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Cell based therapy enhances activation of ventral premotor cortex to improve recovery following primary motor cortex injury.

ABSTRACT: Stroke results in enduring damage to the brain which is accompanied by innate neurorestorative processes, such as reorganization of surviving circuits. Nevertheless, patients are often left with permanent residual impairments. Cell based therapy is an emerging therapeutic that may function to enhance the innate neurorestorative capacity of the brain. We previously evaluated human umbilical tissue-derived cells (hUTC) in our non-human primate model of cortical injury limited to the hand area of primary motor cortex. Injection of hUTC 24?h after injury resulted in significantly enhanced recovery of fine motor function compared to vehicle treated controls (Moore et al., 2013). These monkeys also received an injection of Bromodeoxyuridine (BrdU) 8?days after cortical injury to label cells undergoing replication. This was followed by 12?weeks of behavioral testing, which culminated 3?h prior to perfusion in a final behavioral testing session using only the impaired hand. In this session, the neuronal activity initiating hand movements leads to the upregulation of the immediate early gene c-Fos in activated cells. Following perfusion-fixation of the brain, sections were processed using immunohistochemistry to label c-Fos activated cells, pre-synaptic vesicle protein synaptophysin, and BrdU labeled neuroprogenitor cells to investigate the hypothesis that hUTC treatment enhanced behavioral recovery by facilitating reorganization of surviving cortical tissues. Quantitative analysis revealed that c-Fos activated cells were significantly increased in the ipsi- and contra-lesional ventral premotor but not the dorsal premotor cortices in the hUTC treated monkeys compared to placebo controls. Furthermore, the increase in c-Fos activated cells in the ipsi- and contra-lesional ventral premotor cortex correlated with a decrease in recovery time and improved grasp topography. Interestingly, there was no difference between treatment groups in the number of synaptophysin positive puncta in either ipsi- or contra-lesional ventral or dorsal premotor cortices. Nor was there a significant difference in the density of BrdU labeled cells in the subgranular zone of the hippocampus or the subventricular zone of the lateral ventricle. These findings support the hypothesis that hUTC treatment enhances the capacity of the brain to reorganize after cortical injury and that bilateral plasticity in ventral premotor cortex is a critical locus for this recovery of function. This reorganization may be accomplished through enhanced activation of pre-existing circuits within ventral premotor, but it could also reflect ventral premotor projections to the brainstem or spinal cord.

SUBMITTER: Orczykowski ME

PROVIDER: S-EPMC5955823 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Cell based therapy enhances activation of ventral premotor cortex to improve recovery following primary motor cortex injury.

Orczykowski Mary E ME Arndt Kevin R KR Palitz Lauren E LE Kramer Brian C BC Pessina Monica A MA Oblak Adrian L AL Finklestein Seth P SP Mortazavi Farzad F Rosene Douglas L DL Moore Tara L TL

Experimental neurology 20180311

Stroke results in enduring damage to the brain which is accompanied by innate neurorestorative processes, such as reorganization of surviving circuits. Nevertheless, patients are often left with permanent residual impairments. Cell based therapy is an emerging therapeutic that may function to enhance the innate neurorestorative capacity of the brain. We previously evaluated human umbilical tissue-derived cells (hUTC) in our non-human primate model of cortical injury limited to the hand area of p ...[more]

PMID: 29540323

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Project description:The functional connection between ventral premotor cortex (PMv) and primary motor cortex (M1) is critical for the organization of goal-directed actions. Repeated activation of this connection by means of cortico-cortical paired associative stimulation (cc-PAS), a transcranial magnetic stimulation (TMS) protocol, may induce Hebbian-like plasticity. However, the physiological modifications produced by Hebbian-like plasticity in the PMv-M1 network are poorly understood. To fill this gap, we investigated the effects of cc-PAS on PMv-M1 circuits. We hypothesized that specific interactions would occur with I2 -wave interneurons as measured by the short intracortical facilitation protocol (SICF). We used different paired-pulse TMS protocols to examine the effects of PMv-M1 cc-PAS on SICF, on GABAergic circuits as measured by short (SICI) and long (LICI) intracortical inhibition protocols, and varied the current direction in M1 to target different M1 neuronal populations. Finally, we examined the effects of cc-PAS on PMv-M1 connectivity using a dual coil approach. We found that PMv-M1 cc-PAS induces both a long-term potentiation (LTP)- or long-term depression (LTD)-like after-effect in M1 neuronal activity that is strongly associated with a bidirectional-specific change in I2 -wave activity (SICF = 2.5 ms ISI). Moreover, cc-PAS induces a specific modulation of the LICI circuit and separately modulates PMv-M1 connectivity. We suggest that plasticity within the PMv-M1 circuit is mediated by a selective mechanism exerted by PMv on M1 by targeting I2 -wave interneurons. These results provide new mechanistic insights into how PMv modulates M1 activity that are relevant for the design of brain stimulation protocols in health and disease. KEY POINTS: The I2 -wave is specifically modulated by the induction of ventral premotor cortex - primary motor cortex (PMv-M1) plasticity. After PMv-M1 cortico-cortical paired associative stimulation (cc-PAS), corticospinal excitability correlates negatively with I2 -wave amplitude. Different cc-PAS coil orientations can lead to a long-term potentiation- or long-term depression-like after-effect in M1.

Project description:Interactions between the ventral premotor (PMv) and the primary motor cortex (M1) are crucial for transforming an object's geometrical properties, such as its size and shape, into a motor command suitable for grasp of the object. Recently, we showed that PMv interacts with M1 in a specific fashion, depending on the hand posture. However, the functional connectivity between PMv and M1 during the preparation of an actual grasp is still unknown. To address this issue, PMv-M1 interactions were tested while subjects were preparing to grasp different visible objects requiring either a precision grip or a whole hand grasp. A conditioning-test transcranial magnetic stimulation (TMS) paradigm was used: a test stimulus was applied over M1 either in isolation or after a conditioning stimulus delivered, at different delays, over the ipsilateral PMv. Motor evoked potentials (MEPs) were recorded in the first dorsal interosseus and abductor digiti minimi muscles, which show highly differentiated activity according to grasp. While subjects prepared to grasp, delivering a conditioning PMv pulse 6 or 8msec before a test pulse over M1 strikingly facilitated MEPs in the specific muscles that were used in the upcoming grasp. This degree of facilitation correlated with the amount of muscle activity used later in the trial to grasp the objects. The present results demonstrate that, during grasp preparation, the PMv-M1 interactions are muscle-specific. PMv appears to process the object geometrical properties relevant for the upcoming grasp, and transmits this information to M1, which in turn generates a motor command appropriate for the grasp. We also reveal that the grasp-specific facilitation resulting from PMv-M1 interactions is differently related to the upcoming grasp muscle activity than is that from paired-pulse stimulation over M1, suggesting that these two TMS paradigms assess the excitability of cortico-cortical pathways devoted to the control of grasp at two different levels.

Dataset Information

Cell based therapy enhances activation of ventral premotor cortex to improve recovery following primary motor cortex injury.

Publications

Cell based therapy enhances activation of ventral premotor cortex to improve recovery following primary motor cortex injury.

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