SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement.

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit. Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives. Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy. Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05486195.

Headache Related Alterations of Visual Processing in Migraine Patients.

Migraine is characterized by an increased sensitivity to visual stimuli that worsens during attacks. Recent evidence has shown that feedforward volleys carrying incoming visual information induce high-frequency (gamma) oscillations in the visual cortex, while feedback volleys arriving from higher order brain areas induce oscillatory activity at lower frequencies (theta/alpha/low beta). We investigated visually induced high (feedforward) and low (feedback) frequency activations in healthy subjects and various migraine patients. Visual evoked potentials from 20 healthy controls and 70 migraine patients (30 interictal and 20 ictal episodic migraineurs, 20 chronic migraineurs) were analyzed in the frequency domain. We compared power in the theta-alpha-low beta and gamma range between groups, and searched for correlations between the low-to-high frequency activity ratio and number of monthly headache and migraine days. Compared to healthy controls, interictal migraine patients had increased visually induced low frequency (feedback) activity. Conversely, ictal and chronic migraine patients showed an augmented gamma band (feedforward) power. The low-frequency-to-gamma (feedback/feedforward) activity ratio correlated negatively with monthly headache days and tended to do so with migraine days. Our findings show that visual processing is differentially altered depending on migraine cycle and type. Feedback control from higher order cortical areas predominates interictally in episodic migraine while migraine attacks and chronic migraine are associated with enhanced incoming afferent activity, confirming their similar electrophysiological profile. The presence of headache is associated with proportionally higher gamma (feedforward) activities. PERSPECTIVE: This study provides an insight into the pathophysiology of migraine headache from the perspective of cortical sensory processing dynamics. Patients with migraine present alterations in feedback and feedforward visual signaling that differ with the presence of headache.

Age related metabolic modifications in the migraine brain.

PURPOSE: The aim of this study was to evaluate the possibility that migraine patients exhibit specific age-related metabolic changes in the brain, which occur regardless of disease duration or the frequency of attacks. METHODS: We analysed the relation between brain glucose (18F-fluorodeoxyglucose) uptake and age in healthy volunteers (n = 20) and episodic migraine patients (n = 19). In the latter, we additionally compared the correlation between 18F-fluorodeoxyglucose uptake and disease duration and monthly migraine days. RESULTS: In contrast to controls, in migraine patients advancing age was positively correlated to increased metabolism in the brainstem (especially the posterior pons), hippocampus, fusiform gyrus and parahippocampus. Conversely, no significant correlations between cerebral metabolism and disease duration or migraine days were observed. CONCLUSIONS: Findings of this cross-sectional study show that episodic migraine patients exhibit specific metabolic brain modifications while ageing. As such, age is correlated with metabolic changes in key regions of the brain previously associated with migraine's pathophysiology to a better extent than disease duration or the number of monthly migraine days. More than the repeated headache attacks, the continuous interaction with the environment seemingly models the brain of migraine sufferers in an adaptive manner. A positive control (e.g. chronic pain) is missing in this study and therefore findings cannot be proven to be migraine-specific.

Correlation between deep brain stimulation effects on freezing of gait and audio-spinal reflex.

OBJECTIVE: A network of cortical, subcortical and brainstem structures might be involved in freezing of gait (FOG). Subthalamic nucleus (STN) deep brain stimulation (DBS) could modulate this network. The audio-spinal reflex (ASR), reduced in PD, but increased by treatment, can be used to further investigate that locomotor network. The aim of this study is to find whether a correlation exists between ASR and FOG in PD patients under DBS. METHODS: In 14 PD patients with STN DBS and previous FOG, ASR was recorded, with DBS switched on and off. We also assessed FOG Questionnaire (FOGQ) and Unified Parkinson's Disease Rating Scale (UPDRS) Part III. RESULTS: Switching "on" DBS increased ASR amplitude (+ 33.2% with DBS ON, p = 0.048). We also found a significant inverse correlation between FOGQ and modulation of ASR by DBS (r = -0.59, r2 = 0.35, p < 0.05). CONCLUSIONS: This study shows that the incremental effect of DBS on ASR is greater in PD patients with less severe FOG. SIGNIFICANCE: This study shows a link between electrophysiological and clinical data about gait control. It might contribute to better understand why some DBS patients report heavy FOG and others do not. ASR might be used to evaluate or maybe predict the effect of stimulation parameters changes on FOG.

Anodal frontal tDCS for chronic cluster headache treatment: a proof-of-concept trial targeting the anterior cingulate cortex and searching for nociceptive correlates.

BACKGROUND: Percutaneous occipital nerve stimulation (ONS) is effective in refractory chronic cluster headache (rCCH) patients. Responders to ONS differ from non-responders by greater glucose metabolism in subgenual anterior cingulate cortex (sgACC). We reasoned that transcranial direct current stimulation (tDCS), a non-invasive approach, might be able to activate this area and thus improve rCCH patients. Our objective was to explore in a pilot trial the therapeutic potential of tDCS (anode at Fz, cathode over C7) and its possible effects on pain perception, frontal executive functions and mood in rCCH patients. METHODS: Thirty-one patients were asked to apply daily 20-min sessions of 2 mA tDCS for 4 or 8 weeks after a 1-month baseline. CH attacks were monitored with paper diaries. The primary outcome measure was change in weekly attacks between baseline and the last week of tDCS. Twenty-three patients were available for a modified ITT analysis, 21 for per-protocol analysis. We also explored treatment-related changes in thermal pain thresholds and nociceptive blink reflexes (nBR), frontal lobe function and mood scales. RESULTS: In the per-protocol analysis there was a mean 35% decrease of attack frequency (p = 0.0001) with 41% of patients having a ≥ 50% decrease. Attack duration and intensity were also significantly reduced. After 8 weeks (n = 10), the 50% responder rate was 45%, but at follow-up 2 weeks after tDCS (n = 16) mean attack frequency had returned to baseline levels. The treatment effect was significant in patients with high baseline thermal pain thresholds in the forehead (n = 12), but not in those with low thresholds (n = 9). The Frontal Assessment Battery score increased after tDCS (p = 0.01), while there was no change in depression scores or nBR. CONCLUSION: tDCS with a Fz-C7 montage may have a preventive effect in rCCH patients, especially those with low pain sensitivity, suggesting that a sham-controlled trial in cluster headache is worthwhile. Whether the therapeutic effect is due to activation of the sgACC that can in theory be reached by the electrical field, or of other prefrontal cortical areas remains to be determined.

Evidence of an increased neuronal activation-to-resting glucose uptake ratio in the visual cortex of migraine patients: a study comparing 18FDG-PET and visual evoked potentials.

BACKGROUND: Migraine attacks might be triggered by a disruption of cerebral homeostasis. During the interictal period migraine patients are characterized by abnormal sensory information processing, but this functional abnormality may not be sufficient to disrupt the physiological equilibrium of the cortex unless it is accompanied by additional pathological mechanisms, like a reduction in energetic reserves. The aim of this study was to compare resting cerebral glucose uptake (using positron emission tomography (18fluorodeoxyglucose-PET)), and visual cortex activation (using visual evoked potentials (VEP)), between episodic migraine without aura patients in the interictal period and healthy volunteers. METHODS: Twenty episodic migraine without aura patients and twenty healthy volunteers were studied. 18FDG-PET and VEP recordings were performed on separate days. The overall glucose uptake in the visual cortex-to-VEP response ratio was calculated and compared between the groups. Additionally, PET scan comparisons adding area under the VEP curve as a covariate were performed. For case-wise analysis, eigenvalues from a specific region exhibiting significantly different FDG-PET signal in the visual cortex were extracted. Standardized glucose uptake values from this region and VEP values from each subject were then coupled and compared between the groups. RESULTS: The mean area under the curve of VEP was greater in migraine patients compared to healthy controls. In the same line, patients had an increased neuronal activation-to-resting glucose uptake ratio in the visual cortex. Statistical parametric mapping analysis revealed that cortical FDG-PET signal in relation to VEP area under the curve was significantly reduced in migraineurs in a cluster extending throughout the left visual cortex, from Brodmann's areas 19 and 18 to area 7. Within this region, case-wise analyses showed that a visual neuronal activation exceeding glucose uptake was present in 90% of migraine patients, but in only 15% of healthy volunteers. CONCLUSION: This study identifies an area of increased neuronal activation-to-resting glucose uptake ratio in the visual cortex of migraine patients between attacks. Such observation supports the concept that an activity-induced rupture of cerebral metabolic homeostasis may be a cornerstone of migraine pathophysiology. This article has been selected as the winner of the 2018 Enrico Greppi Award. The Enrico Greppi Award is made to an unpublished paper dealing with clinical, epidemiological, genetic, pathophysiological or therapeutic aspects of headache. Italian Society for the Study of Headaches (SISC) sponsors this award, and the award is supported through an educational grant from Teva Neuroscience. This article did not undergo the standard peer review process for The Journal of Headache and Pain. The members of the 2018 Enrico Greppi Award Selection Committee were: Francesco Pierelli, Paolo Martelletti, Lyn Griffiths, Simona Sacco, Andreas Straube and Cenk Ayata.

Brain Correlates of Single Trial Visual Evoked Potentials in Migraine: More Than Meets the Eye.

Background: Using conventional visual evoked potentials (VEPs), migraine patients were found to be hyperresponsive to visual stimulus. Considering that a significant portion of neuronal activity is lost for analysis in the averaging process of conventional VEPs, in this study we investigated visual evoked responses of migraine patients and healthy volunteers using a different approach: single trial analysis. This method permits to preserve all stimulus-induced neuronal activations, whether they are synchronized or not. In addition, we used MRI voxel-based morphometry to search for cortical regions where gray matter volume correlated with single trial (st) VEP amplitude. Finally, using resting-state functional MRI, we explored the connectivity between these regions. Results: stVEP amplitude was greater in episodic migraine patients than in healthy volunteers. Moreover, in migraine patients it correlated positively with gray matter volume of several brain areas likely involved in visual processing, mostly belonging to the ventral attention network. Finally, resting state functional connectivity corroborated the existence of functional interactions between these areas and helped delineating their directions. Conclusions: st-VEPs appear to be a reliable measure of cerebral responsiveness to visual stimuli. Mean st-VEP amplitude is higher in episodic migraine patients compared to controls. Visual hyper-responsiveness in migraine involves several functionally-interconnected brain regions, suggesting that it is the result of a complex multi-regional process coupled to stimulus driven attention systems rather than a localized alteration.

Sunlight irradiance and habituation of visual evoked potentials in migraine: The environment makes its mark.

Background Migraine is a complex multifactorial disease that arises from the interaction between a genetic predisposition and an enabling environment. Habituation is considered as a fundamental adaptive behaviour of the nervous system that is often impaired in migraine populations. Given that migraineurs are hypersensitive to light, and that light deprivation is able to induce functional changes in the visual cortex recognizable through visual evoked potentials habituation testing, we hypothesized that regional sunlight irradiance levels could influence the results of visual evoked potentials habituation studies performed in different locations worldwide. Methods We searched the literature for visual evoked potentials habituation studies comparing healthy volunteers and episodic migraine patients and correlated their results with levels of local solar radiation. Results After reviewing the literature, 26 studies involving 1291 participants matched our inclusion criteria. Deficient visual evoked potentials habituation in episodic migraine patients was reported in 19 studies. Mean yearly sunlight irradiance was significantly higher in locations of studies reporting deficient habituation. Correlation analyses suggested that visual evoked potentials habituation decreases with increasing sunlight irradiance in migraine without aura patients. Conclusion Results from this hypothesis generating analysis suggest that variations in sunlight irradiance may induce adaptive modifications in visual processing systems that could be reflected in visual evoked potentials habituation, and thus partially account for the difference in results between studies performed in geographically distant centers. Other causal factors such as genetic differences could also play a role, and therefore well-designed prospective trials are warranted.

Evidence of activation of vagal afferents by non-invasive vagus nerve stimulation: An electrophysiological study in healthy volunteers.

Background Benefits of cervical non-invasive vagus nerve stimulation (nVNS) devices have been shown in episodic cluster headache and preliminarily suggested in migraine, but direct evidence of vagus nerve activation using such devices is lacking. Vagal somatosensory evoked potentials (vSEPs) associated with vagal afferent activation have been reported for invasive vagus nerve stimulation (iVNS) and non-invasive auricular vagal stimulation. Here, we aimed to show and characterise vSEPs for cervical nVNS. Methods vSEPs were recorded for 12 healthy volunteers who received nVNS over the cervical vagus nerve, bipolar electrode/DS7A stimulation over the inner tragus, and nVNS over the sternocleidomastoid (SCM) muscle. We measured peak-to-peak amplitudes (P1-N1), wave latencies, and N1 area under the curve. Results P1-N1 vSEPs were observed for cervical nVNS (11/12) and auricular stimulation (9/12), with latencies similar to those described previously, whereas SCM stimulation revealed only a muscle artefact with a much longer latency. A dose-response analysis showed that cervical nVNS elicited a clear vSEP response in more than 80% of the participants using an intensity of 15 V. Conclusion Cervical nVNS can activate vagal afferent fibres, as evidenced by the recording of far-field vSEPs similar to those seen with iVNS and non-invasive auricular stimulation.

Cerebral metabolism before and after external trigeminal nerve stimulation in episodic migraine.

Background and aim A recent sham-controlled trial showed that external trigeminal nerve stimulation (eTNS) is effective in episodic migraine (MO) prevention. However, its mechanism of action remains unknown. We performed 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate brain metabolic changes before and after eTNS in episodic migraineurs. Methods Twenty-eight individuals were recruited: 14 with MO and 20 healthy volunteers (HVs). HVs underwent a single FDG-PET, whereas patients were scanned at baseline, directly after a first prolonged session of eTNS (Cefaly®) and after three months of treatment (uncontrolled study). Results The frequency of migraine attacks significantly decreased in compliant patients ( N = 10). Baseline FDG-PET revealed a significant hypometabolism in fronto-temporal areas, especially in the orbitofrontal (OFC) and rostral anterior cingulate cortices (rACC) in MO patients. This hypometabolism was reduced after three months of eTNS treatment. Conclusion Our study shows that metabolic activity of OFC and rACC, which are pivotal areas in central pain and behaviour control, is decreased in migraine. This hypometabolism is reduced after three months of eTNS. eTNS might thus exert its beneficial effects via slow neuromodulation of central pain-controlling areas, a mechanism also previously reported in chronic migraine and cluster headache after percutaneous occipital nerve stimulation. However, this finding needs to be confirmed by further studies using a sham condition.

Familial history of migraine influences habituation of visual evoked potentials.

Background Lack of habituation of visual evoked potentials (VEP) is a common finding in migraine patients between attacks. Previous studies have suggested an electrophysiological familial aggregation pattern associated with migraine. The aim of this study was to evaluate the influence of a positive familial history of migraine on VEP amplitude and habituation. Methods We recorded six blocks of 100 VEP during continuous pattern-reversal stimulation in 30 patients with migraine between attacks (MO) and in 30 healthy volunteers, of whom 15 had a first-degree relative suffering from migraine (HVm) and 15 had not (HV). Results Both MO and HVm had a significant deficit of VEP habituation and similarly reduced N1-P1 first block amplitudes, compared to HV (habituation slope: MO = 0.033, HVm = 0.021, HV = -0.025, HV vs. MO p = 0.002, HV vs. HVm p = 0.036; mean N1-P1 amplitude in the first block: MO = 9.08 µV, HVm = 9.29 µV, HV = 12.19 µV. HV vs. MO p = 0.041, HV vs. HVm p = 0.076). The first block N1-P1 amplitude was negatively correlated with the habituation slope for both MO (ρ = -.44, p = 0.015) and HVm (ρ = -.56, p = 0.031) while no significant correlation was found in HV (ρ = .17, p = 0.53). There were no differences in VEP latencies between the groups. Conclusions Our study suggests that lack of habituation of visual evoked potentials is probably a genetically determined endophenotypic trait that is associated with both migraine and migraine susceptibility. We hypothesize that genetic diversity of populations could account for some of the discrepancies between electrophysiological studies performed in migraine and for interindividual variations among the subgroups.

Invasive and Non-invasive Electrical Pericranial Nerve Stimulation for the Treatment of Chronic Primary Headaches.

Chronic primary headaches are widespread disorders which cause significant quality of life and socioprofessional impairment. Available pharmacological treatments have often a limited efficacy and/or can generate unbearable side effects. Electrical nerve stimulation is a well-known non-destructive method of pain modulation which has been recently applied to headache management. In this review, we summarise recent advances in invasive and non-invasive neurostimulation techniques targeting pericranial structures for the treatment of chronic primary headaches, chiefly migraine and cluster headache: occipital nerve, supraorbital nerve, vagus nerve, and sphenopalatine ganglion stimulations. Invasive neurostimulation therapies have offered a new hope to drug-refractory headache sufferers but are not riskless and should be proposed only to chronic patients who failed to respond to most existing preventives. Non-invasive neurostimulation devices are user-friendly, safe and well tolerated and are thus taking an increasing place in the multidisciplinary therapeutical armamentarium of primary headaches.

The Network Model of Depression as a Basis for New Therapeutic Strategies for Treating Major Depressive Disorder in Parkinson's Disease.

The high prevalence of major depressive disorder in people with Parkinson's disease (PD), its negative impact on health-related quality of life and the low response rate to conventional pharmacological therapies call to seek innovative treatments. Here, we review the new approaches for treating major depressive disorder in patients with PD within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation (NIBS) using high frequency repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex has been proposed as a feasible and effective strategy with minimal risk. The neurobiological basis of its therapeutic effect may involve neuroplastic modifications in limbic and cognitive networks. However, the way this networks reorganize might be strongly influenced by the environment. To address this issue, we propose a combined strategy that includes NIBS together with cognitive and behavioral interventions.

Effects of 10 Hz and 20 Hz Transcranial Alternating Current Stimulation on Automatic Motor Control.

BACKGROUND: In a masked prime choice reaction task, presentation of a compatible prime increases the reaction time to the following imperative stimulus if the interval between mask and prime is around 80-250 ms. This is thought to be due to automatic suppression of the motor plan evoked by the prime, which delays reaction to the imperative stimulus. Oscillatory activity in motor networks around the beta frequency range of 20 Hz is important in suppression of movement. Transcranial alternating current at 20 Hz may be able to drive oscillations in the beta range. OBJECTIVE/HYPOTHESIS: To investigate whether transcranial alternating current stimulation (tACS) at 20 Hz would increase automatic inhibition in a masked prime task. As a control we used 10 Hz tACS. METHODS: Stimulation was delivered at alpha (10 Hz) and beta (20 Hz) frequency over the supplementary motor area and the primary motor cortex (simultaneous tACS of SMA-M1), which are part of the BG-cortical motor loop, during the execution of the subliminal masked prime left/right choice reaction task. We measured the effects on reaction times. Corticospinal excitability was assessed by measuring the amplitude of motor evoked potentials (MEPs) evoked in the first dorsal interosseous muscle by transcranial magnetic stimulation (TMS) over M1. RESULTS: The 10 and 20-Hz tACS over SMA-M1 had different effects on automatic inhibition. The 20 Hz tACS increased the duration of automatic inhibition whereas it was decreased by 10 Hz tACS. Neurophysiologically, 20 Hz tACS reduced the amplitude of MEPs evoked from M1, whereas there was no change after 10 Hz tACS. CONCLUSION: Automatic mechanisms of motor inhibition can be modulated by tACS over motor areas of cortex. tACS may be a useful additional tool to investigate the causal links between endogenous brain oscillations and specific cognitive processes.

Effect of coil orientation on strength-duration time constant and I-wave activation with controllable pulse parameter transcranial magnetic stimulation.

OBJECTIVE: To compare the strength-duration (S-D) time constants of motor cortex structures activated by current pulses oriented posterior-anterior (PA) or anterior-posterior (AP) across the central sulcus. METHODS: Motor threshold and input-output curve, along with motor evoked potential (MEP) latencies, of first dorsal interosseus were determined at pulse widths of 30, 60, and 120 µs using a controllable pulse parameter (cTMS) device, with the coil oriented PA or AP. These were used to estimate the S-D time constant and we compared with data for responses evoked by cTMS of the ulnar nerve at the elbow. RESULTS: The S-D time constant with PA was shorter than for AP stimulation (230.9 ± 97.2 vs. 294.2 ± 90.9 µs; p<0.001). These values were similar to those calculated after stimulation of ulnar nerve (197 ± 47 µs). MEP latencies to AP, but not PA stimulation were affected by pulse width, showing longer latencies following short duration stimuli. CONCLUSION: PA and AP stimuli appear to activate the axons of neurons with different time constants. Short duration AP pulses are more selective than longer pulses in recruiting longer latency corticospinal output. SIGNIFICANCE: More selective stimulation of neural elements may be achieved by manipulating pulse width and orientation.

Bi-directional modulation of somatosensory mismatch negativity with transcranial direct current stimulation: an event related potential study.

Appropriate orientation towards potentially salient novel environmental stimuli requires a system capable of detecting change in the sensorium. Mismatch negativity (MMN), an evoked potential calculated by subtracting the response to a standard repeated stimulus and a rare 'oddball' stimulus, is proposed as such a change detection mechanism. It is most widely studied in the auditory domain, but here we chose to explore the mechanism of somatosensory MMN, and specifically its dependence on the cerebellum. We recorded event-related potentials (ERPs) evoked in response to auditory and sensory stimuli from 10 healthy subjects before and after anodal, cathodal and sham transcranial direct current stimulation (tDCS) of the right cerebellar hemisphere. There was a significant increase in peak amplitude of somatosensory MMN after anodal tDCS (F(1,9) = 8.98, P < 0.02, mean difference anodal pre-post: -1.02 µV) and a significant reduction in peak amplitude of somatosensory MMN after cathodal tDCS (F(1,9) = 7.15, P < 0.03, mean difference cathodal pre-post: 0.65 µV). The amplitude of auditory MMN was unchanged by tDCS. These results reveal the capability of tDCS to cause bidirectional modulation of somatosensory MMN and the dependence of somatosensory MMN on the cerebellum.

Impaired automatic and unconscious motor processes in Parkinson's disease.

While it is increasingly recognized that voluntary movements are produced by an interaction between conscious and unconscious processes, the role of the latter in Parkinson's disease has received little attention to date. Here, we administered a subliminal masked prime task to 15 Parkinson's disease patients and 15 age-matched healthy elderly subjects. Compatibility effects were examined by manipulating the direction of the arrows and the interstimuli interval. Analysis of the positive compatibility effect revealed performance differences between the most and the least affected hand in Parkinson's disease patients. Additionally, patients did not show the same tendency toward a negative compatibility effect as compared to elderly controls. These novel findings provide evidence supporting the role of basal ganglia circuits in controlling the balance between automatic motor response facilitation and inhibition.

Role of the supplementary motor area in the automatic activation of motor plans in de novo Parkinson's disease patients.

The role of the basal ganglia-cortical motor loop in automatic and unconscious motor processes is poorly understood. Here, we used event-related functional magnetic resonance imaging in 11 de novo Parkinson's disease patients as they performed a visuomotor masked priming task. The stronger subliminal priming effect for the non-dominant side of motor symptoms than for the dominant side was paralleled by stronger supplementary motor area proper activity in response to lateralized visual stimuli presented below the threshold of awareness. This novel result supports the prediction that this area is involved in the automatic activation of motor plans as a function of striatal dopamine levels.

Exploration of the mechanisms underlying the ISPC effect: evidence from behavioral and neuroimaging data.

The item-specific proportion congruent (ISPC) effect in a Stroop task - the observation of reduced interference for color words mostly presented in an incongruent color - has attracted growing interest since the original study by Jacoby, Lindsay, and Hessels [(2003) Psychonomic Bulletin & Review, 10(3), 638-644]. Two mechanisms have been proposed to explain the effect: associative learning of contingencies and item-specific control through word reading modulation. Both interpretations have received empirical support from behavioral data. Therefore, the aim of this study was to investigate the responsible mechanisms of the ISPC effect with the classic two-item sets design using fMRI. Results showed that the ISPC effect is associated with increased activity in the anterior cingulate (ACC), dorsolateral prefrontal (DLPFC), and inferior and superior parietal cortex. Importantly, behavioral and fMRI analyses specifically addressing the respective contribution of associative learning and item-specific control mechanisms brought support for the contingency learning account of the ISPC effect. Results are discussed in reference to task and procedure characteristics that may influence the extent to which item-specific control and/or contingency learning contribute to the ISPC effect.

Evidence for a role of a cortico-subcortical network for automatic and unconscious motor inhibition of manual responses.

It is now clear that non-consciously perceived stimuli can bias our decisions. Although previous researches highlighted the importance of automatic and unconscious processes involved in voluntary action, the neural correlates of such processes remain unclear. Basal ganglia dysfunctions have long been associated with impairment in automatic motor control. In addition, a key role of the medial frontal cortex has been suggested by administrating a subliminal masked prime task to a patient with a small lesion restricted to the supplementary motor area (SMA). In this task, invisible masked arrows stimuli were followed by visible arrow targets for a left or right hand response at different interstimuli intervals (ISI), producing a traditional facilitation effect for compatible trials at short ISI and a reversal inhibitory effect at longer ISI. Here, by using fast event-related fMRI and a weighted parametric analysis, we showed BOLD related activity changes in a cortico-subcortical network, especially in the SMA and the striatum, directly linked to the individual behavioral pattern. This new imaging result corroborates previous works on subliminal priming using lesional approaches. This finding implies that one of the roles of these regions was to suppress a partially activated movement below the threshold of awareness.