TMS coil positioning.

<p>Schematic drawing of the smallest of the commercially available coils, which was used for this experiment (<i>Upper panel</i>), a custom-made ∼25 mm loop radius figure-of-eight TMS coil (exact dimensions of the coil used indicated in the figure) (Magstim Company, Carmathenshire, Wales). (<i>Bottom panel)</i> X-rays photography of monkey ‘C’. The red target represents the estimated stereotaxic coordinates of the monkey’s FEF area. The length of the white bar illustrates approximate differences in bone thickness between the human and the macaque skull at frontal locations.</p

Estimate of discomfort induced by TMS.

<p>Estimation of discomfort based on the interaction between percent of initiated trials (used as an indirect correlate of the level of discomfort; the higher the discomfort the lower the number of initiated trials) and TMS intensity (% of machine maximal output). (<i>Upper panel)</i> Note that below 50% intensity, low discomfort is inferred from the high percent of initiated trials (grey and black lines) respectively for monkey ‘C’ and ‘Y’, for the TMS condition (dotted lines) as compared to the sham TMS condition (solid lines). (<i>Bottom panel</i>) Representative traces of eye movement with/without TMS (respectively grey, black lines) at 50% intensity for one of the monkeys. At least for the two SOAs used in the study (100 and 150 ms) eye movement metrics were not affected by TMS. Furthermore, no saccades were elicited by the stimulation.</p

Behavioral paradigm illustrating the experimental antisaccade paradigm.

<p>(<i>Upper panel)</i> Antisaccade paradigm practiced by the two monkeys under the online impact of sham (left panel) or active (right panel) TMS single pulses. After fixating on a central stimulus (red), monkeys were to initiate a fast saccade to a location in the opposite direction with respect to a peripheral target (green) appearing on the screen, simultaneously (no gap) to the disappearance of the central fixation. Animals performed within each block, no-TMS trials (white small rectangles) yielding no stimulation at all (Upper Left) and TMS trials (grey small rectangles) during which a single TMS pulse was delivered at a given postarget onset SOA prior to the AS initiation, to modulate the planning of visually guided oculomotor activity <i>(Bottom panel)</i> Example of an experimental session. Animals performed a total of 4 blocks of AS training per session. In one of the blocks they did not receive TMS (white long rectangle), whereas in the remaining 3, they received in half of the trials TMS pulses (see long grey-filled rectangles) at one of the 3 intensities used in the study (30%, 40% and 50%). The order of the four blocks (3 TMS blocks at 30%, 40% or 50% absolute TMS intensities and 1 noTMS block) was randomized within each session. Monkeys performed 100 trials per block (50 no-TMS and 50 TMS trials) for a total of 400 trials per session, and received 50 pulses per TMS block (i.e., only in 50% of the trials), amounting to 150 pulses per experimental session. Independent sessions comprising active TMS pulses delivered at 100 ms or 150 ms SOA post target onset on the FEF, sham TMS pulses and active TMS stimulation in a control location were carried over.</p

Schematic of TMS sites.

<p>Modified picture showing a top view of each of the two monkey’s scalp profiles (animals ‘Y’ and ‘C’), while posted and under training. The dotted line corresponds to the stereotaxic zero bar; the grey dot signals the location and size of the head-post; the orange dot corresponds to the location where digit movements were evoked by TMS pulses; the red dot FEF region of stimulation; the double white/grey dots is an approximate schematic representation of the TMS figure-of-eight coil which was located on the FEF region.</p

Description of patients with Parkinson’s disease.

<p>Age – age on the day of surgery; STN – subthalamic nucleus; GPi – globus pallidus interna; DD – Parkinsońs disease duration; Levodopa – dose/day in mg including levodopa equivalent dosage of dopamine agonist; patient 4 was also treated with mianserin; patients 6, 7, 8, 9, 10 with citalopram and 16 with bupropion; UPDRS III – motor score of the Unified Parkinsońs Disease Rating Scale in OFF medication condition; H-Y – Hoehn and Yahr stage in OFF medication condition; DBS target – nucleus chosen for bilateral deep brain stimulation; SEM – scanning eye movement task; VGS – visually guided saccade task; neurons – number of neurons identified in the basal ganglia.</p

Eye movement (EM) tasks employed in the study.

<p><b>A - The scanning EM task</b>. After the presentation of the black screen with a central cross, a photograph chosen from the International Affective Picture System was presented for 2 s. Patients were asked to initially fix their eyes on the cross (left picture) and then simply watch the photograph (right picture). In total, 24 pictures were consecutively used during the task. The blue line highlights a possible eye scanpath. <b>B - The visually guided saccade task</b> consisted of a presentation of 10 pairs of indifferent central (left picture) and lateral GO (right picture) targets positioned pseudorandomly on the left/right side of the screen. Patients were instructed to initially fixate the central cross and then track to the lateral targets as fast as possible.</p

Time lag of neuronal activity with respect to electrooculography (EOG).

<p>A, B, C - Explanation of the cross-correlation procedure in three examples. Action potentials of three hypothetical neurons along with corresponding instantaneous firing rate (IFR) were correlated with the theoretical EOG signal. Figure A – the IFR correlates with the past EOG signal suggesting a sensory function of the neuron. Figure B – the IFR correlates with the concurrent EOG signal suggesting an executive function of the neuron. Figure C – the IFR correlates with the future EOG signal suggesting a preparatory function of the neuron. The time lag of the IFR in which the maximal (and significant) correlation with EM is reached is called the <i>optimal IFR-to-EM cross-correlation lag</i>. This lag is negative in A, zero in B and positive in C. Figure D - Frequency histograms of the optimal instantaneous firing rate (IFR) to eye movement cross-correlation lags in all eye movement-related neurons during the scanning eye movement task across the subthalamic nucleus (STN), globus pallidus (GP), and substantia nigra pars reticulata (SNr) considering kinematic parameters of the electrooculography (POS, VELOC, ACCEL, in columns). No significant differences in the locations of these distributions were found.</p

Table 2. Numbers of microelectrode recordings and neurons detected.

<p>MER count – number of microelectrode recordings obtained in each nucleus; SEM – scanning eye movement task; VGS – visually guided saccade task; neuron count – number of neurons identified in each nucleus during the SEM task (patients 1-19) and during both the SEM and VGS tasks (patients 16-19); STN – subthalamic nucleus; GP – globus pallidus; SNr – subtantia nigra pars reticulata.</p

Eye movement-related neurons detected in the scanning eye movement task and/or visual guided saccade tasks.

<p>EM-related neurons – the number of eye movement-related neurons associated with at least one kinematic parameter (^†Bonferroni-corrected number of neurons for three kinematic parameters) identified from patients 16-19 which performed both the scanning eye movement task (SEM) and visual guided saccade task (VGS) in the subthalamic nucleus (STN), globus pallidus (GP) and substantia nigra pars reticulata (SNr). Neurons functionally associated with one or more kinematic parameters (POS – eye position; VELOC – eye velocity; ACCEL – eye acceleration) are reported for each nucleus separately.</p

Neuronal activity during the scanning movement task.

<p>Example of neuron related (A, B) and unrelated (C, D) to eye movements based on correlation analysis of the instantaneous firing rate (IFR) and eye position (POS) derived from the electrooculography (EOG). All eye movement-related neuronal populations in the STN, GP and SNr are plotted in figures E, F, and G. Figures A, C show the IFR (blue) and EOG (red) pairs recorded during epochs of the task involving both the black screen and pictures presentations. Figures B, D, E, F, G show the dependency of the normalized eye position (POS) derived from the electrooculography (EOG) on the normalized, sorted and binned amplitude of the instantaneous firing rate (IFR). While the IFR from a single neuron was used on figures B and D; the IFR from all eye sensitive neurons were used on figures E, F, and G for each nucleus separately. The amplitudes of the POS signals which correlated negatively with the IFR signal were reversed. The number of signal samples in each bin is expressed by different shades of grey in the diamond glyphs.</p