Daugelis neurodegeneracinių ligų klinikinių žymenų yra nespecifiniai ir nustatomi tik progresavus ligai. Neurodegeneracinio parkinsonizmo diagnostika remiasi klinikiniais kriterijais, tačiau idiopatinės Parkinsono ligos (PL), kuri yra pati dažniausia neurodegeneracinio parkinsonizmo priežastis, klinikiniai požymiai dažnai pasireiškia ir esant kitiems parkinsonizmo sindromams. Patikimas, neinvazinis, nebrangus ir saugus diagnostinis testas PL, galbūt ir demencijų diagnostikai bei diferencinei diagnostikai yra aktualus dėl kelių pagrindinių priežasčių: skirtingų parkinsonizmo sindromų medikamentinis gydymas ir ligos prognozė labai skiriasi; tiksli diagnozė svarbi imantis neatidėliotinų priemonių užkertant kelią kai kurioms sindromams būdingoms gyvybei grėsmingoms komplikacijoms; PL ankstyvoji diagnostika ikiklinikinėje stadijoje leistų anksčiau parinkti ir pradėti patogenezinį gydymą; atsiradus efektyvios neuroprotekcijos galimybėms, atsirastų ir tam tikro amžiaus populiacijos atrankinės patikros įrankio poreikis. Disertacinio darbo tikslas buvo nustatyti transkranijinės sonografijos vertę neurodegeneracinių ekstrapiramidinės nervų sistemos ligų diagnostikai, diferencinei diagnostikai ir atrankinei patikrai. Užsienio mokslininko dalyvavimas doktorantūros procese finansuojamas Lietuvos mokslo tarybos (konkurso paraiškos Nr. VIZ-DOK-124, doktorantūros tarybos narė doc. dr. Pille Taba). / The most symptoms of neurodegenerative disorders are non-specific and come to clinical attention only when the disease has progressed. The diagnostics of neurodegenerative parkinsonism is based on clinical criteria. However, the symptoms of idiopathic Parkinson‘s disease (PD), which is the most common cause of neurodegenerative parkinsonism, are often observed in patients with other parkinsonian syndromes. A reliable, non-invasive, safe and affordable test for the diagnosis and differential diagnosis of PD and, perhaps, dementia is relevant for multiple reasons: the disease prognosis and treatment of parkinsonian syndromes differs greatly and an unbiased disease marker would facilitate the development of neuroprotective drugs; the exact diagnosis is crucial in order to take urgent measures to avoid life-threatening complications; early diagnosis of PD would enable pathogenetic treatment; with the arrival of neuroprotective options, the need for selective screening of population according to certain age and other risk factors would arise. The aim of the doctoral study was to investigate the value of transcranial sonography for the diagnosis, differential diagnosis and screening of neurodegenerative extrapyramidal disorders. Participation of the Scientist from foreign institution in the Process of Doctoral Studies is financed by the Research Council of Lithuania (Tender-based financing application No VIZ-DOK-124, the Defence Council Member Assoc. Prof. Dr. Pille Taba).

Evidence suggests that cerebral blood flow patterns accompanying a mental activity are retained in many locked-in patients. Thus, real-time monitoring with functional transcranial Doppler (TCD) together with a specific mental task could control a brain-computer interface (BCI), thereby providing self-initiated interaction. The objective of this study was to create an automatic detection algorithm to differentiate hemodynamic responses coincident with one's performance of verbal fluency (VF) versus counting tasks. We recruited 10 healthy adults who each silently performed up to 30 VF tasks and counted between each. Both middle cerebral arteries were simultaneously imaged using TCD. Linear Discriminant Analyses (LDA) successfully differentiated between VF and both prior and post counting tasks. For every participant, LDA achieved the 70% classification accuracy sufficient for BCIs. Results demonstrate automatic detection of a VF task by TCD and warrant further investigation of TCD as a BCI.

Evidence suggests that cerebral blood flow patterns accompanying a mental activity are retained in many locked-in patients. Thus, real-time monitoring with functional transcranial Doppler (TCD) together with a specific mental task could control a brain-computer interface (BCI), thereby providing self-initiated interaction. The objective of this study was to create an automatic detection algorithm to differentiate hemodynamic responses coincident with one's performance of verbal fluency (VF) versus counting tasks. We recruited 10 healthy adults who each silently performed up to 30 VF tasks and counted between each. Both middle cerebral arteries were simultaneously imaged using TCD. Linear Discriminant Analyses (LDA) successfully differentiated between VF and both prior and post counting tasks. For every participant, LDA achieved the 70% classification accuracy sufficient for BCIs. Results demonstrate automatic detection of a VF task by TCD and warrant further investigation of TCD as a BCI.

This thesis describes experiments designed to investigate the effects of neuromuscular electrical stimulation (NMES) on corticospinal (CS) excitability in humans. NMES delivered at 100 Hz was more effective for increasing CS excitability than 10-, 50-, or 200-Hz NMES. CS excitability increases occurred after 24 min of 100-Hz NMES, were strongest in the stimulated muscle, and were mediated primarily at a supraspinal level. NMES of the common peroneal nerve of the leg increased CS excitability in multiple leg muscles, whereas NMES of the median nerve of the hand increased CS excitability in only the muscle innervated by that nerve. Additionally, CS excitability for the hand increased after 40 min of relatively high intensity and frequency NMES but not after 2 h of lower intensity and frequency NMES. These results have implications for identifying optimal NMES parameters to augment CS excitability for rehabilitation after central nervous system injury.

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

The purpose of this thesis was to investigate the potential mechanisms and sites of neural adaptations that mediate cross-limb transfer of strength and motor learning that can occur subsequent to unilateral training. Better understanding of the mechanisms should allow therapeutic benefits of this effect to be assessed. There are two main classes of mechanisms that could contribute to cross-limb transfer. The first is described by the ??bilateral access?? hypothesis, which suggests that neural adaptations induced by training reside in bilaterally projecting motor areas that are accessible to the untrained (ipsilateral) hemisphere during task execution to facilitate performance. According to the alternative ??cross-activation?? hypothesis, activation of the untrained hemisphere during unilateral training leads to adaptations in the untrained hemisphere that cause improved performance with the opposite untrained limb. A series of studies were conducted in this research. We directly tested the cross-activation hypothesis via a reliable twitch interpolation technique involving transcranial magnetic stimulation (TMS). Four-weeks of strength training for the right wrist increased neural drive (from the untrained motor cortex) to the untrained left wrist. The data demonstrate that strength training of one limb can influence the efficacy of corticospinal pathways that project to the opposite untrained limb, consistent with the cross-activation hypothesis. To investigate the contribution of each hemisphere in cross-limb transfer, we applied repetitive TMS (rTMS) to the trained or the untrained motor cortex to disrupt brain processing after unilateral ballistic training. Learning to produce ballistic movements requires optimization of motor drive to the relevant muscles in a way that resembles high-force contractions performed during strength training. Ballistic skill transferred rapidly to the untrained hand and the improved performance was accompanied by bilateral increases in corticospinal excitability. Performance improvement in each hand was specifically suppressed by rTMS of the opposite hemisphere. Thus the motor cortex ipsilateral to the trained hand is critically altered during unilateral training; and neural adaptations within this untrained hemisphere are crucial in cross-limb transfer of ballistic skill. Overall, the data are in agreement with the cross-activation hypothesis for high-force and ballistic tasks, although they do not exclude the potential involvement of bilateral access mechanisms.

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Neuroplasticity provides the basis for many of our most fundamental processes including learning, memory and the recovery of function following injury. This thesis is concerned with the neurophysiological and functional correlates of sensorimotor neuroplasticity in the healthy and focal dystonic populations. My initial experiments were conducted to determine the functional correlates of neuroplasticity induced in the primary motor (M1) and primary sensory (S1) cortices during a grip lift task. In healthy subjects these experiments further quantified the role of M1 in the anticipatory control of grip force scaling and demonstrated a role for S1 in triggering subsequent phases of the motor plan. My second series of experiments served to extend these findings by examining the functional correlates of neuroplasticity induced in the supplementary motor area (SMA). This study provided evidence for the role of left SMA in the control of grip force scaling and a role for left and right SMA in the synchronization of grip force and load force during the grip-lift synergy. Afferent input is known to be a powerful driver of cortical reorganisation. In particular, the timing and pattern of afferent input is thought to be crucial to the induction of plastic change. In healthy subjects, I examined the neurophysiological effects of applying “associative” (synchronous) and “non-associative” (asynchronous) patterns of afferent input to the motor points or digits of the hand. I observed an increase in the volume and area of the cortical representation of stimulated muscles when associative stimulation was applied over the motor points of two hand muscles. This pattern of stimulation also caused the centres of gravity of the stimulated muscles to move closer together, mimicking the maladaptive changes seen in focal hand dystonia. Non-associative stimulation and stimulation applied to the digits did not produce such an effect. Task-specific focal dystonia is characterised by excessive representational plasticity resulting in cortical representations which are significantly larger, and demonstrate greater overlap, than those seen in healthy individuals. These changes are thought to be driven, in part, by repetitive movement patterns which promote associative patterns of afferent input over an extended time period. On the basis of this knowledge, I applied non-associative stimulation to the hand muscles of dystonic subjects. Following this intervention, I noted a contraction of representational maps and a separation in the centres of gravity of the stimulated muscles. These neurophysiological changes were accompanied by improvements on a cyclic drawing task. This thesis demonstrates the functional correlates of neuroplasticity in M1, S1 and SMA during object manipulation using a precision grasp. These findings further extend our knowledge on the mechanisms underlying effective grasp control and assist us in the development of future rehabilitation protocols for neurological conditions involving grasp dysfunction. In addition, this thesis is the first to demonstrate an improvement in both neurophysiological and functional measures in focal dystonia following a period of non-associative afferent stimulation. These results open up exciting new avenues for the development of effective treatment protocols in those with focal hand dystonia. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010

Neuromuscular electrical stimulation (NMES) has become an increasingly popular rehabilitative treatment approach for swallowing disorders (dysphagia). However, its precise effects on swallowing biomechanics and measures of swallowing neurophysiology are unclear. Clearly defined NMES treatment protocols that have been corroborated by thorough empirical research are lacking. The primary objective of this research programme was therefore to establish optimal NMES treatment parameters for the anterior hyo-mandibular (submental) musculature, a muscle group that is critically involved in the oral and pharyngeal phases of swallowing. Based on previous research, the primary hypothesis was that various NMES treatment protocols would have differential effects of either enhancing or inhibiting the excitability of corticobulbar projections to this muscle group. The research paradigm used to test this hypothesis was an evaluation of MEP amplitude and onset latency, recorded in the functional context of volitional contraction of the submental musculature (VC) and contraction of this muscle group during the pharyngeal phase of volitional swallowing (VPS, volitional pharyngeal swallow). Outcome measures were recorded before and at several time points after each NMES treatment trial. This methodology is similar to, but improved upon, research paradigms previously reported. Changes in corticobulbar excitability in response to various NMES treatment protocols were recorded in a series of experiments. Ten healthy research participants were recruited into a study that evaluated the effects of event-related NMES, whereas 15 healthy research participants were enrolled in a study that investigated the effects of non-event-related NMES. In a third cohort of 35 healthy research participants, task-dependent differences in corticobulbar excitability were evaluated during three conditions of submental muscle contraction: VC, VPS and submental muscle contraction during the pharyngeal phase of reflexive swallowing (RPS, reflexive pharyngeal swallowing). Event-related NMES induced frequency-depended changes in corticobulbar excitability. NMES administered at 80 Hz facilitated MEP amplitude, whereas NMES at 5 Hz and 20 Hz inhibited MEP amplitude. No changes were observed after NMES at 40 Hz. Maximal excitatory or inhibitory changes occurred 60 min post-treatment. Changes in MEP amplitude in response to event-related NMES were only observed when MEPs were recorded during the VC condition, whereas MEPs recorded during the VPS condition remained unaffected. Non-event-related NMES did not affect MEP amplitude in either of the muscle contraction conditions. Similarly, MEP onset latencies remained unchanged across all comparisons. MEPs were detected most consistently during the VC contraction condition. They were less frequently detected and were smaller in amplitude for the VPS condition and they were infrequently detected during pre-activation by RPS. The documented results indicate that event-related NMES has a more substantial impact on MEP amplitude than non-event-related NMES, producing excitatory and inhibitory effects. Comparison of MEPs recorded during VC, VPS and RPS suggests that different neural networks may govern the motor control of submental muscle activation during these tasks. This research programme is the first to investigate the effects of various NMES treatment protocols on the excitability of submental corticobulbar projections. It provides important new information for the use of NMES in clinical rehabilitation practices and our understanding of the neural networks governing swallowing motor control.

The purpose of this thesis was to investigate the potential mechanisms and sites of neural adaptations that mediate cross-limb transfer of strength and motor learning that can occur subsequent to unilateral training. Better understanding of the mechanisms should allow therapeutic benefits of this effect to be assessed. There are two main classes of mechanisms that could contribute to cross-limb transfer. The first is described by the ??bilateral access?? hypothesis, which suggests that neural adaptations induced by training reside in bilaterally projecting motor areas that are accessible to the untrained (ipsilateral) hemisphere during task execution to facilitate performance. According to the alternative ??cross-activation?? hypothesis, activation of the untrained hemisphere during unilateral training leads to adaptations in the untrained hemisphere that cause improved performance with the opposite untrained limb. A series of studies were conducted in this research. We directly tested the cross-activation hypothesis via a reliable twitch interpolation technique involving transcranial magnetic stimulation (TMS). Four-weeks of strength training for the right wrist increased neural drive (from the untrained motor cortex) to the untrained left wrist. The data demonstrate that strength training of one limb can influence the efficacy of corticospinal pathways that project to the opposite untrained limb, consistent with the cross-activation hypothesis. To investigate the contribution of each hemisphere in cross-limb transfer, we applied repetitive TMS (rTMS) to the trained or the untrained motor cortex to disrupt brain processing after unilateral ballistic training. Learning to produce ballistic movements requires optimization of motor drive to the relevant muscles in a way that resembles high-force contractions performed during strength training. Ballistic skill transferred rapidly to the untrained hand and the improved performance was accompanied by bilateral increases in corticospinal excitability. Performance improvement in each hand was specifically suppressed by rTMS of the opposite hemisphere. Thus the motor cortex ipsilateral to the trained hand is critically altered during unilateral training; and neural adaptations within this untrained hemisphere are crucial in cross-limb transfer of ballistic skill. Overall, the data are in agreement with the cross-activation hypothesis for high-force and ballistic tasks, although they do not exclude the potential involvement of bilateral access mechanisms.