The role of ventromedial prefrontal cortex and temporo-parietal junction in third-party punishment behavior.

Third parties punish, sacrificing personal interests, offenders who violate either fairness or cooperation norms. This behavior is defined altruistic punishment and the degree of punishment typically increases with the severity of the norm violation. An opposite and apparently paradoxical behavior, namely anti-social punishment, is the tendency to spend own money to punish cooperative or fair behaviors. Previous fMRI studies correlated punishment behavior with increased activation of brain areas belonging to the reward system (e.g. the ventromedial prefrontal cortex, VMPFC), the mentalizing (e.g. the temporoparietal junction, TPJ) and central-executive networks. In the present study, we aimed at investigating the causal role of VMPFC and TPJ in punishment behaviors through the application of anodal transcranial direct current stimulation (tDCS). Sixty healthy participants were randomly assigned to three tDCS conditions: (1) anodal tDCS over VMPFC, (2) anodal tDCS over right TPJ (rTPJ), (3) sham stimulation. At the end of the stimulation, participants played a third-party punishment game, consisting in viewing a series of fair or unfair monetary allocations between unknown proposers and recipients. Participants were asked whether and how much they would punish the proposers using their own monetary endowment. To test membership effects, proposers and recipients could be either Italian or Chinese. Anodal tDCS over VMPFC increased altruistic punishment behavior whereas anodal tDCS over rTPJ increased anti-social punishment choices compared with sham condition, while membership did not influence participant's choices. Our results support the idea that the two types of punishment behaviors rely upon different brain regions, suggesting that reward and mentalizing systems underlie, respectively, altruistic and anti-social punishment behaviors.

Altering spatial priority maps via reward-based learning.

Spatial priority maps are real-time representations of the behavioral salience of locations in the visual field, resulting from the combined influence of stimulus driven activity and top-down signals related to the current goals of the individual. They arbitrate which of a number of (potential) targets in the visual scene will win the competition for attentional resources. As a result, deployment of visual attention to a specific spatial location is determined by the current peak of activation (corresponding to the highest behavioral salience) across the map. Here we report a behavioral study performed on healthy human volunteers, where we demonstrate that spatial priority maps can be shaped via reward-based learning, reflecting long-lasting alterations (biases) in the behavioral salience of specific spatial locations. These biases exert an especially strong influence on performance under conditions where multiple potential targets compete for selection, conferring competitive advantage to targets presented in spatial locations associated with greater reward during learning relative to targets presented in locations associated with lesser reward. Such acquired biases of spatial attention are persistent, are nonstrategic in nature, and generalize across stimuli and task contexts. These results suggest that reward-based attentional learning can induce plastic changes in spatial priority maps, endowing these representations with the "intelligent" capacity to learn from experience.

Fair play doesn't matter: MEP modulation as a neurophysiological signature of status quo bias in economic interactions.

Transcranial magnetic stimulation (TMS) studies show that watching others' movements enhances motor evoked potential (MEPs) amplitude of the muscles involved in the observed action (motor facilitation, MF). MF has been attributed to a mirror neuron system mediated mechanism, causing an excitability increment of primary motor cortex. It is still unclear whether the meaning an action assumes when performed in an interpersonal exchange context could affect MF. This study aims at exploring this issue by measuring MF induced by the observation of the same action coupled with opposite reward values (gain vs loss) in an economic game. Moreover, the interaction frame was manipulated by showing the same actions within different economic games, the Dictator Game (DG) and the Theft Game (TG). Both games involved two players: a Dictator/Thief and a receiver. Experimental participants played the game always as receivers whereas the Dictator/Thief roles were played by our confederates. In each game Dictator/Thief's choices were expressed by showing a grasping action of one of two cylinders, previously associated with fair/unfair choices. In the DG the dictator decides whether to share (gain condition) or not (no-gain condition) a sum of money with the receiver, while in TGs the thief decides whether to steal (loss condition) or not to steal (no-loss condition) it from the participants. While the experimental subjects watched the videos showing these movements, a single TMS pulse was delivered to their motor hand area and a MEP was recorded from the right FDI muscle. Results show that, in the DG, MF was enhanced by the status quo modification, i.e. MEP amplitude increased when the dictator decided to change the receivers' status quo and share his/her money, and this was true when the status quo was more salient. The same was true for the TG, where the reverse happened: MF was higher for trials in which the thief decided to steal the participants' money, thus changing the status quo, in the block in which the status quo maintenance occurred more often. Data support the hypothesis that the economic meaning of the observed actions differently modulates MEP amplitude, pointing at an influence on MF exerted by a peculiar interaction between economic outcomes and variation of the subjects' initial status quo.

Cognitive outcomes in patients treated with neuromuscular electrical stimulation after coronary artery bypass grafting.

Objective: Mechanisms of neurocognitive injury as post-operative sequelae of coronary artery bypass grafting (CABG) are not understood. The systemic inflammatory response to surgical stress causes skeletal muscle impairment, and this is also worsened by immobility. Since evidence supports a link between muscle vitality and neuroprotection, there is a need to understand the mechanisms by which promotion of muscle activity counteracts the deleterious effects of surgery on long-term cognition. Methods: We performed a clinical trial to test the hypothesis that adding neuromuscular electrical stimulation (NMES) to standard rehabilitation care in post-CABG patients promotes the maintenance of skeletal muscle strength and the expression of circulating neuroprotective myokines. Results: We did not find higher serum levels of neuroprotective myokines, except for interleukin-6, nor better long-term cognitive performance in our intervention group. However, a greater increase in functional connectivity at brain magnetic resonance was seen between seed regions within the default mode, frontoparietal, salience, and sensorimotor networks in the NMES group. Regardless of the treatment protocol, patients with a Klotho increase 3 months after hospital discharge compared to baseline Klotho values showed better scores in delayed memory tests. Significance: We confirm the potential neuroprotective effect of Klotho in a clinical setting and for the first time post-CABG.

Keeping memory for intentions: a cTBS investigation of the frontopolar cortex.

The present study aimed to investigate the role of frontopolar cortex in prospective memory (PM) by means of inhibitory theta-burst stimulation (cTBS). "Experiment 1"-8 volunteers were evaluated after inhibitory cTBS over left Brodmann area (BA) 10, right BA10, and Cz. In the PM procedure, sequences of 4 words each were presented. During the intersequence delay, subjects had to repeat the sequence in the observed order (ongoing task forward) or in the reverse order (backward). At the occurrence of a target word, subjects had to press a key on the keyboard (PM task). Recall and recognition of the target words were also tested. PM accuracy was lower after cTBS over left BA10 compared with Cz (P = 0.012), whereas it was comparable in right BA10 and Cz conditions. No other significant differences between the 3 conditions were found. "Experiment 2"-8 subjects were administered the same experimental PM procedure as above after inhibitory cTBS over left BA46 and Cz. In this case, none of the tested effects were significant. Our findings corroborate the hypothesis that within the prefrontal cortex, the left BA10 is specifically involved in the mediation of processes related to the execution of delayed intentions.

Changes in cerebello-motor connectivity during procedural learning by actual execution and observation.

The cerebellum is involved in motor learning of new procedures both during actual execution of a motor task and during observational training. These processes are thought to depend on the activity of a neural network that involves the lateral cerebellum and primary motor cortex (M1). In this study, we used a twin-coil TMS technique to investigate whether execution and observation of a visuomotor procedural learning task is related to modulation of cerebello-motor connectivity. We observed that, at rest, a magnetic conditioning pulse applied over the lateral cerebellum reduced the motor-evoked potentials obtained by stimulating the contralateral M1, indicating activation of a cerebello-motor connection. Furthermore, during procedural learning, cerebellar stimulation resulted in selective facilitation, not inhibition, of contralateral M1 excitability. The effects were evident when motor learning was obtained by actual execution of the task or by observation, but they disappeared if procedural learning had already been acquired by previous observational training. These results indicate that changes in cerebello-motor connectivity occur in relation to specific phases of procedural learning, demonstrating a complex pattern of excitatory and inhibitory drives modulated across time.

Visual and semantic processing of living things and artifacts: an FMRI study.

We carried out an fMRI study with a twofold purpose: to investigate the relationship between networks dedicated to semantic and visual processing and to address the issue of whether semantic memory is subserved by a unique network or by different subsystems, according to semantic category or feature type. To achieve our goals, we administered a word-picture matching task, with within-category foils, to 15 healthy subjects during scanning. Semantic distance between the target and the foil and semantic domain of the target-foil pairs were varied orthogonally. Our results suggest that an amodal, undifferentiated network for the semantic processing of living things and artifacts is located in the anterolateral aspects of the temporal lobes; in fact, activity in this substrate was driven by semantic distance, not by semantic category. By contrast, activity in ventral occipito-temporal cortex was driven by category, not by semantic distance. We interpret the latter finding as the effect exerted by systematic differences between living things and artifacts at the level of their structural representations and possibly of their lower-level visual features. Finally, we attempt to reconcile contrasting data in the neuropsychological and functional imaging literature on semantic substrate and category specificity.

TMS activation of interhemispheric pathways between the posterior parietal cortex and the contralateral motor cortex.

Using a twin coil transcranial magnetic stimulation (tc-TMS) approach we have previously demonstrated that facilitation may be detected in the primary motor cortex (M1) following stimulation over the ipsilateral caudal intraparietal sulcus (cIPS). Here we tested the interhemispheric interactions between the IPS and the contralateral motor cortex (M1). We found that conditioning the right cIPS facilitated contralateral M1 when the conditioning stimulus had an intensity of 90% resting motor threshold (RMT) but not at 70% or 110% RMT. Facilitation was maximal when the interstimulus interval (ISI) between cIPS and M1 was 6 or 12 ms. These facilitatory effects were mediated by interactions with specific groups of interneurons in the contralateral M1. In fact, short intracortical inhibition (SICI) was reduced following cIPS stimulation. Moreover, additional comparison of facilitation of responses evoked by anterior-posterior versus posterior-anterior stimulation of M1 suggested that facilitation was more effective on early I1/I2 circuits than on I3 circuits. In contrast to these effects, stimulation of anterior IPS (aIPS) at 90% RMT induced inhibition, instead of facilitation, of contralateral M1 at ISIs of 10-12 ms. Finally, we found similar facilitation between left cIPS and right M1 although the conditioning stimuli had to have a higher intensity compared with stimulation of right cIPS (110% instead of 90% RMT). These findings demonstrate that different subregions of the posterior parietal cortex (PPC) in humans exert both facilitatory and inhibitory effects towards the contralateral primary motor cortex. These corticocortical projections could contribute to a variety of motor tasks such as bilateral manual coordination, movement planning in space and grasping.

Representation of time intervals in the right posterior parietal cortex: implications for a mental time line.

Space and time interact with each other in the cognitive system. Recent studies indicate the posterior parietal cortex (PPC) as the neural correlate of spatial-temporal interactions. We studied whether the contribution of the PPC becomes critical in tasks requiring the performance of spatial computations on time intervals. We adopted an integrated neuropsychological and transcranial magnetic stimulation (rTMS) approach, presenting behavioural timing tasks to both healthy subjects and right-brain-damaged patients with and without evidence of spatial neglect. rTMS of the right PPC of healthy subjects induced a lateralised bias during a task requiring setting the midpoint of a time interval. This bias mimicked the rightward bias observed in tasks requiring setting the midpoint of line intervals. These effects were selectively encountered when rTMS was applied during the retrieval phase of the task, while no effects were observed during the initial encoding phase of the time interval. Similar effects were also observed during bisection of time intervals by right-brain-damaged patients with spatial neglect. The specific role of the right PPC in bisection of physical intervals was confirmed by an experiment in which line segments were used. These findings document the neural correlates of spatial-temporal interactions and argue for a linear metric representation of time intervals.

Effects of inhibitory rTMS on bladder function in Parkinson's disease patients.

Patients affected by Parkinson's disease (PD) may present with lower urinary tract (LUT) dysfunction characterized by involuntary detrusor overactivity. We evaluated possible impact of a 2-week course of low frequency 1 Hz repetitive transcranial magnetic stimulation (rTMS) on LUT behavior in eight advanced PD patients complaining of urinary disturbances. We tested the effects of rTMS measuring urodynamic examination and the International Prostate Symptoms Score (IPSS) questionnaire, used for evaluation of subjective LUTS. rTMS was able to improve temporarily LUT behavior in PD patients, increasing bladder capacity and the first sensation of filling phase. Moreover, a reduction of IPSS score was noticed, due to an improvement on filling phase symptoms. The beneficial effects assessed with the IPSS lasted for up to 2 weeks after the end of the stimulation. rTMS seems to be an effective, noninvasive alternative treatment for PD patients with urinary disturbances.

Hyperexcitability of parietal-motor functional connections in the intact left-hemisphere of patients with neglect.

Hemispatial neglect is common after unilateral brain damage, particularly to perisylvian structures in the right-hemisphere (RH). In this disabling syndrome, behaviour and awareness are biased away from the contralesional side of space towards the ipsilesional side. Theoretical accounts of this in terms of hemispheric rivalry have speculated that the intact left-hemisphere (LH) may become hyper-excitable after a RH lesion, due to release of inhibition from the damaged hemisphere. We tested this directly using a novel twin-coil transcranial magnetic stimulation (TMS) approach to measure excitability within the intact LH of neglect patients. This involved applying a conditioning TMS pulse over left posterior parietal cortex (PPC), in order to test its effect on the amplitude of motor evoked potentials (MEPs) produced by a subsequent test pulse over left motor cortex (M1). Twelve RH stroke patients with neglect, an age-matched group of eight RH stroke patients without neglect, and 10 healthy controls were examined. We found that excitability of left PPC-M1 circuits was higher in neglect patients than the other groups, and related to the degree of neglect on clinical cancellation tests. A follow-up found that 1 Hz repetitive TMS over left PPC normalized this over-excitability, and also ameliorated visual neglect on an experimental measure with chimeric objects. Our results provide 'direct' evidence for pathological over-excitability of the LH in the neglect syndrome, as quantified by left PPC influences on left M1, with implications for possible treatment.

Changes in intracortical circuits of the human motor cortex following theta burst stimulation of the lateral cerebellum.

OBJECTIVE: The cerebellum takes part in several motor functions through its influence on the motor cortex (M1). Here, we applied the theta burst stimulation (TBS) protocol, a novel form of repetitive Transcranial Magnetic Stimulation (rTMS) over the lateral cerebellum. The aim of this study was to test whether TBS of the lateral cerebellum could be able to modulate the excitability of the contralateral M1 in healthy subjects. METHODS: Motor-evoked potentials (MEPs) amplitude, short intracortical inhibition (SICI), long intracortical inhibition (LICI) and short intracortical facilitation (SICF) were tested in the M1 before and after cerebellar continuous TBS (cTBS) or intermittent TBS (iTBS). RESULTS: We found that cTBS induced a reduction of SICI and an increase of LICI. On the other hand, cerebellar iTBS reduced LICI. MEPs amplitude also differently vary following cerebellar stimulation with cTBS or iTBS, resulting in a decrease by the former and an increase by the latter. CONCLUSIONS: Although the interpretation of these data remains highly speculative, these findings reveal that the cerebellar cortex undergoes bidirectional plastic changes that modulate different intracortical circuits within the contralateral primary motor cortex. SIGNIFICANCE: Long-lasting modifications of these pathways could be useful to treat various pathological conditions characterized by an altered cortical excitability.

As Time Goes by: A rTMS Study on Age-Related Changes in Sentence Comprehension.

It is well established that off-line sentence judgment tasks (oSJTs) typically rely on phonological working memory (WM), beyond specific linguistic processing. Nevertheless, empirical findings suggest that a juvenile level of performance in an oSJT could be associated with the recruitment of age-specific additional supportive neural network in healthy aging. In particular, in one of our previous study, healthy elderlies showed the additional activation of associative visual cortices when compared with young controls. We suggested that age-related hyperactivations, during an auditory sentence judgment task, might represent the neurofunctional correlate of the recruitment of compensatory strategies that are necessary to maintain a juvenile level of performance. To explicitly test this hypothesis we adopted repetitive transcranial magnetic stimulation (rTMS). Twelve healthy elderlies and 12 young participants were engaged in an off-line semantic plausibility judgment task while rTMS was delivered over: (1) the left inferior frontal gyrus (LIFG; i.e., a core region of the WM network); (2) the precuneus; and (3) a Control Site (vertex). Results showed a significant main effect of Stimulation Site and a significant Group-by-Stimulation Site interaction effect. In particular, the rTMS stimulation of the LIFG slowed down reaction times (RTs) both in young and healthy elderly participants, while only healthy elderlies showed an increment of RTs during the stimulation of the precuneus. Taken together our results further support the idea that the maintenance of a juvenile level of performance in graceful aging may be associated with task-specific compensatory processes that would manifest them-selves, from the neurofunctional point of view, by the recruitment of additional neural supportive regions.

Can Monetary Reward Modulate Social Attention?

Selective visual attention is a primary cognitive function, which allows the selection of the most relevant stimuli in the environment by prioritizing their processing. Several studies showed that this process can be influenced by both social signals, such as gaze direction (i.e., the Gaze Cueing Effect, GCE) and by the motivational valence of gratifying stimuli, such as monetary rewards. The aim of this study was to explore whether GCE could be modulated by a monetary reward. To this end, we created an experiment in which participants performed a gaze cuing task before and after an implicit learning task aiming to induce an association between gaze direction and monetary reward (experimental condition), or after a perceptual task (control condition). Statistical analyses were conducted following both a frequentist and a Bayesian approach. Results supported previous findings showing the presence of the GCE, i.e., faster responses in congruent trials when the target appeared in the gazed-at location. Interestingly, our results did not reveal significant differences among the conditions. Therefore, contrary to what was reported by previous attentional orienting studies with non-social stimuli, monetary reward does not seem to be able to modulate (or interfere with) the orienting of attention mediated by gaze direction as measured by the GCE. Taken together our results suggest that social signals such as gaze direction have a greater impact than monetary reward in orienting selective attention.

FEF Excitability in Attentional Bias: A TMS-EEG Study.

The role of distinct cortical regions in guiding social orienting needs further investigation. Our aim was to explore the contribution of the frontal eye field (FEF) in early orienting of attention towards stimuli with social value. We used a TMS-EEG approach to investigate event related potentials (ERPs; no-TMS block) and TMS evoked potentials (TEPs; TMS block) during the cueing phase of a modified version of the dot-probe task, comparing competing (face vs. house) and not competing (house vs. house) conditions. Our results revealed an increased amplitude of ERP components in the competing condition, showing greater posterior N170 and fronto-central vertex positive potential (VPP) and an enhanced frontal negative component at 250-270 ms from cue onset. TMS pulses over the FEF induced similar N170 and VPP amplified components. In addition, in the ERPs, a reduced positivity at 400 ms was shown when the face appeared on the left side vs. the right side of space. In contrast, in the TMS blocks, we found lateralized effects on N170 depending on the side of face presentation. The enhanced cortical excitability induced by TMS over the right FEF significantly correlated with the performance on the behavioral task, suggesting a link between the FEF activity during the cueing phase of the dot-probe task and the subsequent behavioral response times to the targets.

Goal Achievement Failure Drives Corticospinal Modulation in Promotion and Prevention Contexts.

When making decisions, people are typically differently sensitive to gains and losses according to the motivational context in which the choice is performed. As hypothesized by Regulatory Focus Theory (RFT), indeed, goals are supposed to change in relation to the set of possible outcomes. In particular, in a promotion context, the goal is achieving the maximal gain, whereas in a prevention context it turns into avoiding the greatest loss. We explored the neurophysiological counterpart of this phenomenon, by applying Transcranial Magnetic Stimulation (TMS) and recording the motor evoked potentials (MEPs) in participants taking part in an economic game, in which they observed actions conveying different goal attainment levels, framed in different motivational contexts. More than the actual value of the economic exchange involved in the game, what affected motor cortex excitability was the goal attainment failure, corresponding to not achieving the maximal payoff in a promotion context and not avoiding the greatest snatch in a prevention context. Therefore, the results provide support for the key predictions of RFT, identifying a neural signature for the goal attainment failure.

Cortical networks of procedural learning: evidence from cerebellar damage.

The lateral cerebellum plays a critical role in procedural learning that goes beyond the strict motor control functions attributed to it. Patients with cerebellar damage show marked impairment in the acquisition of procedures, as revealed by their performance on the serial reaction time task (SRTT). Here we present the case of a patient affected by ischemic damage involving the left cerebellum who showed a selective deficit in procedural learning while performing the SRTT with the left hand. The deficit recovered when the cortical excitability of an extensive network involving both cerebellar hemispheres and the dorsolateral prefrontal cortex (DLPFC) was decreased by low-frequency repetitive transcranial magnetic stimulation (rTMS). Although inhibition of the right DLPFC or a control fronto-parietal region did not modify the patient's performance, inhibition of the right (unaffected) cerebellum and the left DLPFC markedly improved task performance. These findings could be explained by the modulation of a set of inhibitory and excitatory connections between the lateral cerebellum and the contralateral prefrontal area induced by rTMS. The presence of left cerebellar damage is likely associated with a reduced excitatory drive from sub-cortical left cerebellar nuclei towards the right DLPFC, causing reduced excitability of the right DLPFC and, conversely, unbalanced activation of the left DLPFC. Inhibition of the left DLPFC would reduce the unbalancing of cortical activation, thus explaining the observed selective recovery of procedural memory.

Augmenting distractor filtering via transcranial magnetic stimulation of the lateral occipital cortex.

Visual selective attention (VSA) optimizes perception and behavioral control by enabling efficient selection of relevant information and filtering of distractors. While focusing resources on task-relevant information helps counteract distraction, dedicated filtering mechanisms have recently been demonstrated, allowing neural systems to implement suitable policies for the suppression of potential interference. Limited evidence is presently available concerning the neural underpinnings of these mechanisms, and whether neural circuitry within the visual cortex might play a causal role in their instantiation, a possibility that we directly tested here. In two related experiments, transcranial magnetic stimulation (TMS) was applied over the lateral occipital cortex of healthy humans at different times during the execution of a behavioral task which entailed varying levels of distractor interference and need for attentional engagement. While earlier TMS boosted target selection, stimulation within a restricted time epoch close to (and in the course of) stimulus presentation engendered selective enhancement of distractor suppression, by affecting the ongoing, reactive instantiation of attentional filtering mechanisms required by specific task conditions. The results attest to a causal role of mid-tier ventral visual areas in distractor filtering and offer insights into the mechanisms through which TMS may have affected ongoing neural activity in the stimulated tissue.

The cerebellum and visual perceptual learning: evidence from a motion extrapolation task.

Visual perceptual learning is widely assumed to reflect plastic changes occurring along the cerebro-cortical visual pathways, including at the earliest stages of processing, though increasing evidence indicates that higher-level brain areas are also involved. Here we addressed the possibility that the cerebellum plays an important role in visual perceptual learning. Within the realm of motor control, the cerebellum supports learning of new skills and recalibration of motor commands when movement execution is consistently perturbed (adaptation). Growing evidence indicates that the cerebellum is also involved in cognition and mediates forms of cognitive learning. Therefore, the obvious question arises whether the cerebellum might play a similar role in learning and adaptation within the perceptual domain. We explored a possible deficit in visual perceptual learning (and adaptation) in patients with cerebellar damage using variants of a novel motion extrapolation, psychophysical paradigm. Compared to their age- and gender-matched controls, patients with focal damage to the posterior (but not the anterior) cerebellum showed strongly diminished learning, in terms of both rate and amount of improvement over time. Consistent with a double-dissociation pattern, patients with focal damage to the anterior cerebellum instead showed more severe clinical motor deficits, indicative of a distinct role of the anterior cerebellum in the motor domain. The collected evidence demonstrates that a pure form of slow-incremental visual perceptual learning is crucially dependent on the intact cerebellum, bearing the notion that the human cerebellum acts as a learning device for motor, cognitive and perceptual functions. We interpret the deficit in terms of an inability to fine-tune predictive models of the incoming flow of visual perceptual input over time. Moreover, our results suggest a strong dissociation between the role of different portions of the cerebellum in motor versus non-motor functions, with only the posterior lobe being responsible for learning in the perceptual domain.

Altered parietal-motor connections in Alzheimer's disease patients.

Alzheimer's disease (AD) is characterized by altered functional cortico-cortical connectivity likely due to loss of afferent and efferent connections between different cortical areas. Here we explored parieto-frontal functional connectivity in 15 AD patients and 12 healthy control subjects by means of bifocal transcranial magnetic stimulation (TMS). Conditioning stimuli were applied over the right posterior parietal cortex (PPC) at different intensities (90% and 110% of resting motor threshold, RMT). Motor evoked potentials (MEPs) were then recorded from the ipsilateral primary motor cortex at different interstimulus intervals (ISIs) ranging between 2 and 15 ms. Results showed that in healthy subjects, a conditioning TMS pulse applied over the ipsilateral PPC at 90%, but not at 110%, of RMT intensity was able to increase the excitability of the right M1. This functional interaction peaked at ISI = 6 ms. Conversely, in AD patients the facilitatory pattern of parieto-motor connections was evident only when TMS was delivered at an intensity of 110% of RMT with a peak at ISI = 8 ms. Moreover in AD patients, treatment with cholinesterase inhibitors did not induce any significant modification in the strength of the connection. In subsequent analyses, we found that, in AD patients, the effects induced by PPC conditioning at 110% RMT correlated with neuropsychological measures of episodic memory and executive functions, implying that patients with better cognitive performance had less impaired connectivity. Our findings reveal that parieto-frontal cortico-cortical functional connectivity is altered in AD patients, providing further evidence for a disconnection-based interpretation of AD symptoms.