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.