Anticipatory Planning Reveals Segmentation of Cortical Motor Output During Action Observation

It has been argued that the variation in brain activity that occurs when observing another person reflects a representation of actions that is indivisible, and which plays out in full once the intent of the actor can be discerned. We used transcranial magnetic stimulation to probe the excitability of corticospinal projections to 2 intrinsic hand muscles while motions to reach and grasp an object were observed. A symbolic cue either faithfully indicated the required final orientation of the object and thus the nature of the grasp that was required, or was in conflict with the movement subsequently displayed. When the cue was veridical, modulation of excitability was in accordance with the functional role of the muscles in the action observed. If however the cue had indicated that the alternative grasp would be required, modulation of output to first dorsal interosseus was consistent with the action specified, rather than the action observed-until the terminal phase of the motion sequence during which the object was seen lifted. Modulation of corticospinal output during observation is thus segmented-it progresses initially in accordance with the action anticipated, and if discrepancies are revealed by visual input, coincides thereafter with that of the action seen.

Contribution of primary motor cortex to compensatory balance reactions

Background: Rapid compensatory arm reactions represent important response strategies following an unexpected loss of balance. While it has been assumed that early corrective actions arise largely from sub-cortical networks, recent findings have prompted speculation about the potential role of cortical involvement. To test the idea that cortical motor regions are involved in early compensatory arm reactions, we used continuous theta burst stimulation (cTBS) to temporarily suppress the hand area of primary motor cortex (M1) in participants prior to evoking upper limb balance reactions in response to whole body perturbation. We hypothesized that following cTBS to the M1 hand area evoked EMG responses in the stimulated hand would be diminished. To isolate balance reactions to the upper limb participants were seated in an elevated tilt-chair while holding a stable handle with both hands. The chair was held vertical by a magnet and was triggered to fall backward unpredictably. To regain balance, participants used the handle to restore upright stability as quickly as possible with both hands. Muscle activity was recorded from proximal and distal muscles of both upper limbs.

Results: Our results revealed an impact of cTBS on the amplitude of the EMG responses in the stimulated hand muscles often manifest as inhibition in the stimulated hand. The change in EMG amplitude was specific to the target hand muscles and occasionally their homologous pairs on the non-stimulated hand with no consistent effects on the remaining more proximal arm muscles.

Conclusions: Present findings offer support for cortical contributions to the control of early compensatory arm reactions following whole-body perturbation.

Elevated Circulation Levels of an Antiangiogenic SERPIN in Patients with Diabetic Microvascular Complications Impair Wound Healing through Suppression of Wnt Signaling

Wound healing, angiogenesis and hair follicle maintenance are often impaired in the skin of diabetic patients, but the pathogenesis has not been well understood. Here, we report that circulation levels of kallistatin, a member of the serine proteinase inhibitor (SERPIN) superfamily with anti-angiogenic activities, were elevated in Type 2 diabetic patients with diabetic vascular complications. To test the hypothesis that elevated kallistatin levels could contribute to a wound healing deficiency via inhibition of Wnt/β-catenin signaling, we generated kallistatin-transgenic (KS-TG) mice. KS-TG mice had reduced cutaneous hair follicle density, microvascular density, and panniculus adiposus layer thickness as well as altered skin microvascular hemodynamics and delayed cutaneous wound healing. Using Wnt reporter mice, our results showed that Wnt/β-catenin signaling is suppressed in dermal endothelium and hair follicles in KS-TG mice. Lithium, a known activator of β-catenin via inhibition of glycogen synthase kinase-3β, reversed the inhibition of Wnt/β-catenin signaling by kallistatin and rescued the wound healing deficiency in KS-TG mice. These observations suggest that elevated circulating anti-angiogenic serpins in diabetic patients may contribute to impaired wound healing through inhibition of Wnt/β-catenin signaling. Activation of Wnt/β-catenin signaling, at a level downstream of Wnt receptors, may ameliorate the wound healing deficiency in diabetic patients.Journal of Investigative Dermatology accepted article preview online, 24 January 2014. doi:10.1038/jid.2014.40.

Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes

Hyperglycemia plays a pivotal role in the development and progression of vascular complications, which are the major sources of morbidity and mortality in diabetes. Furthermore, these vascular complications often persist and progress despite improved glucose control, possibly as a result of prior episodes of hyperglycemia. Epigenetic modifications mediated by histone methyltransferases are associated with gene-activating events that promote enhanced expression of key proinflammatory molecules implicated in vascular injury. In this study, we investigated genetic polymorphisms of the SETD7, SUV39H1, and SUV39H2 methyltransferases as predictors of risk for micro- and macrovascular complications in type 1 diabetes.

Speed of processing in the primary motor cortex: A continuous theta burst stimulation study

‘Temporally urgent’ reactions are extremely rapid, spatially precise movements that are evoked following discrete stimuli. The involvement of primary motor cortex (M1) and its relationship to stimulus intensity in such reactions is not well understood. Continuous theta burst stimulation (cTBS) suppresses focal regions of the cortex and can assess the involvement of motor cortex in speed of processing. The primary objective of this study was to explore the involvement of M1 in speed of processing with respect to stimulus intensity. Thirteen healthy young adults participated in this experiment. Behavioral testing consisted of a simple button press using the index finger following median nerve stimulation of the opposite limb, at either high or low stimulus intensity. Reaction time was measured by the onset of electromyographic activity from the first dorsal interosseous (FDI) muscle of each limb. Participants completed a 30 min bout of behavioral testing prior to, and 15 min following, the delivery of cTBS to the motor cortical representation of the right FDI. The effect of cTBS on motor cortex was measured by recording the average of 30 motor evoked potentials (MEPs) just prior to, and 5 min following, cTBS. Paired t-tests revealed that, of thirteen participants, five demonstrated a significant attenuation, three demonstrated a significant facilitation and five demonstrated no significant change in MEP amplitude following cTBS. Of the group that demonstrated attenuated MEPs, there was a biologically significant interaction between stimulus intensity and effect of cTBS on reaction time and amplitude of muscle activation. This study demonstrates the variability of potential outcomes associated with the use of cTBS and further study on the mechanisms that underscore the methodology is required. Importantly, changes in motor cortical excitability may be an important determinant of speed of processing following high intensity stimulation.

Human parietal and primary motor cortical interactions are selectively modulated during the transport and grip formation of goal-directed hand actions

Posterior parietal cortex (PPC) constitutes a critical cortical node in the sensorimotor system in which goal-directed actions are computed. This information then must be transferred into commands suitable for hand movements to the primary motor cortex (M1). Complexity arises because reach-to-grasp actions not only require directing the hand towards the object (transport component), but also preshaping the hand according to the features of the object (grip component). Yet, the functional influence that specific PPC regions exert over ipsilateral M1 during the planning of different hand movements remains unclear in humans. Here we manipulated transport and grip components of goal-directed hand movements and exploited paired-pulse transcranial magnetic stimulation (ppTMS) to probe the functional interactions between M1 and two different PPC regions, namely superior parieto-occipital cortex (SPOC) and the anterior region of the intraparietal sulcus (aIPS), in the left hemisphere. We show that when the extension of the arm is required to contact a target object, SPOC selectively facilitates motor evoked potentials, suggesting that SPOC-M1 interactions are functionally specific to arm transport. In contrast, a different pathway, linking the aIPS and ipsilateral M1, shows enhanced functional connections during the sensorimotor planning of grip. These results support recent human neuroimaging findings arguing for specialized human parietal regions for the planning of arm transport and hand grip during goal-directed actions. Importantly, they provide new insight into the causal influences these different parietal regions exert over ipsilateral motor cortex for specific types of planned hand movements

A new comparator account of auditory verbal hallucinations: how motor prediction can plausibly contribute to the sense of agency for inner speech

The comparator account holds that processes of motor prediction contribute to the sense of agency by attenuating incoming sensory information and that disruptions to this process contribute to misattributions of agency in schizophrenia. Over the last 25 years this simple and powerful model has gained widespread support not only as it relates to bodily actions but also as an account of misattributions of agency for inner speech, potentially explaining the etiology of auditory verbal hallucination (AVH). In this paper we provide a detailed analysis of the traditional comparator account for inner speech, pointing out serious problems with the specification of inner speech on which it is based and highlighting inconsistencies in the interpretation of the electrophysiological evidence commonly cited in its favor. In light of these analyses we propose a new comparator account of misattributed inner speech. The new account follows leading models of motor imagery in proposing that inner speech is not attenuated by motor prediction, but rather derived directly from it. We describe how failures of motor prediction would therefore directly affect the phenomenology of inner speech and trigger a mismatch in the comparison between motor prediction and motor intention, contributing to abnormal feelings of agency. We argue that the new account fits with the emerging phenomenological evidence that AVHs are both distinct from ordinary inner speech and heterogeneous. Finally, we explore the possibility that the new comparator account may extend to explain disruptions across a range of imagistic modalities, and outline avenues for future research.