipexole is considered to be effective. Pramipexole is well tolerated and has a high selectivity for DA 2 and DA 3 -receptors. A single oral dose of 0.125-0.750 mg alleviates in most cases sensorimotor RLS symptoms in the legs (Tuisku et al., 2002, Montplaisir et al., 2006, McCormack et al., 2007, Trenkwalder et al., 2007, Garcia-Borreguero et al., 2012).

However, many people with restless legs syndrome � nd that medications that work initially become less effective over time. Clinicians and persons with RLS have recognized that there is no single medication that works for every person with RLS and that a drug that relieves one person’s restless legs may actually make symptoms in another person worse. All these facts, inclusing the broad spectrum of pharmacological agents used to alleviate RLS symptoms, are confounding factors. A placebo effect and a possibility of psychogenic features cannot be ruled out.

2.4. The human motor control system and its integration to the central nervous system

2.4.1. MOTOR CONTROL

The CNS consists of the brain and spinal cord. The posterior gray horns of the spinal cord contain somatic and visceral sensory nuclei. The anterior grey horn nuclei contain somatic motor neurons. The white matter in the spinal cord can be divided into six columns, each of which contains tracts. Ascending tracts relay information

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from the spinal cord to the brain and descending tracts carry information from the brain to the spinal cord. The peripheral nervous system (PNS) forms the nerve tissue that takes care of the rest of the human body. The sensory neurons deliver information to the CNS and motor neurons distribute commands to peripheral effectors. Interneurons interpret information and coordinate responses.

Re� exes are automatic responses to stimuli coming from inside or outside of the body. Spinal re� exes can be monosynaptic, polysynaptic or intersegmental. A monosynaptic re� ex, like the stretch re� ex, automatically regulates skeletal muscle length and muscle tone, involving as sensory receptors muscle spindles. The postural re� ex maintains one`s normal upright position. Polysynaptic re� exes can provide more complicated responses than monosynaptic re� exes and involve pools of interneurons. Their anatomical distribution may contain several segmental levels and involve reciprocal inhibition, too. They also have reverberating circuits, which prolong the re� exive motor response. When several re� exes co-operate, a coordinated response can be produced.

The brain can facilitate or inhibit re� ex motor patterns based in the spinal cord. Spinal re� exes produce consistent stereotyped motor patterns that are triggered by speci� c external stimuli, but they can also as needed be activated by certain brain centers. Relatively few descending pathways can control complex motor functions. Motor control involves a series of interacting levels, of which the monosynaptic re� exes form the lowest and highest levels consist of the brain areas that modulate and build on re� exive motor patterns (Martini, 2006).

2.4.2. VISUAL PROCESSING

Vision is one of the most important special sense that humans own. The visual pathway begins at the photoreceptors and ends at the visual cortex of cerebral hemispheres. The perception of a visual image re� ects the integration of information arriving at the visual cortex of the occipital lobes. Many centers of the brain stem receive visual information from the lateral geniculate nuclei or through the collaterals from the optic tract. Motor commands issued by superior colliculi of mecencephalon control unconscious eye, head or neck movements in response to visual stimuli. Visual information will be established also to control and regulate the circadian rhythm and daily pattern of visceral functions. Beside the detection of light and dark, motion perception is one of the most important capabilities of the visual system (Berne and Levy, 2000).

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2.4.3. POSTURAL CONTROL SYSTEM

Various re� exes assist in postural adjustments that occur as the head is moved or the neck is bent. These re� exes are triggered by the receptors including the vestibular apparatus and stretch receptors in the neck. Also the visual system contributes to postural control.

The vestibulocochlear re� ex occurs, when the head is turned to one side, so the eyes will be automatically rotated to the opposite site and both eyes are directed to the same direction through the same angle as head (conjugation). The alternating slow and fast eye movements are called nystagmus, which take place when the eyes respond to head movements and keep on tracking the object. A similar response pattern affects the neck muscles, called vestibulocollic re� ex. Simultaneously contractions of extensor (antigravity) muscles increase and prevent the body to fall to the stimulus side. The neural mechanisms behind these re� exes lie in the semicircular ducts and the stimulation of their receptors.

Other postural re� exes depending on the vestibular apparatus tend to keep the body position normal without bending the neck. Tonic neck re� exes are triggered, if the neck is bent. Then the body position is kept by postural correction opposite to those evoked by vestibular stimulation. Righting re� exes tend to restore the position of head and body in space to normal, involving vestibular apparatus, neck stretch receptors and mechanoreceptors in the body wall.

Movements in the eyes are generally conjugate. A rapid conjugate movement of the eyes is called a saccade. Once the eyes have targeted a visual object, � xation is maintained by smooth pursuit movements. These do not take place in the dark, because they require a visual target. Without these microsaccades the retina would lose sight of the target and adapt.

Horizontal eye movements are organized by the horizontal gaze center, located near the abducens nucleus in the pons. There is also a vertical gaze center in the midbrain area. Connections to the motor nuclei are made to inhibit the antagonistic muscles of eyes. The frontal eye � elds in the premotor region of the frontal lobe trigger voluntary saccadic eye movements. The occipital eye � elds are involved in smooth pursuit movements, optokinetic nystagmus and visual � xation and in� uence the vertical and horizontal gaze centers. A lesion in the posterior parietal cortex causes de� cit in visual guided movements. Humans may develop a neglect syndrome, where one is unable to recognize objects placed in the contralateral hand and unable to draw three-dimensioned objects accurately. One can even believe that the contralateral limbs even do not belong to him (Berne and Levy, 2000).

Mechanoreceptors are sensitive to stimuli that distort their cell membranes. Tactile receptors provide sensations of touch, pressure and vibration. The sensitiveness to tactile sensations may be altered by infections, diseases, or by damaged sensory neurons or pathways. Proprioceptors monitor the positions of

26


joints (receptors in joint capsules), the tension in tendons and ligaments (Golgi tendon organs) and the state of muscle contraction (muscle spindles).

The cerebellum coordinates rapid, automatic adjustments that maintain balance and equilibrium. The corrections in muscle tone and position are made by modifying the activities of motor centers in the brain stem. The cerebellum registers and compares the motor commands with proprioceptive information performs the needed adjustments to make the movement smooth. (Martini, 2006)

2.5. Transcranial magnetic stimulation

2.5.1. INTRODUCTION

The examination of the descending motor pathways from motor cortex has become more easily available after the introduction of transcranial magnetic stimulation (TMS) (Barker et al., 1985). The device for TMS, the magnetic stimulator, consists of a high voltage capacitor and a coil. The capacitor is charged to a high voltage state, which it is rapidly discharged through the coil. The respective current � owing through the coil generates the desired magnetic � eld. A time-varying � ux density of the magnetic � eld induces an electrical � eld in any conductive volume through which it passes. Neural tissue, such as cortex of the brain is easily elicitable by TMS. Activation of motor cortex can be measured as different types of motor responses in the desired muscles (Barker et al., 1985, 1986, 1991).

Motor cortical excitability can be explored by several measures with the help of TMS, like axon excitability and inhibitory and excitatory synaptic excitability. Cortical inhibition can be measured as short-interval intracortical inhibition (SICI), cortical silent period (CSP) and long-interval intracortical inhibition (LICI) and short latency afferent inhibition (SAI). TMS or repeated TMS themselves can also cause modulation on neurotransmitters or neuromodulators. TMS measures can be used to study drug-effects at the system levels of cerebral cortex. The following cited acute drug effects on the TMS measures can differ from the chronic drug effects.

2.5.2. TMS PARAMETERS: MOTOR CONDUCTION AND MOTOR THRESHOLD

The threshold for inducing motor evoked potentials is called motor threshold (MT). Motor threshold is a basic measure of excitability within the corticospinal system, showing rather stable values, but minor hemispheric differences within individuals (Cicinelli et al., 1997). It is de� ned as the minimum intensity that is necessary to elicit a small motor evoked potential (MEP) at rest (RMT; resting motor threshold) or during a muscle contraction (AMT; active motor threshold) in the target muscle

27

in at least half of the trials. A decrease in MT refers to increased neuronal excitability and the increase of MT indicates decreased neuronal excitability. Motor threshold is lower in the voluntarily contracting muscle than in the resting muscle. Acute intake of drugs relevant in this study and having a main mode of action with neurotransmitters GABA (A,B), dopamine (DA agonists, antagonist), norepinehrine (NE), serotonin or acetylcholine (Ach) do not signi� cantly affect the motor threshold. (Di Lazzaro et al., 2000, Ziemann et al., 2004).

Motor evoked potential amplitude is a measure of distribution of the excitability in the corticospinal system. Amplitude increases with stimulus intensity in a sigmoidal fashion. The MEP size re� ects the number of activated motor neurons by a TMS pulse. A MEP amplitude may be affected by neurotransmitters glutamate GABA and modulators of neurotransmission like DA, NE, 5-HT and Ach. Drugs relevant to this study, like lorazepam (modulating GABA A) and cabergoline (dopamine agonist) may reduce the MEP amplitude, whereas haloperidol (DA antagonist) may increase it.

Motor conduction time (MCT), sometimes described as MEP latency, is the time taken between activation of pyramidal neurons in the cortex by a TMS pulse and time taken for contraction of the target muscle (Ziemann et al., 2004, Edwards et al., 2008). Central motor conduction time (CMCT) can be calculated by subtracting from the MCT the time taken from the stimulation of the exit zone in the spinal root to the beginning of the contraction in the peripheral target muscle (Edwards et al., 2008).

2.5.3. TMS MEASURES OF INHIBITION: CENTRAL SILENT PERIOD

Central silent period (CSP) re� ects the interruption of voluntary activity in the electromyography (EMG) of the target muscle induced by TMS. CSP duration increases almost linearly with stimulus intensity and may raise to 200–300ms in hand muscles. The early part of CSP is assumed to originate in the spinal cord and the later part in supraspinal structures, probably in the motor cortex (Inghilleri et al., 1993, Ziemann et al., 1996). The whole CSP is claimed to be of cortical origin and generated in the primary motor cortex (Roick et al., 1993, Schnitzler et al., 1994). CSPs are well repeatable within individual measurements and occurrence is normally symmetric (Roick et al., 1993). The CSP is probably controlled by complex extrapyramidal systems having numerous interneuronal synapses associated with (GABA-B ergic) inhibitory circuits onto the pyramidal cells (Capaday et al., 2000, Siebner et al., 2000, Trompetto et al., 2001, Edwards et al., 2008). Drugs relevant to this study, like lorazepam, L-DOPA (dopamine precursor) and DA agonists may lengthen CSP (Priori et al., 1994, Zieman et al., 2004).

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2.5.4. OTHER TMS METHODS FOR MEASURING INHIBITION: MEASURES OF PAIRED PULSES TMS

This method will be elicited by stimulating the motor cortex by two successive TMS pulses: � rst a conditioning pulse followed by a test pulse, which has to be delivered within a short interstimulus interval through the same stimulator coil. If the motor response to the test pulse is decreased, this re� ects inhibition, if it is increased this indicates facilitation, however depending on the time interval between the stimuli.

SICI can be measured by using a preconditioning (sub-threshold) pulse followed after a short interstimulus interval (2–5 ms) by a supra-threshold second pulse. It is assumed that the � rst pulse produces an inhibitory post-synaptic potential at the corticospinal neurones, through activation of a low-threshold cortical inhibitory circuit. This inhibits generation of action potential by excitatory post-synaptic potentials (EPSPs) elicited by the supra-threshold second pulse. Benzodiazepines, like lorazepam and diazepam, GABA-A agonists and DA agonists seem to enhance SICI (Inghillieri et al., 1996, Daskalakis et al., 2003, Ziemann et al., 2004).

Intracortical facilitation (ICF) is tested in the same way as SICI, but by using longer inter-stimulus intervals of 7–20 ms. In short-interval intracortical facilitation tests follow also the same protocol, but the � rst pulse is supra-threshold and the second subthreshold or both pulses are about the threshold intensity. Benzodiazepines, other GABA A and DA agonists seem to reduce ICF, whereas DA antagonists (haloperidol, olanzapine) increase it (Inghillieri et al., 1996, Daskalakis et al., 2003, Ziemann et al., 2004)

Duration and magnitude of LICI that seems to re� ect a long-lasting inhibition depend on the intensity of supra-threshold pulses. LICI differs from SICI, but it is moreover similar to CSP. LICI is assumed to be mediated via GABA-B receptors. Benzodiazepines and GABA A agonists seem to reduce LICI (Inghillieri et al., 1996, Ziemann et al., 2004).

SAI is de� ned to be an inhibition or reduction of MEP. SAI is produced by applying a conditioning afferent pulse to the median nerve at the wrist about 20 ms prior to TMS of the contralateral motor cortex, relevant to hand muscles. SAI is reduced by Ach-antagonist (scopolamine) and thus distinct from SICI (Di Lazzaro et al., 2000).

2.5.5. TRANSCALLOSAL INHIBITION

Transcallosal inhibition can be measured as transcallosal conduction time, meaning the conduction time from ipsilateral to contralateral motor cortex through the corpus callosum. Transcallosal inhibition can be investigated with single pulse and paired pulse techniques (Ziemann et al., 2004, Berardelli et al., 2008, Edwards

29

et al., 2008). Conventional and typical antipsychotics may have different effects on the inhibitory systems. Olanzapine has been observed to enhance the transcallosal inhibition and increase the duration correlating with the dose compared to persons with schizophrenia on risperidon and to controls (Fitzgerald et al., 2002).

2.6. Computerized force platform posturography (CFPP)

Postural stability can be measured with force platform posturographic technique that reveals more information on the muscular efforts needed to maintain the balance than other traditional methods, like visual observation of the body sway. Many diseases may affect the complicated multisensory postural control system. If one´s human sensory system fails, another structure will try to compensate it. Control reduction of one sensory system will cause changes in postural control forces. Postural control is age-dependent. Middle-aged persons manage to control their postural stability better than children and elderly subjects. The importance of visual information grows with growing age of elderly people (Hytönen et al., 1993). Persons with training background, like shooters, can control their postural stability better than not trained persons.

The force platform used in our studies was borrowed from Heikki Aalto (Master of Science in engineering), who constructed and built the combination of a computerized tape-machine and the force platform and based his academic dissertation on this methodical aspects and practical applications (Aalto, 1997). The model originates to the platform, introduced 1974 by Terekhov (Terekhov, 1974). It measures force differences between sides in the vertical direction. Force sensing elements are located in each four corner between two rectangular steel plates. The analog signal captured by the load cells, was converted to a digital one.

The standing subject applies his mass and gravity forces on the platform surface with his feet. Practically, center of foot pressure or center point of force (CPF) is calculated to omit the weight of the subjects from the measured forces at the moment. The CPF is an imaginary point, where all the forces applied on the platform are thought to concentrate. As direction-dependent parameters can be calculated the average position of CPF, the movement of the CPF in forward-backward or right –left directions. The length of the trace of the CPF is the most commonly used direction-independent parameter. The path length divided by the duration of test gives the average CPF velocity (CPFV, m/s). The acceleration of the CPF can also be used. The subjects can be exposed to different disturbing stimuli to test the neural machinery involved in the postural control, including visual � eld, muscle stimulation with local vibration, support surface vibration or low-frequency sound, to get further distinguished information of the sensorial conditions.

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The force platform posturography provides an accurate and objective method of measuring postural stability with reliable applications in vestibular research and in clinical use (Aalto H, 1997). The measurements are easily repeatable, but the method is non-speci� c meaning that no diagnoses can be based only on the results obtained with the help of this method (Di Fabio et al., 1996, Kingma et al., 2011)

2.7. Review of the earlier TMS studies

2.7.1. SCHIZOPHRENIA

Over the last two decades the interest in investigating schizophrenia by TMS has been wide. The very � rst TMS investigation of motor function in schizophrenia (Puri et al., 1996) showed, that in non-medicated schizophrenic patients the MEP latency following TMS was signi� cantly shorter than in healthy subjects, but no signi� cant differences were obtained in the mean latency of suppression of EMG activity (CSP) or in the stimulus thresholds for MEPs or CSPs between schizophrenia and control groups. Behind these original � ndings it was proposed to be a relative lack of corticospinal inhibition of motor responses, a direct activation of corticospinal neurons or an abnormal function of peripheral nerve or neuromuscular junction in schizophrenia.

Healthy individuals demonstrate differences between dominant and non-dominant hemispheric sides, seen as shortened silent period in the dominant hand. Healthy right-handed people generally show a lower motor threshold in their dominant left hemisphere, eventually because of more frequent use of their right hand (Priori et al., 1999). In general, handedness is associated with a complex asymmetry in cortical motor representation (Kawashima et al., 1997, Cracco et al., 1999, Solodkin et al., 2001).

Investigation results concerning brain asymmetry and MT in schizophrenia have shown a lot variation. MT has been found lower over left hemisphere in medicated individuals with schizophrenia (Abarbanel et al.,1998, Daskalakis et al., 2002), higher in medicated individuals and lower (for non-dominant compared to dominant hemisphere) in unmedicated individuals with schizophrenia (Pascual-Leone et al., 2002, Fitzgerald et al. 2002b). Deviations from the normal asymmetry in human brain and corticospinal excitability may re� ect a higher risk of developing a schizophrenic disorder or refer to a higher severity of general psychopathological symptoms (Tiihonen et al., 1999).

However, several other TMS studies have not shown signi� cant differences in the motor threshold, in the amplitude or in the latency of MEPs in non-medicated individuals with schizophrenia compared to individuals with schizophrenia on conventional /atypical antipsychotics and to healthy controls (Abarnel et al., 1996,

31

Boroojerdi et al., 1999, Davey et al., 1997, Pascual-Leone et al., 2002). Some single pulse TMS studies have demonstrated that the CSP duration was indifferent or signi� cantly shorter in medicated subjects with schizophrenia than in healthy controls (Fitzgerald et al., 2002 a, b, Daskalakis et al., 2002). Davey et al., 1997 found that in subjects with schizophrenia on conventional antipsychotic medication, the CSP was divided into an early part with a weak suppression of voluntary EMG and a later component with a strong suppression of voluntary EMG, whereas the latency of CSP was indifferent.

In some paired pulse studies the � ndings indicated a disrupted cortical inhibition in persons with schizophrenia on conventional antipsychotics and in healthy persons after intake of haloperidol (Pascual-Leone et al., 2002, Ziemann et al., 1997). The observed delay of the maximum suppression of the muscle contraction was supposed to be caused by antipsychotic medication that may disrupt the basal ganglia inputs to the inhibitory circuits in the motor cortex. Similar deformed CSPs have also been seen in persons with Parkinson`s disease (Ridding et al. 1995). CSPs tend to increase with increasing stimulation intensities in persons with schizophrenia on antipsychotic medical treatment (Wobrock et al., 2009, Soubasi et al., 2010).

Most of the transcallosal inhibition studies with single pulse TMS technique have suggested a longer silent period duration in schizophrenia than in controls. Stimuli seem to be transferred normally from one brain hemisphere to another, but contralateral inhibitory mechanisms may be activated by the transcallosal stimuli, appearing as lengthening of CSP in the contralateral target muscles in persons with schizophrenia (Boroojerdi et al., 1999, Fitzgerald et al. 2002a, Hoppner et al., 2001).

Paired pulse TMS studies have shown rather varying results concerning schizophrenia. Shorter CSP duration and reduced SICI have been observed in drug-free persons compared to medicated persons and shorter CSP in medicated persons compared to healthy controls (Daskalakis et al. 2002). Reduced SICI has come out in subjects with � rst-episode schizophrenia with limited history of medication (Wobrock et al., 2008) and in medicated subjects with schizophrenia in comparison to controls (Pascual-Leone et al., 2002, Fitzgerald et al., 2002b). A group of drug-naïve subjects with schizophrenia had a signi� cantly lower resting motor threshold to TMS as compared with healthy controls whereas SICI and ICF failed to show signi� cant differences between the groups (Eichhammer et al., 2004). In general, ICF seemed to show rather inconsistent results in the cited studies. A reduced SICI has been linked to increased MT and to high symptom severity of schizophrenia. A reduced SICI has also been found in other neuropsychiatric disorders (Wobrock et al., 2008, 2009).

It can be concluded that drug-free persons with schizophrenia seem to show reduced CSP, but in medicated persons with schizophrenia the CSP duration and SICI show a lot of variation depending on the current type of antipsychotic medical

32


treatment and the applicated stimulation intensity. Results concerning motor threshold, motor conduction time, MEP size and ICF are rather consistent. The obvious differences in the results between various cited studies may re� ect different methodologies applied in the studies.

2.7.2. RESTLESS LEGS SYNDROME

In general, earlier TMS studies have shown that descending corticospinal motor pathways function correctly in RLS compared to healthy controls. But there are several studies showing inconsistent results concerning central inhibitory control, especially central silent period (CSP) and intracortical inhibition (ICI). In one of the earliest studies, cortical silent period was found reduced in hand and foot target muscles (Entezari-Taher et al., 1999).

In another study ICI was found decreased in muscles of upper and lower limbs, whereas intracortical facilitation (ICF) was decreased in the lower limb muscles referring to changes in the corticocortical motor excitability in RLS (Tergau et al., 1999). Another study demonstrated no signi� cant differences in CSP (in ADM, TA both sides) in between subjects with RLS and controls, but reduced ICI and increased ICF were obtained in both ADM and TA muscles. These changes were correlating to the body side affected more by sensory-motor symptoms of RLS, involving especially arms (Quattrale et al., 2003). A month´s treatment with a dopamine agonist did not affect CSP duration in hand muscles (Abductor Pollicis Brevis) but it signi� cantly increased CSP in foot (TA) muscles (Kutucku et al., 2006).

In another study with a same kind of study protocol, the results showed that after single pulse TMS no speci� c CSP (pre- and post-treatment) changes were obtained, but after paired pulse TMS SICI was signi� cantly increased after 4week´s medication intervention with pramipexole (Scalise et al., 2006, 2010). One study reported a preliminary shorter CSP duration, resulting within 14 days intervention with cabergoline in an increase of CSP duration and ending in 90 days´ treatment with a decrease of CSP duration, which, however, was still longer compared to controls. The symptom severity of RLS did not correlate with the changes of CSP, because the RLS symptoms continued improving even after the CSP duration had diminished (Gorsler et al., 2007).

Some other paired pulse studies have also demonstrated that cortical hyperexcitability in RLS can be reversed by dopaminergic agents (cabergoline, pramipexole) (Nardone et al., 2006, Rizzo et al., 2010). In addition to SICI, SAI was observed to be reduced in drug-free subjects with RLS and to be restored by dopaminergic medication. The reduction of SAI was considered to be a possible contributer in releasing involuntary movements, like typical sensorimotor symptoms of RLS (Rizzo et al., 2010).

33

In one study, in which TMS measurements were performed besides at daytime also at night-time, active MT tended to increase in healthy controls, whereas it and the CSP tended to decrease in drug-naive RLS subjects, without any other signi� cant differences in other TMS parameters between the groups. Thus, active MT and CSP may show circadian variation in RLS, indicating normal corticospinal axonal functioning, but possible loss of subcortical inhibition at night time (Gunduz et al., 2012).

Conclusive, earlier TMS studies have not demonstrated signi� cant differences in MT, MEP latency, MEP amplitude, MCT or CMCT in RLS compared to healthy controls, neither signi� cant side-to-side differences. CSP � ndings have varied, but for the most CSP and ICI have been found reduced in persons with RLS compared to controls. Dopaminergic agents seem to lengthen or normalize the observed inhibitory de� cits temporarily, however without loss of improvement in RLS symptoms. The clinical symptoms of RLS do not seem to correlate with any observable changes in CSP.

2.7.3. MEDICATION EFFECTS OF CLINICAL RELEVANCE IN SCHIZOPHRENIA AND IN RLS

Central dopamine dysfunction plays an important role in schizophrenia and RLS. Dopamine-blocking agents are effective in schizophrenia, whereas dopaminergic agents are the drugs of choice in RLS. Dopaminergic drugs (bromocriptine, pergolide) and monoamines (serotonin, noradrenaline) may modulate cortical excitability in healthy persons (Nikulin et al., 2003, Kähkonen et al., 2004). GABAergic agents, like lorazepam, do not affect the motor threshold, but obviously increase intracortical facilitation. Intravenous given diazepam and lorazepam probably affect differently the central inhibition (Di Lazzaro, 2005). Atypical antipsychotics, especially clozapine, seem to lengthen central inhibition in persons with schizophrenia, probably due to interference with GABA B –interneurons, serotonin (5HTC2) and D2 receptors (Daskalakis et al., 2008).

2.8. Postural control in schizophrenia and in RLS

There are only few studies about postural stability in schizophrenia. In a gravimeter study schizophrenic patients with high SANS (Scale for the Assessment of Negative Symptoms of Schizophrenia) scores, presented a larger gravimetric area than the normal subjects and the patients with schizo-affective disorder (Nakai et al., 1992). In another study subjects with schizophrenia demonstrated more postural sway than

34


did the healthy controls. There were no signi� cant correlations between neuroleptic medication levels and degrees of postural sway (Marvel et al, 2004). Another study compared non-alcoholic and alcoholic subjects with schizophrenia and without schizophrenia. The study results revealed gait and balance de� cit in subjects with schizophrenia especially in visual condition (Sullivan et al., 2004). To our knowledge there are no earlier studies concerning postural control in RLS.

However, there are several studies demonstrating alterations of postural re� exes in Parkinson´s disease, especially in the advanced stages (Rocchi et al., 2002, Frenklach et al., 2009). Dopaminergic treatment (levodopa) relieves the symptoms of Parkinsonism like stiffness of the limbs and the body, but seems to increase the postural sway, which may be in connection to risk of falling. Early automatic postural re� exes are only partially corrected by dopaminergic treatment and later occurring voluntary postural corrections are not improved at all.

In neuroleptic induced Parkinsonism, like in other similar set of syndromes, postural balance destabilizing re� exes are considered normal. Other mechanisms than dopaminergic motor control systems are suggested to be involved in the altered responses observed in Parkinson`s disease (Bloem et al., 1996, Rocchi et al., 2002).

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3. THE AIMS OF THE STUDY (I–IV)

SCHIZOPHRENIA RESTLESS LEGS SYNDROME

CFPP STUDY I STUDY IV

TMS STUDY III STUDY II

3.1. CFPP In schizophrenia (study I)

There are only few earlier studies dealing with postural control in schizophrenia. The aim of the study was to examine postural stability in subjects with schizophrenia in order to see if persons with chronic schizophrenia on antipsychotic medical treatment differ from healthy controls in regard with their sway velocity or direction of the sway path. The hypothesis was that persons with schizophrenia would have dif� culties in maintaining the postural balance based on the motor control and visual perception deviations associated with schizophrenia. In addition, antidopaminergic medication might worsen the postural control compared to non-medicated healthy controls. Visual impact on the postural stability was expected to be important in maintaining the upright stance in persons with schizophrenia.

3.2. TMS in RLS and schizophrenia (studies II–III)

The aims of these studies were to characterize motor control of the central nervous system in individuals with RLS and with schizophrenia with the help of the TMS. The main interests of these studies were to investigate these two different chronic disorders with over-lapping clinical manifestations of motor symptoms. Even though there is a rich literature on TMS research dealing with motor control, especially central inhibitory processes and dopamine regulation in these disorders, the pathophysiological backgrounds of these motor symptoms are still unclear. A different, but replicable and precise technique was applied in this study: the motor cortex was stimulated with the help of single pulse TMS on both brain hemispheres and muscle responses were measured by using intramuscular recording electrodes in the respective target muscles in both under and upper extremities. It was expected to � nd no differences in the function of the corticospinal direct motor pathways in between the groups (i.e. schizophrenia, RLS, controls) based on the earlier reports.

The main interests of these studies were to investigate if the central inhibition differed signi� cantly between the subjects of schizophrenia (study III) or with RLS

36

3. THE AIMS OF THE STUDY

(study II) compared to healthy controls. In addition, it was interesting to see if any similarities or signi� cant differences were observable in the inhibitory responses between the disorder groups and if the results depended on the site or side of stimulation and re� ected the motor symptoms the subjects mostly suffered.

3.3. CFPP in RLS (study IV)

The aim of this study was to research further motor control by examining postural control in individuals with RLS with help of the CFPP. The main interest of this study was to see how vision and a dopaminergic agent affect the postural control in individuals with RLS, because central dopamine regulation and vision play an important integrative role in sustaining postural stability and because dopamine has a therapeutic effect on symptoms of RLS. It was expected to see to some extent symptom relief, but mainly growth of sway velocity and area after intake of a dopamine agonist, based on the earlier investigations showing alterations of postural re� exes and impairment of postural balance in individuals with Parkinson´s disease (Bloem et, 1996, Rocchi et al., 2002, Frenklach et al., 2009).

37

4. SUBJECTS AND METHODS (STUDIES I–IV)

4.1. General aspects regarding subjects (I–IV)

Persons having epilepsy, cardiac pacemaker or any magnetically active particles in the cranium or brain were excluded from the TMS studies. Also persons with other neurological, serious somatic or mental diseases or with a history of alcohol or drug abuse, or serious traumatic injuries of the extremities were also excluded.

Subjects were asked to refrain from taking any psychoactive, CNS affecting or any RLS symptoms relieving medications (tramadol, benzodiazepines, levodopa) for one week prior the investigation. Subjects with schizophrenia remained on their prescribed medication as prescribed by their psychiatrists. Subjects’ height and weight including sociodemographic data were documented.

The right-handedness of the subjects was assessed with the help of the Edinburgh Handedness inventory. The Edinburgh Handedness Inventory is a measurement scale used to assess the dominance of a person’s right or left hand in everyday activities. A more reliable way to use the inventory is to let an observer assess the person, than allow the person himself report the hand use because of the common tendency to over-estimate tasks to the dominant hand (Old� eld, 1971). In this study, the dominance of the brain parts/limbs was de� ned by observing and asking the subjects. The footedness was mainly based on inquiring the subjects. A computerized tomogram of the brain (CT) and an electroencephalography (EEG) had been controlled in most of the subjects with schizophrenia recently if this had been seen to be necessary to exclude any neurological or neurophysiological abnormalities of the brain behind the psychiatric symptoms.

4.1.1. SUBJECTS WITH SCHIZOPHRENIA AND CONTROLS (STUDY I)

In total 22 right-handed medicated subjects with schizophrenia (8 females, 14 males) were recruited and diagnosed according to DSM-IV criteria (8 paranoid schizophrenia, 12 undifferentiated types and 2 disorganized types) (Table 1). The duration of illness was averaged 16.3 years. The mean dose of anti-psychotic medication used by the patients was 652 mg in chlorpromazine equivalents. 14 age (+2 years) and gender matching right-handed controls were recruited from the hospital personnel. Exclusion criteria for all participants included symptoms

38

4. SUBJECTS AND METHODS

or diagnosis of other mental diseases or current mental symptoms, neurological diseases, orthostatic symptoms, a history of alcohol or drug abuse, or a history of serious traumatic head injury or lesions of the extremities that might in� uence postural control. Each participant was clinically examined for neurological and somatic symptoms.

Prior to the clinical investigations, subjects with schizophrenia were evaluated using the psychiatric rating scale PANSS (positive and negative syndrome scale), which is a medical scale used for measuring symptom severity of persons with schizophrenia. Positive symptoms refer to an excess or distortion of normal functions (e.g., hallucinations and delusions) while negative symptoms represent a diminution or loss of normal functions. PANSS is a 30-item scale, which includes seven points that measure positive symptoms, seven points for negative symptoms, and 16 points for general psychopathology (Kay et al., 1987) (Table 1).

Movement disorders and side-effects of antipsychotic medicines were evaluated with the help of the following clinical rating scales:

1. AIMS (abnormal involuntary movement scale) is a medical rating scale that was designed to measure involuntary movements known as tardive dyskinesia (TD), often related to chronic schizophrenia (Munetz & Benjamin, 1988).2. SAS (Simpson -Angus scale of extrapyramidal symptoms) is a medical scale used for assessing especially neuroleptic induced Parkinsonism (Simpson & Angus, 1970).3. BAS (Barnes Akathisia Scale) is a medical rating scale that is used for assessing the severity of drug-induced akathisia. It is the most widely used rating scale for akathisia including objective and subjective items such as the level of the patient’s restlessness (Barnes, 1989).

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Table1. Antipsychotic medications (in 100mg chlorpromazine equivalents, CPZ) and sociodemographic data of subjects with schizophrenia in study I are presented in table 1. Legend: No= subject identifi cation number, DUI = duration of schizophrenia in years, PANSS= Positive and Negative Syndrome Scale.

No Subtype ofschizophrenia Gender Age

(years)DUI

(years)PANSS

(records)Antipsychotics

(100mgCPZ equiv.)

1 paranoid female 60 >30 99 500

2 paranoid female 50 14 64 450

3 undifferentiated female 41 20 72 242

4 undifferentiated female 45 17 81 720

5 disorganized female 31 14 103 900

6 undifferentiated female 54 >30 53 472



9 disorganized male 51 >30 109 1200

10 paranoid male 39 21 96 1180

11 undifferentiated male 47 27 102 700





16 undifferentiated male 24 1,5 57 500







4.1.2. SUBJECTS WITH RLS AND CONTROLS (STUDY II)

A total number of six right-handed volunteers with an ICD -10 diagnosis of RLS (3 females and 3 males, between the ages of 44 to 71 years) were selected from a university hospital clinical population, among which secondary causes for RLS had been excluded by carrying out necessary blood tests and specialist medical consultations. RLS symptoms were checked prior to the clinical investigation part of this study with the help of the Diagnostic checklist criteria for RLS in subjects with RLS: ad modum Gibb and Lees (1986) and essential features according to Walters IRLSSG (The international Restless Legs Syndrome Study Group, 1995):

40


A. Desire to move the limbs usually associated with paresthesias or dysesthesias. B. Motor restlessness. C. Symptoms are worse or exclusively present at rest with at least partial or temporary relief with activity. D. Symptoms are worse during the evening or at night.

The recruited participants with RLS had a chronic duration of RLS lasting several years. They all reported a positive family anamnesis for RLS. Characteristic was the worsening of symptoms by time and sensations with same type of unusual, but milder symptoms in the arms as in the legs. PLMD was excluded on grounds of a clinical interview performed by an experienced sleep-researcher.

In addition, six healthy right-handed volunteers (3 females and 3 males between the ages of 22 to 49 years) from the hospital personnel were recruited as a control group. Clinical somatic and neurological examinations were conducted in all participants to rule out any serious somatic, neurological or sensorimotor diseases. A history of substance abuse, mental disease or use of neurotropic or any somatic medications by potential participants that may impact study � ndings were excluded by conducting a short structured psychiatric interview.

4.1.3. SUBJECTS WITH SCHIZOPHRENIA AND CONTROLS (STUDY III)

A total number of 11 subjects with an ICD -10 diagnosis of schizophrenia (5 females, 6 males, aged from 21 to 70 years old) were included in this study (Table 2). In addition, nine healthy volunteers (5 females, 4 males, aged from 22 to 49 years) were included as a control group (Table 2). All subjects with schizophrenia were on medication: four subjects had clozapine and six subjects had combinations of conventional antipsychotics. One of the subjects had since three years treatment with zotepine medication, which is an atypical antipsychotic agent like clozapine. Three subjects with schizophrenia had additionally lorazepam as needed. The clinical duration of chronic schizophrenia was at least one year. Four subjects were left-handed, the rest of the subjects were right-handed.

Prior the clinical investigation part of the study subjects with schizophrenia were evaluated with the help of the medical rating scales (PANSS, AIMS and SAS). Calgary depression scale (Addington & Addington, 1999) was also used to assess the level of depression associated with schizophrenia. It appears sensitive towards changes in both relapsed and remitted patients with schizophrenia (Table 2).

41

Tabl

e 2.

Soc

iode

mog

raph

ic d

ata

and

clin

ical

par

amet

ers

(mea

n va

lues

+SD

) ob

tain

ed in

the

sub

ject

s of

stu

dy II

I are

pre

sent

ed in

tab

le 2

. Le

gend

:Tot

al=

all

subj

ects

with

sch

izop

hren

ia; C

A=

subj

ects

with

sch

izop

hren

ia, u

sers

of c

onve

ntio

nal n

euro

lept

ics;

AA

= su

bjec

ts w

ith s

chiz

ophr

enia

, use

rs o

f aty

pica

l neu

role

ptic

s;

AP=

dai

ly d

ose

of a

ntip

sych

otic

s (C

PZ, m

g in

100

mg

chlo

prom

azin

equ

ival

ents

); D

UI=

dur

atio

n of

ill

ness

(in

yea

rs)

and

age

(in y

ears

) of

the

sub

ject

s w

ith

schi

zoph

reni

a; m

=mea

n va

lue,

SD

= st

anda

rd d

evia

tion;

n=

num

ber o

f sub

ject

s; P

AN

SS =

Pos

itive

and

Neg

ativ

e Sy

ndro

me

Scal

e (t

otal

sco

re);

AIM

S= A

bnor

mal

in

volu

ntar

y m

ovem

ent s

cale

; SA

S= S

imps

on &

Ang

us S

cale

for E

xtra

pyra

mid

al S

igns

; BA

S =

Barn

es A

kath

isia

Rat

ing

Scal

e (g

loba

l clin

ical

ass

essm

ent o

f aka

this

ia);

undi

ffer./

para

noid

=un

diffe

rent

iate

d/pa

rano

id s

ubty

pe o

f sch

izop

hren

ia; A

naly

sis:

sta

tistic

al a

naly

sis

of th

e di

ffere

nces

bet

wee

n th

e us

ers

of C

A a

nd A

A (

Man

n W

hitn

ey U

-te

st, p

=pro

babi

lity,

leve

l of s

igni

fi can

ce w

as s

et <

0.0

5).

No

PAN

SSA

IMS

B

AS

SA

SA

P (m

g)D

UI

A

GE

SUB

TYPE

CA

LGA

RY

TOTA

L 11

74.0

9�15

.06

7.36�5

.78

1.18�

1.17

1.27�

1.19

638.

84�4

39.9

017

.27�

12.16

42.0

9�13

.67

Para

noid

3, U

ndiff

er. 8

5.55�2

.8

CA

6

73.8

3�17

.53

10.6

7�5.

961.8

3�1.1

71.3

3�1.5

170

0.0

0�4

96.5

22.5

0�1

2.63

49.5

0�1

2.45

Para

noid

1, U

ndiff

er. 5

4.

83�3

.31

AA

5

74.4

0�1

3.51

3.40

�1.8

2 0.

40�0

.55

1.20�0

.84

565.

45�4

04.

03

11.0

0�8

.94

33.2

0�9

.60

Para

noid

2, U

ndiff

er. 3

6.40

�2.0

7

AN

ALY

SIS

betw

een

user

s of

CA

and

AA

(M

ann

Whi

tney

tes

t)U

-tes

t14

.54.

54.

513

115.

54

8

p-va

lue

0.93

0.0

50.

05

0.93

0.54

0.0

80.

05

0.25

AN

ALY

SIS

betw

een

CON

TRO

LS, u

sers

of

AA

and

CA

and

(K

rusk

al W

allis

Tes

t)C

hi-s

quar

e5.

94

p-va

lue

0.0

51

42


4.1.4. SUBJECTS WITH RLS AND CONTROLS (STUDY IV)

A total number of 12 right-handed volunteers with RLS (11 females and 1 male, mean age 50.7, range 26–62), were included to this study. They were recruited by advertising in a health magazine. Inclusion criteria were an age of 18–65 years, diagnosis of RLS based on IRLSSG (Walters et al., 1995) criteria together with chronic over one year lasting symptoms, frequent at least half night occurring symptoms and subjectively distressing and harmful symptoms of RLS and right-handedness. 12 right-handed controls (11 females, 1 male, mean age 49.4 and range 38–57) were recruited from the psychiatric hospital personnel and from a prison personnel. Exclusion criteria for all subjects were current medication during past two weeks, a long-term use of any neurotropic drugs, major somatic illnesses, serious traumatic injuries of head or lesions of extremities, orthostatic syndromes, secondary subtypes of RLS, any other medical causes of insomnia than RLS, and psychiatric disorders diagnosed by the structured clinical interview (SCID-I, clinician version) (First et al., 1997). In addition, clinical neurological and somatic investigations were performed in all the participants, to exclude any symptoms or diseases that might cause dizziness or interfere with postural control.

The subjective symptom severity of RLS, including the latency of falling in sleep was evaluated by asking and recorded on both study protocol days in a self-made simple model of visual analogue scale (VAS). VAS was selected to be used due to lack of validated rating scales for RLS at the time of study procedure (Chokroverty et al., 1999). Figure 1 presents an example of VAS and the obtained scores in a subject with RLS (Figure 1).

43

Figure 1. An example of VAS (Study IV)

Symptoms of akathisia like restlessness were characterized with the help of BAS in subjects with RLS (Tuisku et al., 2005). Blood tests (for renal and hepatic function, blood glucose, ferritin B-12 vitamin, blood cell account and plasma level of haemoglobin) were controlled prior to the investigations to exclude the secondary causes for RLS in participants with RLS.

4.2. Methods

4.2.1. TMS STUDIES II AND III

The methods and the procedure of the studies II and III were identical. TMS was performed in both studies by using a commercially available magnetic stimulator,

44


Cadwell MES-10, supplied with a round coil that has an external diameter of about 9 cm. The stimulation intensity exceeded constantly the motor threshold level. A biphasic stimulation pulse was used with an intensity of 60 to 80% of the maximum capacity of the device in each series of stimuli. In each series of stimuli, altogether � ve repetitive pulses were given with a time interval of 1 to 5 seconds. For the stimulation of muscles in upper extremities, the center of the coil was placed at the on the corresponding temporal area, contralateral to the side of recording of the responses. The most optimal site of stimulation of the muscles in the lower extremities was the central area close to the vertex. Adjustments of coil positions were made to achieve the most favorable site of the stimuli of respective muscles.

Two types of responses, the muscle activation in inactive muscle and inhibition of muscle activity in maximum preactivated muscle were measured. The recording of the responses was performed with Dantec KeyPoint device. The responses were recorded by using a pair of monopolar needle electrodes that were inserted to Abductor Digiti Minimi (ADM) and Anterior Tibial (TA) muscles at a distance of 3 cm from each other. The cathode was positioned proximal to anode. The intramuscular recording with needle electrodes enables the measurement of the high frequency components of the muscular activity. To measure the motor distal latency (MDL) and the latency of F-responses (F) electrical stimuli (rectangular pulses with duration of 0.2 ms and intensities of 10 to 50 mA) were given at ulnar and peroneal nerves at wrist and at the � bular head on the lateral side of the knee, respectively.

For the analysis of the muscle activation, the following parameters were recorded and calculated: 1) Motor conduction time from cortex to ADM (MCTa) and to TA (MCTt). 2) MDL= Respective motor distal latency to the stimulation of ulnar and peroneal nerves. 3) Latency of F-response to the ulnar nerve stimulation at the wrist (Fu) and to the peroneal nerve stimulation at the � bular head (Fp). MDL was excluded from the F latency. 4) Central motor conduction time from the motor cortex to the neck: CMCTn = MCTa - (Fu/2 + MDL). 5) Central motor conduction time from the motor cortex to the lumbar area: CMCTl = MCTt - (Fp/2+MDL).

Based on studies with TMS of motor cortex, the MEPs show considerable amplitude variation (Hess et al. 1987, Rothwell et al. 1987). We therefore considered the assessment of amplitudes as such as probably not suitable for quantitative analysis. These commonly used TMS parameters measured in this study are presented in a semantic picture of a human body (Figure 2).

45

Figure 2. The TMS parameters measured in this study (II, III) are presented in a semantic picture of a human body in fi gure 2. Legend: MCT= Motor conduction time, CMCT= central motor conduction time,ADM= Abductor digiti minimi muscle, TA= Tibialis anterior muscle

For the analysis of the CSP in each voluntarily maximally preactivated muscle, the following parameters were recorded on the contralateral side to a series of � ve magnetic stimuli: the latency, the duration and the total number of the silent periods of the activated muscle (ADM, TA). Maximum preactivation of the muscle was de� ned as a full interference pattern of the muscle activity in a time frame of 500 ms and a sensitivity of 1 mV/div. The presence of the CSP was de� ned as a simultaneous decrease of amplitude of muscular activity below 0.05 mV/division in � ve consecutive measurements. Stimulation intensity was the same used to elicit MEPs.

4.2.2. THE METHODS IN CFPP STUDIES I AND IV

The basic measurements were performed in the same way in studies I and IV. A custom made force platform was used to evaluate the postural control of the standing subjects (Starck et al., 1993). In computerized force platform posturography, the force platform is connected to a computer and this measuring system determines

46


center point of force (CPF) from the forces that the standing subject applies with his or her feet to the platform. The system also analyses the movement of the CPF during the test. This movement re� ects the postural control activity; the used forces which maintain the balance, their magnitude, duration and direction.

One of the most used parameters in computerized force platform posturography is the center point pressure which is closely correlated to velocity (CPFV), the length of the trace of the CPF divided by the duration of the test. Any increase in the activity of postural control forces is re� ected in this parameter. The average position of the CPF is obtained, as the values of the CPF are averaged over a period. When the length of the sway path is averaged for a second, the average position of the CPF re� ects the position of body’s center of mass on the platform surface. From this variable the visible leaning angle of the body can be calculated. In this study the change of average position is used to quantify the effect of eye closure. This parameter has been calculated separately in lateral and anterior-posterior directions.

The platform was placed in both studies in a peaceful, undecorated investigation room, at a distance of one meter from a white wall. The subjects stood with their shoes on, arms crossed over the chest, heels distanced about 2 centimeters from each other, and feet abducted at 30 degrees angle mimicking apendulum position for body sway. The subjects were asked to look at a piece of paper placed at the height of their eyes and stand still on the platform. The patient stance was recorded � rst during the eyes open condition for 30 seconds, and then 30 seconds eyes closed, in between there was a 15 seconds adaptation period. In study I the posturographic measurements were performed three times per each subject. Figure 3 presents an example of posturographic measurements in a participant with schizophrenia and in a control of the study I (Figure 3).

47

Figure 3 presents the sway of a subject with schizophrenia (1) and of a healthy control person (2) in study I. Lines a show forward-backward leaning tendency (upwards-downwards, respectively) and lines b leaning to the right and left (upwards-downwards, respectively). The fi rst 30 seconds were recorded eyes open and the last 30 seconds eyes closed. There was an adaptation time of 15 seconds between the recordings.

4.2.3 THE PROCEDURE OF THE STUDY IV WITH PRAMIPEXOLE INTERVENTION

The basic measurements with the help of the CFPP were performed as described in chapter 4.2.2., but posturographic measurements were performed only once (instead of three measurements as in study I) in non-medicated and medicated conditions. The measurements in subjects with RLS were at � rst measured without medication. After intake of pramipexole the posturographic measurements were repeated within three-day intervals in between. Subjects with RLS were administered pramipexole after the � rst day measurement and informed to take a dose of 0.88mg t.i.d (8.00 am, 2.00 pm and 8.00 pm). The measurements were performed at 4 pm-6 pm. The severity of the symptoms in subjects with RLS were rated and documented in non-medicated and medicated conditions. The posturographic measurements were not repeated in controls and they did not undergo intervention with medication.

4.3. Statistical methods

4.3.1. TMS STUDIES II AND III

To analyse differences in between the subjects with schizophrenia (study III) and matching controls and in between subjects with RLS (study II) and matching controls the groups (i.e. schizophrenia/RLS and control groups) were compared using the

48


Mann Whitney test. Side-to-side differences within the groups were compared using Wilcoxon signed rank test for related samples. Non-parametric tests were applied, because of the small sample sizes (n<11), which were not normally distributed. The level of signi� cance was set p< 0.05. PASW for Windows version 18 was used in studies II–III.

In addition, in study III the subjects with schizophrenia were divided into two subgroups according to the type of the antipsychotic medical treatment they were taking (conventional or clozapine type of antipsychotics). Intercorrelations between the clinical parameters and the TMS measures were calculated with the help of the Spearman´s correlation test using Bonferroni -correction in between the subgroups. In study II the comparison for the several inhibition periods was performed with the help of the Chi-square test.

4.3.2. CFPP STUDIES I AND IV

In study I non-parametric tests were used because of the relatively small number of subjects (n=22). The results were statistically analyzed using medians of the three measurements (mean value), 95% con� dence limits of median differences and Mann-Whitney two-tailed test. SPSS for Windows was used to analyze the results.

In study IV the statistical analysis for the sway velocity and CPF shift and the changes from conditions eyes open to eyes closed conditions in controls and in non-treated and treated conditions of participants with RLS were performed with the help of non-parametric Mann Whitney -test for independent samples between the groups (i.e. RLS non-medicated / medicated and controls). Wilcoxon -test for related samples was used to analyse results within the groups (i.e. RLS non-medicated, RLS medicated and controls). The Spearman`s test with Bonferroni-correction was used to analyze intercorrelations between the Romberg´s quotient and the CPFP parameters and clinical parameters, before and after medication intervention in subjects with RLS. The level of signi� cance was set p<0.05. PASW for Windows version 18 was used to analyze the results.

4.4. Ethical considerations

Clinical evaluations and measurements of the subjects with schizophrenia in studies I and III as well as the controls in study II were performed at the Laboratory of Clinical neurophysiology in Ekåsen Psychiatric Hospital, which belongs to Helsinki University Hospital. Respective clinical parts of the study II in subjects with RLS were performed in the university and community hospitals in Turku.

49

Clinical evaluations and measurements of the RLS subjects of the study IV were performed at the department of psychiatry in Lapinlahti Hospital, belonging to Helsinki University Hospital. The evaluations and measurements of the controls were performed in Psychiatric Hospital of Vantaa Prison. Informed consent was obtained from all the participants and the study was approved by the Ethics Committees of Helsinki University Hospital in Helsinki and in Ekenäs attributable to ethical standards stipulated in the1965 Declaration of Helsinki.

There were some ethical aspects to be considered in this study. All subjects had to be able to cope with the investigation according to the study procedure. The methods of TMS and intramuscular electrodes were not causing pain, but they could be experienced to some extent inconvenient.

51

5. RESULTS

5.1. CFPP and schizophrenia (study I)

There were no signi� cant differences between subjects with schizophrenia and controls in the CPFVs (Table 3), but subjects with schizophrenia seemed to stand more stable both during eyes open and eyes closed, compared to the controls. The difference between the groups was signi� cant (median change, p = 0.0006). The visual control did not seem to have a signi� cant role in maintaining the postural balance in upright position. The change of the CPFV was much lower in subjects with schizophrenia than in controls, which seemed to have it more dif� cult to hold their upright standing position stabile eyes closed. Also the mean CPFV was lower among the subjects with schizophrenia during eyes closed condition.

Subjects with schizophrenia tended to lean to the left and the controls to the right side. The difference between the groups respective the lateral body shift was suggestively signi� cant (p = 0.025). The body shift and its range in anterior-posterior direction seemed to be wider among the subjects with schizophrenia, but the difference between the groups was not signi� cantly different (p=0.05). Figure 3 presents position shifts (posturographies) of a standing subject with schizophrenia and a control person during eyes open and eyes closed conditions and in anterior-posterior and lateral directions.

Table 3. presents the obtained CPFV measures (means+SD and medians) during eyes open and eyes closed conditions, the change of CPFV from eyes open to eyes closed condition; lateral and anterior-posterior (AP) shifts of body position among schizophrenics (n = 22) and their normal controls (n = 14) in study I. In shifts during eye closure, negative values denote moving to the left (lateral) and backwards, positive values denote shifts to the right and forwards. NS= non-signifi cant, CL= confi dence limit, CPFV= Center Point of Force Velocity.

Table 3. CPFV eyes open NS (cm/s)

CPFV eyes closed NS(cm/s)

Change of CPFV from eyes open to eyes closed condition, %

Lateral shift during eye closure (cm)

AP shift during eye closure NS(cm)

Controls mean+SD 0.91+0.22 1.54+0.46 68+22 0.45+1.20 1.10+1.17median 0.84 1.35 70* 0.52** 0.99range 0.68-1.46 0.95-2.44 29-119 -2.50-2.84 -0.40-3.7195% CL of median 0.73-1.12 1.26-2.21 44-88 -0.09-1.19 -0.04-1.89

Schizo-phrenics mean+SD 1.07+0.34 1.43+0.35 38+25 -0.44+1.31 0.37+1.82

median 0.98 1.37 36* -0.28** 0.42range 0.53-1.80 0.81-2.34 -10-91 -4.34-1.74 -3.41-5.7495% CL of median 0.84-1.23 1.22-1.68 30-54 -0.93-0.57 -0.67-1.35

*p < 0.05, median difference 30, 95% CL:s of median difference are 12 and 42 **p < 0.05, median difference 0.85, 95% CL:s of median difference are 0.19 and 1.51. (Mann-Whitney two-tailed test for differences between the groups)

52

5. RESULTS

5.2. TMS AND RLS (study II)

The groups (i.e. RLS and controls) did not differ signi� cantly from each other in respect of MEPs and their peripheral components (F-waves, MDLs) (tables 4a and 4b). Thus, the corticospinal motor pathways functioned correctly in RLS compared to controls. No signi� cant side-to-side differences were observed within the groups (i.e. RLS and controls).

Table 4a and 4b present results (mean + SD) of study II of motor conduction times (MCT), central motor conduction times (CMCT), F-waves and motor distal latencies (MDL) in milliseconds (ms) after transcranial magnetic stimulation (TMS) on the dominant and non-dominant motor cortex of brain. Responses were measured in the target muscles of Abductor Digiti Minimi (ADM) (table 4a) and Tibialis Anterior (TA) (table 4b) in respective dominant and non-dominant extremities. The measured values did not differ signifi cantly between the subjects with RLS and controls

Table 4a

Variable ADM Non-dominant ADM Dominant

(ms) Control RLS Control RLS

MCT 21.1�1.1 21.4�1.0 21.2�1.3 20.8�0.7

CMCT 6.2�1.1 7.5�0.6 8.5�1.7 6.8�0.4

F- wave 24.7�2.9 23.5�.8 24.1�4.1 23.4�1.3

MDL 2.5�0.2 2.2�0.3 2.7�0.4 2.2�0.3

Table 4b

Variable TA Non-dominant TA Dominant

(ms) Control RLS Control RLS

MCT 28.6�1.6 28.2�3.0 29.2�2.3 28.1�2.5

CMCT 11.0�1.2 11.3�3.2 11.9�1.6 11.7�2.9

F- wave 26.7�2.1 24.1�1.8 26.2�1.5 23.7�1.7

MDL 4.3�0.6 4.9�0.4 4.2�0.6 4.6�0.6

The central inhibition showed tendency to disrupt and consisted of up to one to three, separate compounds of CSPs (Table 5). The number of the CSPs (mean�SD) was signi� cantly higher in both ADMs (dominant: 1.5�1.1 and non-dominant: 1.7�0.8; p<0.05) and in the dominant TA (RLS:1.3�1;controls:1.2�0.4; p<0.05) in subjects with RLS compared to the controls, but no significant differences for the number of the CSPs were obtained in the non-dominant TA (RLS: 1.5�0.6; controls: 1.3�0.5; p>0.05).

The separate compounds of the CSPs (Table 5) did not differ signi� cantly on the duration or on the latency between the RLS and the control groups. The recurrent CSPs showed a diminishing duration. Table 5 presents the results of measurements in central silent periods (CSP) in study II.

53

Tabl

e 5.

Con

tral

ater

al m

easu

rem

ents

(mea

n�SD

) of t

he fi

rst C

SP, t

he s

econ

d CS

P an

d th

e th

ird C

SP d

urat

ions

(Dur

) and

the

late

ncie

s (L

at) a

nd th

e to

tal C

SP d

urat

ions

in

mill

isec

onds

(m

s) a

s w

ell a

s th

e nu

mbe

r of t

he C

SPs

and

thei

r abs

olut

e to

tal n

umbe

r (ab

s.) in

the

Abd

ucto

r Dig

iti M

inim

i (A

DM

) an

d Ti

bial

is A

nter

ior (

TA)

mus

cles

in

the

par

ticip

ants

with

RLS

and

con

trol

s (C

TRL)

.

DO

M=

Dom

inan

t, N

D=

Non

-dom

inan

t he

mis

pher

ic s

ide,

SD

= st

anda

rd d

evia

tion,

CSP

= c

entr

al s

ilent

per

iod

(*p

=0.0

1, **

p=0.

009)

Gro

upSi

te o

f re

cord

ing

1.C

SP D

ur2.

CSP

Dur

3.C

SP D

ur1.

CSP

Lat

2.C

SP L

at3.

CSP

Lat

CSP

Num

ber

CSP

Dur

Tot

al

RLS

AD

M

DO

M44

.8+3

2.3

16.7

+22.

110

.0 (

abs.

)44

.7+2

2.3

225+

141.1

34

6 (a

bs.)

1.5+1

.1(ab

s) *

63.2

+44.

1

ND

58.5

+39.

512

.7+1

5.0

10.0

(ab

s.)

53.0

+4.6

251+

128.

442

0 (

abs.

)

1.7+0

.8 (

10 a

bs.)

**

72.8

+48.

0

TA DO

M36

.2+3

3.2

5.0

+8.9

15.0

(ab

s.)

64.2

+13.

227

0.5+

102.

532

7 (a

bs.)

1.3

+1.0

(8

abs.

)*43

.7+4

6.3

ND

44.7

+45.

312

.3+2

0.1

064

.7+1

3.0

125.

5+14

7

0

1.5+0

.6 (

9 ab

s.)

57.0

+65.

0

CTR

LA

DM

DO

M67

.3+3

2.3

00

54.7

+4.8

00

1.0+0

.0 (

6 ab

s.)

67.3

+32.

3

ND

93.3

+64.

70

055

.5+7

.80

01.2

+0.4

(7

abs.

)93

.3+6

4.7

TA DO

M70

.7+5

6.0

4.0

+9.8

067

.0+7

.823

1 (a

bs.)

01.2

+0.4

(7

abs.

)74

.7+6

5.1

ND

42.7

+45.

37.

5+11

.70

59.8

+12.

322

3.5+

127.

70

1.3+0

.5 (

8 ab

s.)

50.2

+48.

3

54

5. RESULTS

5.3. TMS and schizophrenia (study III)

The groups (i.e. schizophrenia and controls) did not differ signi� cantly from each other in respect of MEPs or their peripheral components (F-waves, MDL). Within the groups there could not be demonstrated any signi� cant side-to-side differences. The function of descending corticospinal motor pathways in schizophrenia seemed to be intact compared to healthy controls. Table 6 presents the main results of TMS measurements.

The central inhibition was disrupted into several separate compounds, silent periods (CSP) predominantly in subjects with schizophrenia. After each TMS impulse there could be up to one to three sets of inhibited muscular activity within 500 ms after the stimulation. The number of CSPs (mean+SD) differed statistically signi� cantly in the dominant ADM in subjects with schizophrenia from controls (1.8+0.6, U=13.5, p=0.004, signi� cant even after Bonferroni correction, p=0.024) but more than one sets of CSPs could also be observed in the non-dominant ADM and in the dominant TA in subjects with schizophrenia, even though these differences were not statistically signi� cant. Table 6 presents the results of the TMS measurements and signi� cant differences in the subjects with schizophrenia compared to controls.

High PANSS scores correlated signi� cantly with multiple CSPs in the non-dominant ADM (Table 2). The users of conventional antipsychotics seemed, even though this was not statistically signi� cant, to show shorter CSPs and in average more extrapyramidal signs, like akathisia and abnormal involuntary movements. The PANSS and SAS rates did not differ signi� cantly between the users of atypical or conventional antipsychotics (Table 2). The users of atypical antipsychotics seemed to have longer CSPs and disrupted central inhibition, mainly in the non-dominant body side and in the under extremities. They also tended to have the longest CSP durations (Table 6).

5.4. CFPP and RLS (study IV)

Table 7 presents the mean values of CPFV in participants with RLS and in controls eyes open and eyes closed and the change in CPFV and in average position shifts (cm) in anterior – posterior and lateral directions from eyes open to eyes closed conditions. The main � nding of the study was that with eyes open the sway velocity (mean+SD) in non-treated condition of subjects with RLS (CPFV eyes open: 0.68+0.12) was signi� cantly (p<0.05) lower than in the controls (CPFV eyes open:

55

Tabl

e 6.

The

mai

n TM

S re

sults

of s

tudy

III (

mea

n va

lues

+ s

tand

ard

devi

atio

ns ,S

D)

are

pres

ente

d in

Tab

le 6

. Le

gend

: Tim

e va

lues

are

in m

illis

econ

ds (

ms)

(p=

prob

abili

ty; *

p= 0

.007

, U=1

5.0,

**p

= 0.

004,

U=

13.5

, **

*p=0

.009

, U=1

.0, *

***p

=0.0

05, U

=4.5

, **

***p

=0.0

04, U

=0.0

, ***

***p

=0.0

04, U

=2.0

),N

D =

non

-dom

inan

t he

mis

pher

e an

d bo

dy s

ide,

Dom

= d

omin

ant

hem

isph

ere

and

body

sid

e,

AD

M=

Abd

ucto

r di

giti

mus

cle,T

A=

Tibi

alis

ant

erio

r m

usle

, CA

= us

er o

f con

vent

iona

l ant

ipsy

chot

ic,

AA

= us

er o

f aty

pica

l ant

ipsy

chot

ic, T

otal

= al

l sub

ject

s w

ith s

chiz

ophr

enia

, MCT

= m

otor

con

duct

ion

time,

CM

CT=

cent

ral m

otor

con

duct

ion

time,

CSP

= ce

ntra

l sile

nt p

erio

d, n

= nu

mbe

r

Con

trol

N

D (

n=9)

T

otal

N

D (

n=11

) C

A

ND

(n=

6)A

A N

D (

n=5)

Con

trol

D

OM

(n=

9)

Tota

lD

OM

(n=

11)

CA

DO

M (

n=6)

AA

DO

M (

n=5)

Gro

up /

AD

MM

CT

21.5

+1.4

21.2

+1.8

20

.7+1

.821

.8+1

.621

.8+1

.621

.4+1

.720

.9+1

.921

.9+1

.4

CM

CT

6.6+

1.26.

5+1.5

6.1+

1.37.

0+1

.66.

9+1.5

6.5+

1.36.

0+1

.57.

0+1

.1

CSP

1.d

urat

ion

Tota

l dur

atio

nTo

tal n

umbe

r

104.

2+59

.283

.1+57

.81.2

+0.4

101.8

+5.7

166.

9+76

.7*

2.1+

0.9

72.0

+57.

297

.3+8

1.62.

2+1.2

137.

60+8

5.6

169.

4+10

2.0

2.0

+0.7

83.1+

57.8

106.

0+6

0.6

1.0+0

.0

140.

1+79

.713

0.1+

94.4

1.8+0

.6**

137.

2+91

.616

6.8+

79.4

2.0

+0.6

***

*

143.

6+73

.316

7.0

+82.

81.6

+0.6

CSP

late

ncy

56,0

+7.6

53.2

+6.2

54.5

+6.6

51.6

+6.1

56.6

+7.0

54.9

+9.4

56.2

+10.

753

.4+8

.6

Gro

up /

TA

MC

TC

MC

T28

.9+1

.511

.7+1

.529

.9+2

.312

.8+1

.629

.9+2

.412

.6+1

.231

.1+1.6

12.9

+1.5

29.5

+2.1

12.2

+1.5

29.0

+4.2

12.0

+3.7

27.5

+5.0

11.0

+4.9

30.9

+2.1

13.2

+1.3

CSP

1.d

urat

ion

Tota

l dur

atio

nTo

tal n

umbe

r

60.3

+47.

873

.9+5

8.0

1.3+0

.5

88.8

+67.

213

8.7+

101.8

1.4+0

.5

48.3

+10.

648

.3+1

0.6

1.0+0

.0

137.

4+75

.7**

*17

9.4+

88.6

1.8+0

.5

71.2

+51.7

67.1+

53.3

1.1+0

.3

96.3

+59.

010

7.9+

88.8

1.7+0

.6

73.2

+37.

587

.8+5

9.3

1.3+0

.5

124.

0+7

2.1

199.

8+11

3.9*

****

2.2+

0.5*

****

*

CSP

late

ncy

63.8

+10.

867

.3+7

.364

.8+8

.870

.2+4

.168

.0+8

.069

.1+8.

867

.0+9

.5

71.6

+8.2

56

5. RESULTS

0.99+0.34), whereas CPFV eyes closed did not differ signi� cantly (p>0.05) between RLS group (1.62+0.47) and controls (1.68+1.11). The Romberg´s quotient (mean + SD) was also signi� cantly higher in subjects with RLS (2.42+0.71; p<0.05) than in controls (1.69+0.45). With eyes closed the sway velocity in subjects with RLS did not differ signi� cantly from the level of sway velocity of the controls.

Table 7. presents the mean values+SD of CPFV (Center Pressure Force Velocity, cm/s) in participants with RLS (RLS) and in controls eyes open and eyes closed and the change in CPFV and in average position shifts (cm) in anterior – posterior (+A / - P) and lateral (+ rightwards/ - leftwards ) directions from eyes open to eyes closed conditions. Legend: SD = standard deviation, RQ= Romberg´s quotient, N=number of subjects

Table 7.

CPFV cm/s EYES OPEN

CPFV cm/s EYES CLOSED RQ CPFV cm

change

A-P cm average change

LAT cm average change

VARIABLE

GROUP

RLS non- medic. N=12 0.68*+0.12 1.62**+0.47 2.42*+0.70 0.94+0.44 1.81+1.86 -0.85+0.72

RLS medic. N=12 0.73+0.15 1.61***+0.54 2.21+0.67 0.88+0.47 1.48+1.67 - 1.96+1.02

CTRL N=12 0.99*+0.34 1.68****+1.11 1.69*+0.45 0.69+0.82 0.24+0.20 -1.67+0.69

Signifi cant differences (p < 0.05) were obtained in the following measures:1.*CPFV eyes open was signifi cantly slower in non-treated RLS subjects than in controls 2.*RQ was higher in non-treated RLS subjects than in controls 3. CPFV eyes closed compared to eyes open was signifi cantly higher within **non-treated, *** treated and ****control group, refl ecting normative change between visual and non-visual conditions

After intervention with pramipexole the difference in CPFV (mean+SD) condition eyes open between RLS (0.73+0.15) and control (eyes open: 0.99+0.34; p=0.052) disappeared, while the sway velocity of RLS group seemed to approach the level of the controls eyes open and eyes closed (1.68+1.11; p=0.67). Pramipexole relieved subjective and objective symptoms in subjects with RLS, seen as decrease of the mean values of VAS (67.27 – 20.45) and mean scores of BAS (1 – 0.33). Table 8 presents obtained scores for severity of symptoms and the changes measured in Visual analogue scale (VAS) and BAS (Barnes Akathisia Scale) in subjects with RLS (Table 8).

57

Table 8.

Subjective symptom severity (mean value + SD) gathered in a visual analogue scale (VAS, scale 0–100%) and assessed symptoms of akathisia (Barnes akathisia rating scale, global scores) in subjects with RLS in study IV.

Legend: VAS max= Maximum symptom severity during the past two weeks; non-medicated VAS 1= Symptom severity during the past 24 hours non-medicated VAS 2= Symptom severity during the past 24hours after intake of medication BAS 1= Scores of akathisia non-medicated BAS 2= Scores of akathisia after intake of medication

Evaluated symptoms in RLS n

Meanvalues/change %+SD

VAS max 11 56.82+16.77

67.27+19.25

20.45+19.24

1.00+1.04

0.33+0.64

decrease~ 60%

VAS 1 11

VAS 2 11

BAS 1 12

BAS 2

VAS1-VAS2 andBAS1-BAS2

12

Subjects with RLS tended to sway in average more forward, while eyes closed all study participants tended to sway in average more leftwards. Table 9 presents the mean values and standard deviations of the CPF shift in anterior – posterior and lateral directions in conditions eyes open and eyes closed in non-medicated and medicated subjects with RLS and in controls.

58

5. RESULTS

Table 9.

Mean values and standard deviations (M+ SD) of the CPF shift (cm) in anterior - posterior and lateral directions in conditions eyes open and eyes closed in non-medicated (RLS 1) and medicated (RLS 2) subjects with RLS and in controls (CTR) in study IV.

Legend: AP= (+anterior, - posterior direction), Lat= lateral direction (+ rightwards, - leftwards), max= maximum, ave=average, n=number of subjects, SD =standard deviation

VARIABLE

GROUP

APmaxeyes open

APmaxeyes

closed

AP aveeyesopen

AP aveeyes

closed

Lat maxeyes open

Lat maxeyes

closed

Lat aveeyesopen

Lat aveeyes

closed

RLS 1 Mn=12 + SD

0.23 0.37 -1.16 0.661 -0.11 0.44 1.79 -0.062

0.57 1.10 1.42 0.77 0.54 0.97 0.55 0.36

RLS 2 Mn=12 + SD

0.26 0.38 -1.01 0.473 -0.40 0.01 1.93 -0.034

0.60 1.07 1.16 0.81 0.49 1.03 0.83 0.45

CTRn=12 M + SD

0.01 -0.22 -0.07

0.17 -0.35 -0.15 1.58 -0.095

0.88 1.33 1.65 0.65 0.70 0.87 0.51 0.38

Signifi cant differences (p<0.05, Wilcoxon) between conditions eyes open and eyes closed were obtained:1)within non-treated RLS group in AP average (*Z=-2.51) and lateral average (**Z=-3.06) position shift2)within treated RLS group in AP average(***Z=-2.59) and lateral average(****Z=-3.56) position shifts3)within controls in lateral average (*****Z=-3.06) position shift

59

6. DISCUSSION

6.1. General aspects (I–IV)

Schizophrenia and Restless Legs Syndrome (RLS) are disorders with multifactorial pathogenesis. Schizophrenia is considered to be a neuropsychiatric disorder, associated with impairment of cognitive and perceptive functions, frequently resulting in disorganized thinking, lateralized motor symptoms and attentional abnormalities. RLS is considered to be a sleep disorder, associated with sensorimotor symptoms without impairment of cognitive functions. Symptoms of RLS may come to manifestation due to several factors such as circadian (diurnal) rhythm, due to lack of muscular activity in the lower extremities and the set of the body position.

Although the cardinal symptoms of schizophrenia are considered to be mental, both schizophrenia and RLS are associated with motor symptoms. The origin of these motor symptoms and at the same time the pathomechanisms behind these disorders are assumed to involve dopamine regulating systems in the CNS. This point of view is con� rmed by the facts, that antidopaminergic antipsychotics are effective in treating psychotic symptoms of schizophrenia, whereas dopaminergic agents are useful in relieving symptoms related to movement disturbances in RLS. Conventional antipsychotics often induce extrapyramidal side effects, such as dyskinesias, tremor, rigidity and akathisia, which can easily be misinterpreted symptoms of some other clinical, somatic or neurologic disorders or exhibit symptoms of the actual mental illness. Especially neuroleptic induced akathisia in schizophrenia resembles symptoms related to RLS, such as subjective inner restlessness and objective restless movements of legs, sometimes appearing in the upper extremities, too.

CNS motor control, especially the generators that re� ect the function of the basal ganglia, was in the focus of this study because of the dyskinetic features of these disorders. The central motor system is a very complex system, that is provided with a certain hierarchy of control levels, to be able to maintain the most important and vital functions for the human body. The forebrain represents the highest evolutionary level and the spinal cord the lowest level in the CNS. Then highest levels, like the association areas of neocortex and the basal ganglia have a strategy function, the middle levels, like the motor cortex and cerebellum have a tactic function and the lowest level, the brain stem and the spinal cord have executive functions. A direct motor loop through the basal ganglia of the brain evidently facilitates the initiation

60

6. DISCUSSION

of voluntary movements. Thus, if the inhibition of thalamus were increased by the basal ganglia, this would result in hypokinesia, reduction of movements, whereas the decreased basal ganglia output would result in increased movements, hyperkinesia (Bear, 2007).

The postural control is coordinated by the vestibular system, proprioceptive system and vision. Circadian rhythm, some neurological illnesses and sensorimotor disturbances as well as tiredness, loss of sleep or other one`s attentional ability disturbing factors may individually in� uence the postural control. In turn, sportsmen, for example shooters, may have better postural balance coordination. There could not be found earlier studies focusing on the postural control in RLS. Postural control has not been a much investigated topic in schizophrenia, either. At the time of our TMS study procedures took place, TMS had been introduced as a promising investigation method.

The aim of this study was to demonstrate with the help of modern investigation methods and appropriate technical applications that movement disturbances in schizophrenia and RLS do not only clinically resemble each other but also originate in the same generator area in the central nervous system (CNS).

6.2. Material and methodological questions

6.2.1. SPECIAL QUESTIONS CONCERNING SUBJECTS (STUDIES I–IV)

Handedness is a complex representation of distinguished lateralized functions of CNS. In our studies, handedness was assessed with the help of Edinburgh Handedness Inventory, but footedness was mainly estimated by asking the subject´s own adjustment. Handedness and footedness are not always equal, which makes the interpretation of the results complicated. In our study the dominant brain part was determined due to evaluated handedness for each subject. Because of this possibly interfering factor, much attention was not paid to asymmetric � ndings in the study. No distinct conclusions could be drawn concerning the question of the CNS lateralization in schizophrenia.

The controls were in general healthy persons and they reported physical well-being. The results of the controls were consistent within the group and in comparison to normal values of earlier studies. The controls in both TMS studies were selected from the same control group, aiming to match the gender and age as appropriate.

61

6.2.2. TRANSCRANIAL MAGNETIC STIMULATION (STUDIES II–III)

A lot of research has been focused on the motor control in schizophrenia and in RLS with the help of transcranial magnetic stimulation (TMS) that is a useful tool with its different applications to investigate the function of the motor pathways and the central inhibition in the central nervous system. Earlier results tend to vary depending on the applied material and methods (Haraldsson et al., 2004). Therefore we chose a different, accurate technique for recording the responses in the muscles. Instead of commonly used surface electrodes, we inserted an intramuscular pair of monopolar electrodes in the target muscles. This recording method provides a possibility to record a high number of single motor units simultaneously, thus, re� ecting a comprehensive part of the function of the motor track to the target muscle (Nandedkar et al., 1994, Barkhaus et al., 1994, 2006). The changes in muscular electrical activity, including the � ring frequency, the high frequency components of the muscular activity could be evaluated (Rosenfalck, 1969)

The recording with intramuscular electrodes made it possible to distinguish the high frequency components of the muscle activity (Rosenfalck, 1969) and thus to determine the onset and end of the silent period precisely and to detect all recurrent compounds of CSPs. The methodological differences could explain the variable results for example in the latency of MEP in schizophrenia (Puri et al., 1996) and in the duration of silent period (Davey et al., 1997, Fitzgerald et al., 2002a,b, Daskalakis et al., 2002). Results elicited in homogeneous and heterogeneous subject groups with the help of different types of TMS techniques makes the comparison of these results complicated (Wobrock et al., 2008, 2009).

The study sample sizes were initially planned to be small, especially in concern of the TMS studies. The recording technique and procedure required high professional investigatory skills in neurophysiology and appropriate technical applications. During the measurements, the subjects needed to possess adequate skills to cope with the investigator and follow the required study protocol.

In these studies our main interest was to investigate central inhibition and to characterize the function of the descending corticospinal motor pathways down to the target muscles. Single pulse TMS was chosen because of applicable and suitable method for this purpose. The stimulation intensity constantly exceeded the motor threshold level and could be easily con� rmed as a motor response. The round coil was chosen because of its wider stimulation area compared to butter� y coil type. Thus, it became easier to � nd the appropriate cortical site for stimulation of the target muscles.

Inhibitory responses were measured during maximal activation of target muscles. During maximal contraction the electrophysiological muscle interference pattern re� ects the comprehensive motor recruitment and can be veri� ed by intramuscular needle electrode measurement. The temporary complete suppression

62

6. DISCUSSION

of interference pattern mirrors the inhibition of motor activation during maximal muscle contraction.

Based on literature (Hess et al., 1987, Rothwell et al., 1987) the MEPs show amplitude variation to the considerable extent. We did not � nd relevant to assess amplitude sizes in this study. Generally recommended implications for measuring MEPs and CSP after TMS of motor cortex were applied (Säisänen et al., 2008).

6.2.3. COMPUTERIZED FORCE PLATFORM POSTUROGRAPHY (CFPP)

The CFPP is considered to be a nonspeci� c, but a reliable method that allows the investigation of sensorimotor neural and attentional mechanisms in a standing subject (Kingma et al., 2011). The study procedures can easily be repeated in large populations (Forsman et al., 2007), but because of the pilot art of the studies, the study samples were limited. Center point of pressure forces (CPPF) and the center point of force velocity (CPFV) are the most commonly used parameters that are easily measured and re� ect the changes of the imaginary center point forces of the body mass and its path velocity sway velocity, during one´s stance with eyes open and eyes closed conditions on the platform.

The room used for the measurements was tried to keep unchanged and peaceful. The speci� c features of the subject`s disorder, for example the regular and optimal timing for the measurements (RLS, controls) and the mental and motor conditions (schizophrenia) were taken into account to be able to follow the study protocol accurately. Regarding RLS, the upright standing position requires active muscular work and stimulates CNS feedback, thus, the upright stance may not be the most optimal position to reach the most severe symptoms of RLS in whole. However, it can be concluded that the sensitivity of the CFPP method was high enough to differentiate signi� cant distinct differences in both disorder groups. These pilot art studies were the � rst ones to our knowledge to explore the maintenance of the postural balance in these chronic disorders.

6.3. Results of TMS studies II and III

The results of our TMS studies con� rmed some results of earlier studies, showing that the function of descending motor pathways is correct in schizophrenia and RLS. We did not detect any signi� cant side-to-side differences concerning the TMS results within any of the study groups. Earlier studies have reported, that in healthy persons CSPs are less excitable in the dominant motor cortex (Priori et al. 1999) and that healthy right-handers show more inhibition and less facilitation than left-

63

handers (Civardi et al. 2000). These � ndings may support the signi� cance of the asymmetric CSP results observed in both disorders compared to healthy controls in this study, but because of the interfering factors, such as possible medication effects and inclusion of right-and left-handed subjects with schizophrenia in these studies, the � ndings referring to deviant asymmetry have to be interpreted with concern.

Interestingly after TMS we discovered multiple central silent periods (CSP) in the respective target muscle in schizophrenia and RLS both instead of one complete period of maximal suppression in the voluntary activated muscle. The number of these separate CSP compounds was signi� cantly higher in the dominant Abductor Digiti Minimi muscle (ADM) in RLS and in schizophrenia compared to controls. In literature, the early part of the CSP is described to re� ect a suppression of the spinal motor nuclear activity mediated directly from the motor cortex, whereas the later part of the CSP re� ects a suppression of the muscle activity by supraspinal structures presynaptic to fast descending motor pathways (Cantello et al., 1992). It is unclear if the � rst compounds of CSPs in our study could be interpreted equal to the cited early spinal parts and the later compounds with supraspinal parts.

6.3.1. SPECIAL CONSIDERATIONS IN REGARD WITH STUDY III AND DOPAMINE INTERACTIONS

In our study atypical antipsychotics tended to lengthen CSP preferably in the non-dominant side but to promote occurrence of multiple CSPs on the dominant body side. This lengthening effect could be based on the GABA(B)ergic regulation of the inhibitory neuronal circuits by atypical antipsychotics and on the decrease of dopamine regulation in the CNS.

Atypical antipsychotics improve psychiatric symptoms including anxiety but induce less clinical and distressing extrapyramidal symptoms, especially rigidity. Conventional antipsychotics improve mental conditions with psychotic features, by decreasing dopamine release in the CNS, which often results in subjective inner distress, clinically observable restlessness, stiffness and rigidity in one´s body and limbs (Stahl, 2010) forcing one to move oneself, resembling symptoms in RLS. In our TMS study atypical antipsychotics seemed to normalize or even enhance the central inhibition in schizophrenia. The shortened CSPs could be based on the pathomechanism of the illness itself or on the long-term use of conventional antipsychotics.

In both schizophrenia and RLS the upper extremities were chie� y affected by multiple CSPs and the dominant hemispheric side with respective stimulation sites. The � ndings were signi� cant, especially on the dominant ADM. This could be explained by the fact, that in schizophrenia extrapyramidal symptoms preferably

64

6. DISCUSSION

appear in the upper dominant extremity. However, a clinically known fact is that EP-symptoms such as rigidity induced by antidopaminergic agents are easily identi� able in the non-dominant upper extremity. The phenomenon is evidently linked to hypodopaminergia unrelated to treatment with antipsychotic agents (Caliguri et al. 1993), but could be further strengthened by antidopaminergic agents.

Due to multiple CSPs in RLS and in schizophrenia both, this alteration in central inhibition could be assigned to hypodopaminergia. Central dysregulation of dopamine transmission may promote psychiatric symptoms, but also play a crucial role in causing motor changes (Jarcho et al., 2012). Both disorders, particularly concerning the motor symptoms, according to literature are supposed to have their pathophysiological origin in the basal ganglia or close to the subcortical locations that coordinate voluntary movements in the CNS.

The complex interaction mechanisms between the CNS neurotransmitters along the neural motor pathways may be impaired in RLS and schizophrenia. Thus, multiple CSPs could re� ect an imbalance in the neurotransmitter (GABA, DA) regulating systems in the extrapyramidal tracts (Stahl, 2010). In this study, slightly reduced central inhibition in users of conventional antipsychotics could be connected to slightly increased level of extrapyramidal symptoms (BAS, AIMS, p=0.05) re� ecting tendency to hyperkinesias, whereas the enhanced inhibition in the users of atypical antipsychotics could re� ect tendency to hypokinesias. Some properties of CSPs, like the duration, may be connected to positive or negative symptoms of schizophrenia (Wobrock et al. 2009, Liu et al., 2009). In this study a positive correlation between multiple CSPs in the non-dominant ADM and higher PANSS scores in schizophrenia was obtained. Severe symptoms of schizophrenia often need treatment with high doses of antipsychotics, which may again refer to hypodopaminergia. However, the relevance of this � nding is unclear.

Earlier studies have shown inconsistent results on the duration of the CSPs in RLS. Modi� ed CSP con� gurations were observed in RLS and in Parkinson’s disease. A disturbed basal ganglia control and output to the primary motor cortex have been suggested to explain these � ndings (Ondo et al., 2002, Priori et al., 1994, Cantello et al., 2007, Nardone et al., 2006). The TMS measurements of this study in RLS were not performed during the most optimal time considering the typical occurrence of RLS symptoms- in between the morning to day-time- a possible reason, why subjects with RLS did not show alteration in duration of CSPs compared to control group.

The signi� cant occurrence of recurrent inhibitions among ADMs in our RLS subjects could be contributed to the fact that arms are generally impacted in the chronic forms of RLS. Since central inhibitory circuits of the hand and foot motor cortex areas are connected to each other in human (Tergau et al., 1999), this might partly explain the occurrence of multiple CSPs uncovered in our study in the upper and lower extremities in RLS and schizophrenia. On the other hand, a reduced

65

central inhibition has been found to correlate with sensory-motor symptoms in RLS, especially involving arms (Quatrale et al., 2003). All RLS subjects and their matching controls were right-handed, thus, this should not be an interfering factor in this study. However, the research method used in this study to assess the hemispheric dominance was probably not comprehensive enough.

Since manifestations of mental symptoms in RLS are not typical compared to disorders such as schizophrenia, the phenomenon of multiple CSPs might not re� ect the disorganization of mental conditions. Because the inhibitory motor control were more prone to disrupt in the important dominant hemispheric side, this could also be understood as a protecting mechanism of the higher levels of the motor control hierarchy to preserve the inhibitory functions operational. This could be regarded as a compensation mechanism “� ghting” against hypodopaminergia and the inhibitory de� cit by producing recurrent inhibition.

6.4. Results of the CFPP studies

The posturographic studies demonstrated, that among subjects with schizophrenia closing the eyes had less impact on the center point of velocity (CPFV, cm/s) than in controls. The average change of the sway direction during eye closure tended to shift to the right in controls but to the left in subjects with schizophrenia. Interestingly, subjects with RLS held signi� cantly more stable posture during eyes open, but their CPFV approached the CPFV level observed in controls when the eyes were shut. The average shift of the CPF in subjects with RLS and controls directed to the left and forward during the eye closure. The differences in the anterior-posterior shift between the two positions within the RLS group and the lateral shift were signi� cant within both groups.

The average CPF shift during eye closure tended to direct to the left in RLS and schizophrenia. In schizophrenia this could mean that eye closure facilitates the subclinical right hemineglect (Early et al. 1989, Harvey et al., 1993), however, the effects of medication cannot be ruled out (Lauerma et al. 1994). The symptom relieving dopaminergic agent seemed to have a normalizing effect on the postural sway velocity and on the symptom severity in RLS. This was seen as reduction of akathisia (BAS) and subjective symptom severity (VAS). However, pramipexole did not seem to affect the sway area in RLS. Even though the tendency to sway leftwards during eye closure was present in both disorders, the sway was not corrected after pramipexole intervention in RLS. Thus, this phenomenon may not purely be linked to hypodopaminergia.

Other motor control and sensory-motor integrative functions coordinating systems of the CNS, like cerebellum and related circuits are supposed to be involved

66

6. DISCUSSION

in the deviant maintenance of the postural stability in schizophrenia, too (Kent et al., 2012). The control groups exhibited different results with respect to the average CPF shift in these CFPP studies, thus, the CPF shift alterations in general need further investigation of these disorders in comparison to controls among larger sample groups.

The study results propose that visual component has lost its dominance in the balance control in subjects with schizophrenia while in subjects with RLS, vision aided to hyperstabilize the upright stance. Therefore the strategy of maintaining postural balance and utilize visual information may be impaired in different ways in schizophrenia and RLS. Circadian rhythm regulating organs are located in the thalamus. In both disorders the thalamus, as a subcortical generator of motor control and postural control, may be the key location in the CNS. An altered feedback system of the CNS is suggested lay behind the movement disturbances related to RLS, at least.

6.5. Limitations of the study (I–1V)

6.5.1. STUDY I

Effects of medication cannot be ruled out when interpreting the results because other than dopamine-related neural pathways may also be involved in the management of postural re� exes. Thus, it is possible that altered postural control in subjects with schizophrenia observed in this study is also linked to other de� cits, such as movement and cognitive disturbances, subclinical right hemineglect and long-term medication effects. The small number of subjects with schizophrenia made it impossible to explore plausible differences between paranoid (n=8), disorganized (n=2) and undifferentiated (n=12) subtypes of schizophrenia.

6.5.2. STUDY II

The number of subjects with RLS was limited due to the recruitment procedure. The TMS investigations were performed on two separate dates in the city of Turku. Some volunteers were unable to participate the investigation procedure on scheduled days, which reduced the number of available subject number. The subjects with RLS in the TMS study were recruited from a well selected and clinically examined study population from the city of Turku community and university clinics. An experienced sleep-researcher interviewed the subjects with RLS and ruled out PLMD. At the time this study procedure and the subject recruitment took place,

67

polysomnographic investigations were not common or available. The age difference between the controls and the RLS subjects was expected to be signi� cant, because the controls were recruited from working age population while the typical RLS patient was elderly and/or retired from the workforce.

6.5.3. STUDY III

The age difference was not signi� cant between the schizophrenia and control groups. The recruited participants in the study did not differ considerably regarding the motor symptoms or EP symptoms. Other limitations in the TMS study were the mixed use of various antipsychotics and lorazepam by some of the subjects. In addition, some participants with schizophrenia were left-handed. The limited number of subjects with schizophrenia in the study did not permit exploration of differences between paranoid and undifferentiated subtypes of schizophrenia.

6.5.4. STUDY IV

Limitations of this study was the small number of subjects, a higher number of female (n=11/ total 12) participants with RLS and a lack of placebo control/ versus non-medicated subjects. In addition, the measurements were carried out during a non-optimal position (standing condition) or timing (late afternoon) to capture the maximum symptom severity. The age difference was expected to be signi� cant based on the similar reasons as in the second study. Because all subjects wore their footwear while standing on the platform, the property of the contact surface underneath the feet between the shoes and the platform surface could have slightly in� uenced the results (Qiu et al., 2012).

6.6. Summary: the aims and the results of the study (I–IV)

6.6.1. STUDY I

Subjects with schizophrenia did not � nd more dif� cult to maintain the postural balance than healthy controls. However, the visual impact on the postural sway was less signi� cant for subjects with schizophrenia than for controls. The subjects with schizophrenia in this study were not suffering from severe extrapyramidal symptoms (i.e. symptoms of Parkinsonism). Therefore it is possible to assume the de� ciencies in handling visual control and sensorimotor stimuli may modulate postural control in schizophrenia.

68

6. DISCUSSION

6.6.2. STUDIES II AND III

As expected subjects with schizophrenia and subjects with Restless Legs Syndrome with similar types of clinical manifestations of motor symptoms seemed to show similar inhibitory responses such as disrupted central silent periods in the upper extremities. This might refer to hypodopaminergia and the connection to central dopamine dysregulation may be one of the movement symptoms releasing background factors. As was expected, corticospinal motor pathways in the subjects of these studies were found to function normally.

6.6.3. STUDY IV

The intervention with a dopaminergic agent (pramipexole) relieved RLS symptoms; however a placebo-effect cannot be excluded. Pramipexole caused a little growth of the sway velocity and the sway area. Interestingly the visual in� ux seemed to have a greater impact on the RLS subjects’ ability to control their upright stance compared to controls. Eyes shut and after intake of a dopaminergic agent, the difference disappeared. The study results were consistent with the earlier investigations on the effects of dopaminergic agents on the postural control in persons with Parkinson´s disease. However, the role of vision in the postural control and suggested altered sensorimotor feedback in the CNS need to be researched further.

69

7. CONCLUSIONS

1. TMS studies con� rmed that the elementary function of the central motor pathways was intact in schizophrenia and in RLS. No signi� cant hemispheric differences were observed within the groups (i.e. schizophrenia, RLS, controls).

2. Central inhibition after TMS was observed to be changed in schizophrenia and RLS in the same way: it was disrupted into multiple central silent periods (CSPs). These disrupted CSPs were preferably located in the dominant hemispheric side and especially the motor cortex area of hand muscles.

3. The CFPP studies demonstrated different patterns of utilizing vision in maintaining the upright posture in schizophrenia and RLS: the results suggest a defect of visual compensation in schizophrenia on the postural control whereas a hypercompensatory effect of visual information on the postural control was observed in RLS.

4. Hypodopaminergia is considered to be one of the etiological factors involved in the pathomechanism of the movement disturbances. An imbalance of different CNS neurotransmitters and an impaired regulation of their interactions in the subcortical brain parts, such as basal ganglia is suggested to lie behind the observed motor control changes.

5. A deviant lateralization of the CNS functions in schizophrenia or in RLS could not be veri� ed in this study by using TMS or CFPP: despite the consistency that was obtained in the results pointing to the hemispheric asymmetry in concern of the CSPs and the average sway direction during eye closure in schizophrenia and RLS, the � ndings are not signi� cant because of the previously mentioned limitations of the studies.

71

8. FUTURE CONSIDERATIONS

These studies aimed to solve questions which have not been the focus of earlier research concerning schizophrenia and RLS. Motor control was investigated with the use of methods (TMS and CFPP) considered to be reliable and relevant, although not implemented in wide clinical practice. The CFPP methods and measurements applied in studies I and IV can be performed in large population. The TMS technique utilized in studies II and III was more complicated and requires the knowledge of competency in clinical neurophysiology. In general, these methods and procedures are considered to be useful in further investigations.

CFPP can be applied in clinical practice when evaluating symptoms associated with postural control dif� culties. TMS can be applied in clinical practice to check effects or side effects induced by neuroleptic/ dopaminergic agents or to explore origins of movement disturbances, especially in severe stages of illness.

However, the study procedures should be replicated in larger study populations, in placebo control, and in comparison of non-treated subjects with treated subjects and with other dopamine-related chronic illnesses such as Parkinson´s disease. By combining several different investigation methods such as TMS with appropriate brain imagination techniques, neuropsychological investigations, gait analysis, polysomnography and CFPP with integrated further sensorimotor testing applications, it would be possible to achieve a more comprehensive view of the over-lapping and differing symptom � elds in these diagnosis groups.

73

9. ACKNOWLEDGEMENTS

The main clinical work of this thesis was carried out in Ekenäs, at Ekåsen Psychiatric Hospital, in the Department of Clinical Neurophysiology. It was there, halfway through my specialist training in psychiatry, that I developed an eagerness to discover neurobiological factors behind the etiology of psychosis related symptoms. Docent Ilpo Rimpiläinen, Helsinki University Hospital, presented me an opportunity to investigate motor control of the central nervous system by introducing me to the method of Transcranial magnetic stimulation, and subsequently the method of computerized force platform. Therefore, I am most grateful to him for his professional expertise in neurophysiology and for providing me with practical support and a scienti� c framework within which to apply speci� c techniques and methods.

I wish to express my warmest thanks to Research Professor Hannu Lauerma and Docent Seppo Kähkönen, my principal supervisors, for their constructive and excellent guidance and intellectual support regarding questions pertaining to the scienti� c substance, methodology or any other issues concerning this thesis. I am honoured to have had access to their superb quali� cations and expert knowledge available to me during the course of this thesis. Hannu Lauerma´s impressive ability to describe and analyse psychiatric disorders as well as movement disorders -in the way nobody else is able to- is fascinating thus it inspired me from the very beginning. Seppo Kähkönen helped me enormously with his prompt and expert leadership, close supervision and support consisting of issues related to research methods or relevant techniques, materials or substance. Their unequivocal support throughout has been consistent and incessant.

I am grateful to both Professor Hannu Eskola and Docent Pekka Tani for their valuable feedback when reviewing this thesis. I wish to express my warmest thanks to Heikki Aalto, PhD at Helsinki University Central Hospital, who provided me the technical equipment with the computerized force platform which he himself had designed. He proved to be invaluable with regard to issues both practical and technical in nature. I want to thank Professor Ilmari Pyykkö, Tampere University Hospital, for his valuable and signi� cant advice whenever I needed expert advice on postural control.

I am most grateful to Juha Markkula, MD, PhD, Katinka Tuisku, MD, PhD and Docent Matti Holi, MD, PhD for their excellent collaboration and contribution to research studies on Restless Legs Syndrome. I have the utmost appreciation for Docent Kirsi Suominen, MD, PhD, for her valuable collaboration with regard of my thesis during my employment at the City of Espoo Social and Health Care

74

9. ACKNOWLEDGEMENTS

Services. I would like to thank Docent Jaana Suvisaari for her kind support and advice with superior knowledge of schizophrenia as well as her enthusiastic team for encouragement during my year in the National Institute of Health and Welfare, department of Forensic Psychiatry. I am grateful to Kirsi Niinistö, to Eric and Liz Lähdekorpi for their generous assistance in revising language of the manuscripts.

I am deeply indebted to Rose-Marie Äikäs, PhD, The City University of New York – Queensborough Community College, NY, USA, for her help and excellent support in New York City and Helsinki, and for completing the � nal linguistic revision of this thesis. I wish to express deep gratitude to Leena Gräsbeck in helping me edit the � nal version of this thesis.

I also want to take this opportunity to warmly thank Kaj Palmgren, MD, the Chief Director of Ekåsen Hospital and my previous patients and all participants in this study. I greatly appreciate the collaboration and the time spent among all scientists and clinical co-workers, treatment teams and personnel in the correctional facilities, hospitals, institutions, and clinical settings connected to � elds of psychiatry, neurophysiologicy and mental health care services. These years were � lled with hard work but at the same time they were the most educational and rewarding.

Completing this thesis could not have been possible without support from my sincere friends, Sirpa Knaappila, Tuomo Holmalahti and Irmeli Lähteenmäki, who always believed in me. I want to express my thanks to them all as well as to my sisters and to Rimpiläinen family for their patience and understanding.

Finally, my warmest gratitude is directed to my mother Ritva for her unconditional and caring support, to my son Axel, for his expanding my consciousness in philosophical themes, to my daughter Hilda for her sharp, intellectual and critical feedback on various points of views and lastly, to my husband Ilpo, my colleague and my partner closest to my heart. Without his and my family’s loving care and encouragement while working on this thesis, I could not have been able to complete this challenge.

The journey of this thesis ends where it all began; in Raseborg, which holds a very special place in my heart.

75

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