Direct cortico-motoneuronal (CM) connections of corticospinal tract neurons are a distinctive feature of the primate motor system which are known to be important for the capacity to perform independent finger movements. However, it is still unclear how the appropriate combinations of CM cells are recruited to produce the selective (fractionated) control over muscles of the upper limb that is necessary for independent finger movements. I have investigated whether GABAergic intracortical inhibitory (ICI) circuits in human motor cortex contribute to the selection of the appropriate CM cells during a motor task requiring selective activation of one of several intrinsic hand muscles. Behaviour of ICI circuits during voluntary contraction was compared for the dominant and non-dominant hemisphere of right-handed subjects, as hemispheric differences in ICI may contribute to preferential use of the right hand for fine motor tasks. Finally, I investigated the range of forces over which ICI contributes to selective activation of a hand muscle. Neurologically normal adult human subjects were recruited for all experiments. Surface electrodes recorded electromyographic activity of abductor pollicis brevis (APB), first dorsal interosseous and abductor digiti minimi muscles during controlled isometric contractions of APB at different force levels while subjects attempted to keep the other two muscles relaxed using visual feedback of EMG. Paired-pulse transcranial magnetic stimulation (TMS) was used to assess ICI at rest and during selective activation of a hand muscle. TMS intensity and interstimulus interval were varied in different trials. Data were compared for two different directions of induced current in the brain; posteriorly directed current (PA stimulation) and anteriorly directed current (AP stimulation). ICI is suppressed for corticospinal neurons controlling the muscle targeted for selective activation; no change in ICI was seen for corticospinal neurons controlling the muscles required to be relaxed. This indicates that differential modulation of ICI in human motor cortex contributes to selective activation of a hand muscle. The direction of current flow induced in the brain proved to be critical for demonstrating this effect. It was observed with AP stimulation but not PA stimulation. I argue that this is due to preferential activation by PA stimulation of interneurons producing I1 waves in corticospinal neurons. These interneurons are not acted upon by ICI circuits. This problem makes the conventional PA paired-pulse TMS technique unreliable for the assessment of ICI during voluntary contraction. With AP stimulation it was demonstrated that ICI is not modulated during weak selective activation of a hand muscle (&lt5percent of maximal voluntary contraction), but ICI effects on CM cells controlling the target muscle are progressively suppressed at higher levels of activation. The present study is the first to examine hemispheric differences in ICI during selective isometric contraction of an intrinsic hand muscle. No hemispheric differences were observed. These studies have demonstrated a functional role for ICI in fractionation of hand muscle activity in normal subjects. It also provides an improved basis for investigating the changes in ICI with TMS in various neurological conditions in which it has been reported that GABAergic inhibition is abnormal. / Thesis (Ph.D.)--School of Molecular and Biochemical Science, 2004.

The sensorimotor network receives a rich variety of somesthetic afferents and outputs considerable motor efferents, both of which drive experience-dependent plasticity in the system. It remains unclear to what extent subtle changes in somaesthesis and motor function extrinsic to the brain drive plasticity in the functional organisation and anatomy of the sensorimotor network. This thesis contains a series of multimodal MRI experiments to investigate how altered-use and disuse can induce plastic changes in the sensorimotor network of the human brain. In Chapter 3, a method of mapping digit somatotopy in primary somatosensory cortex at the single-subject level using 7.0 tesla fMRI was developed and applied for a study of healthy participants. Using a phase-encoding paradigm, digit representations were accurately mapped in under 10 minutes. These maps were reproducible over time and comparable to a standard block design. In Chapter 4, a further fMRI study assessed the potential for short-term reorganisation of digit representations in primary somatosensory cortex following a manipulation whereby the right index and right middle fingers were glued together for 24 hours. There was a marked shift in the cortical overlap of adjacent digits after the glued manipulation, not seen across an equivalent control period, providing strong evidence for short-term remapping of primary somatosensory cortex. In Chapter 5, a patient study investigated plasticity associated with chronic unilateral disuse of the upper limb. A cross-sectional comparison with control participants showed reduced grey matter density in the posterior right temporoparietal junction, and increased radial diffusivity in the white matter of the right superior longitudinal fasciculus, consistent with change in the right ventral attention network. A complementary longitudinal study in Chapter 6 investigated structural plasticity associated with rehabilitation of the disused limb. There were localised increases in grey matter density, notably in the right temporoparietal junction, further implicating a potential role for regions responsible for egocentric attention in regaining upper limb use. In Chapter 7, a further patient study investigated candidate predictive biomarkers at the sub-acute stage of stroke recovery, identifying CST-lesion cross-section and sensorimotor network strength as correlates of motor function, which warrant further study. The results of the studies presented in this thesis provide a novel insight into the nature and time frame of functional and structural plasticity associated with altered use and disuse. Further study of how subtle changes in our sensory and motor use shape the sensorimotor network is warranted, particularly in the context of disuse in non-neurological clinical populations.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1960. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Submitted by Cleide Dantas (cleidedantas@ufpa.br) on 2014-07-21T16:07:35Z No. of bitstreams: 2 license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) Dissertacao_MinociclinaAtenuaPrejuizos.pdf: 2544726 bytes, checksum: 3a54c80a11aca9283859e6613d5eab7b (MD5) / Rejected by Ana Rosa Silva (arosa@ufpa.br), reason: Ausência do resumo em português on 2014-09-09T13:51:10Z (GMT) / Submitted by Cleide Dantas (cleidedantas@ufpa.br) on 2014-09-09T15:48:06Z No. of bitstreams: 2 license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) Dissertacao_MinociclinaAtenuaPrejuizos.pdf: 2544726 bytes, checksum: 3a54c80a11aca9283859e6613d5eab7b (MD5) / Approved for entry into archive by Ana Rosa Silva (arosa@ufpa.br) on 2014-09-09T15:49:56Z (GMT) No. of bitstreams: 2 license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) Dissertacao_MinociclinaAtenuaPrejuizos.pdf: 2544726 bytes, checksum: 3a54c80a11aca9283859e6613d5eab7b (MD5) / Made available in DSpace on 2014-09-09T15:49:56Z (GMT). No. of bitstreams: 2 license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) Dissertacao_MinociclinaAtenuaPrejuizos.pdf: 2544726 bytes, checksum: 3a54c80a11aca9283859e6613d5eab7b (MD5) Previous issue date: 2012 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / FAPESPA - Fundação Amazônia de Amparo a Estudos e Pesquisas / Segundo a Organização Mundial da Saúde, o consumo de álcool no mundo tornou-se um problema de saúde pública. Neste contexto, o Brasil figura na 63ª posição no mundo em consumo de álcool per capita para pessoas com 15 anos ou mais de idade. Além de seus efeitos sócio-econômicos, o etanol constitui um importante fator de risco na ocorrência de isquemias cerebrais. O consumo exacerbado desta droga colabora para o mau prognóstico, assim como para o possível tratamento de morbidades relacionadas ao acidente vascular cerebral. O objetivo deste estudo foi avaliar alterações neuromotoras após bloqueio da ativação micróglial com minociclina em ratos submetidos à isquemia focal no córtex motor, quando tratadas cronicamente com etanol da adolescência a fase adulta. Ratos receberam durante 55 dias, por gavagem, etanol (6,5 g/kg/dia, 22,5 p/v). No término destes 55 dias os animais foram submetidos à microinjeções do peptídeo vasoconstritor endotelina-1 (40 pmol), para indução de lesão isquêmica focal córtex motor. Os animais isquemiados foram tratados com minociclina recebendo duas doses diárias de 50 mg/kg nos primeiros dois dias, e mais cinco aplicações diárias únicas de 25 mg/kg, por via intraperitoneal, até o sétimo dia pós-indução isquêmica. Os testes comportamentais realizados foram campo aberto, plano inclinado e rota-rod. Os resultados demonstraram que os animais isquemiados e os expostos ao etanol e isquemiados apresentaram déficits motores em todos os testes comportamentais. Entretanto, o tratamento com minociclina foi capaz de reverte-los, possibilitando melhor desempenho em todos os testes aplicados. Os resultados sugerem que a minociclina foi capaz de reverter os danos motores ocasionados pelo acidente vascular cerebral, mesmo em presença do etanol. O exato mecanismo envolvido neste processo necessita ser investigado em pesquisas futuras. / According to World Health Organization, alcohol consumption in the world has become a public health problem. In this context, Brazil is at 63th position in the world in per capita alcohol consumption for people aged 15 or older. In addition to its socio-economic effects, ethanol is an important risk factor in the occurrence of cerebral ischemia. Exacerbated consumption of this drug contributes to the poor prognosis, as well as possible treatment for health problems related to stroke. The objective of this study was to evaluate neuromotor changes after blocking micróglial activation with minocycline in rats subjected to focal ischemia in the motor cortex, when treated chronically with ethanol from adolescence to adulthood. Rats were given for 55 days by gavage ethanol (6.5 g/kg/dia, 22.5 w/v). At the end of 55 days the animals were microinjected with the vasoconstrictor peptide endothelin-1 (40 pmol) for induction of focal ischemic lesion. The ischemic animals were treated with minocycline receiving two daily doses of 50 mg/kg in the first two days, and five daily applications of single 25mg/kg, intraperitoneally, by the seventh day post-ischemic induction. Behavioral tests consisted of open field, inclined plane and rota-rod. The results showed that the animals were exposed to ethanol showed motor deficits in all behavioral tests. However, treatment with minocycline was able to reverse them, enabling better performance on all tests. The results suggest that minocycline was able to reverse damage caused by motors stroke, even in the presence of ethanol. The exact mechanism involved in this process need to be investigated in future research.

The primary aim of this thesis is to investigate the physiological effects of transcranial direct current stimulation (tDCS) as applied to the primary motor cortex (M1). This research was largely motivated by the need to understand the basic physiological changes of tDCS, in order to evaluate its use as a potential tool in recovery after stroke, as well as its more general applicability as a tool to modulate plasticity. The experiments in this thesis assess the ability of tDCS to modulate the primary motor cortex in healthy controls. The effects of tDCS on cortical GABA and motor resting state functional connectivity were measured with magnetic resonance spectroscopy (MRS) and resting functional MRI (fMRI). Anodal stimulation reduced GABA concentration and increased functional connectivity in the stimulated M1. Testing these changes within the same individuals demonstrated that the magnitude of changes do not correlate across subjects. Novel evidence on the timecourse of GABA change demonstrated that the reduction in GABA is most prominent in the 30-minute period after stimulation. To determine whether the tDCS-induced modulations in inhibition is restricted to the stimulated hemisphere or whether inhibitory changes could be observed in the nonstimulated M1, or in the interhemispheric connections between the M1s, transcranial magnetic stimulation (TMS) was used to measure intracortical inhibition in each M1 and interhemispheric inhibition and facilitation in the contralateral M1. There were no polarity-specifc effects on intracortical inhibition within either M1, and no changes in interhemispheric excitability from the stimulated to non-stimulated M1. Development of a two-voxel MRS method at ultra high field (7 Tesla) allowed for concurrent measurements of cortical neurotransmitters from both M1s with excellent spectral quality and GABA quantifcation. This method was used to demonstrate the timecourse of tDCS-induced changes in neurochemicals concurrently from both M1s. Anodal stimulation reduced GABA in both the anode-targeted and non-stimulated M1. Cathodal stimulation decreased GABA and glutamate in the non-stimulated M1, with no concurrent changes in the cathode-targeted M1. Bilateral stimulation reduced glutamate in both M1 with no change in GABA.

In questa tesi descriviamo una procedura automatizzata per l’analisi della corteccia motoria dello scimpanzè, del Macaca fascicularis e del cavallo, basata su un nuovo metodo computerizzato di analisi delle sezioni colorate attraverso il metodo di Nissl, al fine di studiare la corteccia cerebrale in specie differenti. Le microfotografie delle sezioni sono state elaborate con una procedura standardizzata usando il software ImageJ. Questa procedura ha previsto la suddivisione degli strati corticali, dal primo al sesto, in diversi frames. Per misurare la complessità delle cellule nervose (cioè quanto una cellula fosse diversa dalle adiacenti) abbiamo utilizzato un modello di rappresentazione statistica non-parametrica che mostra come la complessità può essere espressa in termini di un adeguato indice di dispersione statistica quale il MAD (mean absolute deviation). Abbiamo quindi dimostrato che gli strati piramidali della corteccia motoria del cavallo sono più irregolari di quelli di scimpanzè e Macaca fascicularis. La combinazione dell’analisi automatica delle immagini e delle analisi statistiche consente pertanto di confrontare e classificare la complessità della corteccia motoria attraverso diverse specie. Il modello viene proposto come strumento al fine di contribuire a stabilire le somiglianze cerebrali tra umani e animali, rispettando il principio delle 3R. / In this thesis we describe an automated procedure based on a new computerized method of partitioning Nissl-stained sections of the motor cortex of the chimpanzee, crab-eating monkey, and horse, to study the neocortex in different species. Microphotographs of the sections were first processed using a standard procedure in ImageJ, then the stained neuronal profiles were analyzed within continuously adjoining frames from the first to the sixth layer of neocortex. To measure the neuronal complexity (how a given cell is different from its neighbors) we used a general non-parametric data representation model showing that the complexity can be expressed in terms of a suitable measure of statistical dispersion such as the mean absolute deviation. We demonstrated that the pyramidal layers of the motor cortex of the horse are more irregular than those of the monkeys studied. The combination of automated image analysis and statistical analysis made it possible to compare and rank the motor cortex complexity across different species. Therefore, we are confident that our work will help to establish brain similarities between humans and animals used for alimentary purpose, whose brain is often discarded. This, in turn, will allow to carry out the experimental brain research obeying the 3Rs principle.

Spike timing-dependent plasticity (STDP) has been suggested as one of the key mechanism underlying learning and memory. Due to its importance, timing-dependent plasticity studies have been approached in the living human brain by means of non-invasive brain stimulation (NIBS) protocols such as paired associative stimulation (PAS). However, contrary to STDP studies at a cellular level, functional plasticity induction in the human brain implies the interaction among target cortical networks and investigates plasticity mechanisms at a systems level. This thesis comprises of two independent studies that aim at understanding the importance of considering broad cortical networks when predicting the outcome of timing-dependent associative plasticity induction in the human brain. In the first study we developed a new protocol (ipsilateral PAS (ipsiPAS)) that required timing- and regional-specific information transfer across hemispheres for the induction of timing-dependent plasticity within M1 (see chapter 3). In the second study, we tested the influence of individual brain structure, as measured with voxel-based cortical thickness, on a standard PAS protocol (see chapter 4). In summary, we observed that the near-synchronous associativity taking place within M1 is not the only determinant influencing the outcome of PAS protocols. Rather, the online interaction of the cortical networks integrating information during a PAS intervention determines the outcome of the pairing of inputs in M1.