Sensory-motor network functional connectivity in children with unilateral cerebral palsy secondary to perinatal stroke.

BACKGROUND: Perinatal stroke is the most common cause of unilateral cerebral palsy. Mechanisms of post-stroke developmental plasticity in children are poorly understood. To better understand the relationship between functional connectivity and disability, we used resting-state fMRI to compare sensorimotor connectivity with clinical dysfunction. METHODS: School-aged children with periventricular venous infarction (PVI) and unilateral cerebral palsy were compared to controls. Resting-state BOLD signal was acquired on 3 T MRI and analyzed using CONN in SPM12. Functional connectivity was computed between S1, M1, supplementary motor area (SMA), and thalamus of the left/non-lesioned and right/lesioned hemisphere. Primary outcome was connectivity expressed as a Fisher-transformed correlation coefficient. Motor function was measured using the Assisting Hand Assessment (AHA), and Melbourne Assessment (MA). Proprioceptive function was measured using a robotic position matching task (VarXY). RESULTS: Participants included 15 PVI and 21 controls. AHA and MA in stroke patients were negatively correlated with connectivity (increased connectivity = poorer performance). Position sense was inversely correlated with connectivity (increased connectivity = improved performance) between the non-lesioned S1 and thalamus/SMA. In controls, VarXY was positively correlated with connectivity between the thalamus and bilateral sensorimotor regions. CONCLUSIONS: Resting state fMRI measures of sensorimotor connectivity are associated with clinical sensorimotor function in children with unilateral cerebral palsy secondary to PVI. Greater insight into understanding reorganization of brain networks following perinatal stroke may facilitate personalized rehabilitation.

Synthesis and anticonvulsant activities of 3,3-dialkyl- and 3-alkyl-3-benzyl-2-piperidinones (delta-valerolactams) and hexahydro-2H-azepin-2-ones (epsilon-caprolactams).

A series of 3-substituted 2-piperidinone (delta-valerolactam) and hexahydro-2H-azepin-2-one (epsilon-caprolactam) derivatives were prepared and evaluated as anticonvulsants in mice. In the 2-piperidinone series, 3,3-diethyl compound 7b is the most effective anticonvulsant against pentylenetetrazole-induced seizures (ED50, 37 mg/kg; PI (TD50/ED50), 4.46), and 3-benzyl compound 4c (ED50, 41 mg/kg; PI, 7.05) is the most effective anticonvulsant against seizures induced by maximal electroshock. By contrast, none of the epsilon-caprolactams tested had anticonvulsant effects below doses causing rotorod toxicity. log P values were correlated with neurotoxicity and [35S]TBPS displacement, but not with anticonvulsant activity. Electrophysiological evaluations of selected compounds from each series indicated that both the delta-valero-lactams and epsilon-caprolactams potentiated GABA-mediated chloride currents in rat hippocampal neurons.

3,3-Dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones: a new class of anticonvulsant agents.

A series of 3,3-dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones (lactams) have been prepared and evaluated for their anticonvulsant activities. In the pentylenetetrazole mouse seizure model, 3,3-diethyl lactam 7c and 3-benzyl-3-ethyl lactam 7j are the most effective anticonvulsants (ED50 = 46 and 42 mg/kg, respectively) and have protective index (PI = TD50/ED50) values of 5.65 and 3.00, respectively. These protective index values compare favorably to those of the clinically used antiepileptic drugs ethosuximide (ED50 = 161 mg/kg), phenobarbital (ED50 = 22 mg/kg), and valproic acid (ED50 = 133 mg/kg), which have PI values of 2.35, 4.00, and 2.12, respectively. The benzyl compounds [3-substituents are Bn, H (7h); Bn, Me (7i); and Bn, Et (7j)] are also very effective anticonvulsants against seizures induced by maximal electroshock (ED50 = 41, 55, and 74 mg/kg, respectively) and have PI values of 3.51, 3.04, and 1.70, respectively. The corresponding PI values for phenobarbital and valproic acid are 1.37 and 5.18, respectively. As a class of anticonvulsants, the 3,3-disubstituted 2-pyrrolidinones have a broad spectrum of action and may be useful for the treatment of human epilepsies.

Heterogeneity of NH+4 transport in mouse inner medullary collecting duct cells.

Previous studies from our laboratory have demonstrated that NH+4 substitutes for K+ on the Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) in rat terminal inner medullary collecting duct cells (tIMCD). To examine other NH+4 transport pathways, a transgenic mouse cell line, mIMCD-3, was employed. 86Rb+ was used as a K+ congener to explore NH+4/Rb+ (K+) competition on the extracellular K+ binding site of the Na(+)-K(+)-2Cl- cotransporter and the Na(+)-K(+)-ATPase. Addition of K+ or NH+4 reduced both bumetanide- and ouabain-sensitive Rb+ uptake. This reduction in Rb+ uptake with NH+4 addition was not due to intracellular pH-mediated changes in transporter activity. K+ and NH+4 are competitive inhibitors on both transporters. On the Na(+)-K(+)-2Cl- cotransporter, the Michaelis constant (Km) for K+ was 4.6 +/- 0.5 mM with an inhibitory constant (Ki) for NH+4 of 2.8 mM. In contrast, on the Na(+)-K(+)-ATPase, the apparent affinity for K+ was greater than for NH+4. To test Na(+)-K(+)-2Cl- cotransport-mediated NH+4 flux, bumetanide-sensitive NH+4/Rb+ exchange was measured. Bumetanide-sensitive Rb+ efflux was greater with extracellular K+ or NH+4 present relative to efflux with extracellular N-methyl-D-glucamine. This demonstrates both K+/Rb+ and NH+4/Rb+ countertransport by the Na(+)-K(+)-2Cl- cotransporter. In conclusion, NH+4 is transported in a bumetanide-sensitive Na(+)-NH+4-Cl- mode, and both NH+4 and Rb+ (K+) are competitive inhibitors for the extracellular K+ binding site. However, the kinetics of Na(+)-K(+)-2Cl(-)-mediated NH+4 transport differ from other K+ transport-mediated NH+4 pathways, such as the Na(+)-K(+)-ATPase.