Hans Forssberg

Anatomical and physiological evidence for D 1 and D 2 dopamine receptor colocalization in neostriatal neurons

Despite the importance of dopamine signaling, it remains unknown if the two major subclasses of dopamine receptors exist on the same or distinct populations of neurons. Here we used confocal microscopy to demonstrate that virtually all striatal neurons, both in vitro and in vivo, contained dopamine receptors of both classes. We also provide functional evidence for such colocalization: in essentially all neurons examined, fenoldopam, an agonist of the D1 subclass of receptors, inhibited both the Na+/K+ pump and tetrodotoxin (TTX)-sensitive sodium channels, and quinpirole, an agonist of the D2 subclass of receptors, activated TTX-sensitive sodium channels. Thus D1 and D2 classes of ligands may functionally interact in virtually all dopamine-responsive neurons within the basal ganglia.

Neural control of human motor development.

It has been possible to expand considerably our understanding of human motor development by making a detailed analysis of various types of movement and muscular activation patterns during different stages of development. Alterations in development subsequent to the appearance of brain lesions have enabled valuable information to be collected about the underlying neural mechanisms, in addition to new information concerning the pathophysiology of cerebral palsy. Studies on the development of the corticospinal system indicate that plastic changes can take place after perinatal brain damage.

Functional outcome at 5 years in children with obstetrical brachial plexus palsy with and without microsurgical reconstruction

Between 1987 and 1998, 470 patients visited the national clinic for obstetrical brachial plexus palsies at the Karolinska Hospital, Stockholm, Sweden. This study reports on 247 children examined at 5 years of age using a special protocol for testing the sensory and motor function of the hand. The children were distributed in various groups depending on the number of injured nerves, whether they had some muscle activity in their biceps or deltoid muscles at 3 months of age, and whether any operations with nerve reconstruction had been performed. The shoulder range of movement in C5–6 palsies was significantly better in the group which had been operated on (operated group), but otherwise there were no differences between children who had been operated on (non‐operated group) and those who had not. A decrease in grip strength and bimanual function in level C5–6 palsies was found, though these roots should not innervate the distal hand. Outcome was not influenced by the number of avulsions in upper‐plexus palsies or whether the operation took place before or after the age of 6 months. The group with extensive lesions (C5‐Th1) had the most root avulsions, showing a correlation between increased avulsions and decreased hand function. This study does not support operating on children with no activity of the biceps and deltoid muscles at 3 months of age, as other authors have concluded. Rather, it favours waiting for a late recovery.

Hand function in relation to brain lesions and corticomotor-projection pattern in children with unilateral cerebral palsy

Aimu2002 To investigate relationships between hand function, brain lesions, and corticomotor projections in children with unilateral cerebral palsy (CP).

Quantitative assessment of mirror movements in children and adolescents with hemiplegic cerebral palsy

Mirror movements in individuals with hemiplegic cerebral palsy (CP) may result from a reorganization of the central sensorimotor system. Motor performances of both hands were measured to characterize mirror activity (or mirroring) and hand functions in 22 participants (6 to 18 years) with hemiplegic CP and in 17 control participants. During a unimanual repetitive squeezing task, contractions of the active hand and fingertip forces of the opposite hand were recorded simultaneously. In the control group, slight mirror activity (or mirroring) was found that decreased with age. In participants with CP, mirror activity was 15 times stronger than in the control group, and was found at all age levels. Mirroring was more prominent in the unaffected hand of the CP group. The amount of mirror activity was not related to the degree of hemiplegia, which was assessed with measures of spasticity, strength, and dexterity. Mirror movements disturbed functional bimanual skills, although to some extent they could be suppressed by voluntary effort.

Can a therapeutic dose of amphetamine during pre-adolescence modify the pattern of synaptic organization in the brain?

Stimulant drugs such as amphetamine have, for many decades, been the drugs of choice in the treatment of children with attention‐deficit/hyperactivity disorder. However, little is known about their therapeutic mechanisms or about the consequences of their long‐term exposure. In the present study we investigated whether repeated exposure of a low dose of amphetamine (0.5u2003mg/kg) to juvenile rats could induce long‐term morphological alterations in the prefrontal cortex. In addition, to assess possible behavioural consequences of prolonged exposure to this drug, we examined whether changes in the motor response to various dopamine agonists occurred after this treatment. We found that this dose of amphetamine promotes plasma concentrations of amphetamine sulphate in juvenile rats to levels corresponding to the clinical range used for children with attention‐deficit/hyperactivity disorder. Amphetamine (0.5u2003mg/kg; s.c.) was administered twice daily during postnatal days 22–34, and then the brains of the animals were evaluated 2u2003weeks later. This treatment produced an increase in dendritic length and branches of pyramidal neurons of the medial prefrontal cortex, but not in the nucleus accumbens. These changes were associated with an increase in the expression of calcium/calmodulin‐dependent protein kinase II, a highly abundant signalling protein in the postsynaptic densities of excitatory synapses. Interestingly, amphetamine pre‐treatment did not alter the motor response to various dopamine agonists, including amphetamine. These data suggest that clinical doses of stimulant drugs may be acting as a trophic support at the glutamatergic synapses, thereby enhancing dopamine–glutamate interactions in the prefrontal cortex.

Long-term effects of botulinum toxin A in children with cerebral palsy

The long‐term effects of botulinum toxin A (BoNT‐A) treatment in children with cerebral palsy (CP) are still elusive. We studied a prospective clinical cohort of 94 children with different subtypes (50% spastic diplegic CP, 22% hemiplegic CP, 25% tetraplegic CP, 3% dyskinetic CP), sex (55% male, 45% female), severity according to Gross Motor Function Classification System (29% Level I, 15% Level II, 16% Level III, 17% Level IV, 23% Level V), and age (median 5y 4mo, range 11mo–17y 8mo). The longest follow‐up time was 3 years 7 months (median 1y 6mo) and included a maximum of eight injections per muscle (median two injections to a specific muscle). Outcome measurements were muscle tone (Modified Ashworth Scale) and joint range of motion (ROM). Assessments were made at a minimum before and 3 months after each injection. Ninety‐five per cent confidence intervals for differences from baseline were used to identify significant changes. BoNT‐A injections induced reduction of long‐term spasticity in all muscle‐groups examined: the gastrocnemius, hamstring, and adductor muscles. The reduction in tone was most distinct in the gastrocnemius muscle, and each repeated injection produced an immediate reduction in muscle tone. However, improvement in ROM was brief and measured only after the first injections, whereupon the ROM declined. Thus, the results suggest that BoNT‐A can be effective in reducing muscle tone over a longer period, but not in preventing development of contractures in spastic muscles. The dissociation between the effects on muscle tone and ROM indicates that development of contractures is not coupled to increased muscle tone only, but might be caused by other mechanisms.

Effects of Prenatal Dexamethasone Treatment on Physical Growth, Pituitary-Adrenal Hormones, and Performance of Motor, Motivational, and Cognitive Tasks in Juvenile and Adolescent Common Marmoset Monkeys

Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to prevent respiratory distress syndrome in preterm infants, but there is emerging evidence of subsequent neurobehavioral abnormalities (e.g. problems with inattention/hyperactivity). In the present study, we exposed pregnant common marmosets (Callithrix jacchus, primates) to daily repeated DEX (5 mg/kg by mouth) during either early (d 42-48) or late (d 90-96) pregnancy (gestation period of 144 days). Relative to control, and with a longitudinal design, we investigated DEX effects in offspring in terms of physical growth, plasma ACTH and cortisol titers, social and maintenance behaviors, skilled motor reaching, motivation for palatable reward, and learning between infancy and adolescence. Early DEX resulted in reduced sociability in infants and increased motivation for palatable reward in adolescents. Late DEX resulted in a mild transient increase in knee-heel length in infants and enhanced reversal learning of stimulus-reward association in adolescents. There was no effect of either early or late DEX on basal plasma ACTH or cortisol titers. Both treatments resulted in impaired skilled motor reaching in juveniles, which attenuated in early DEX but persisted in late DEX across test sessions. The increased palatable-reward motivation and decreased social motivation observed in early DEX subjects provide experimental support for the clinical reports that prenatal glucocorticoid treatment impairs social development and predisposes to metabolic syndrome. These novel primate findings indicate that fetal glucocorticoid overexposure can lead to abnormal development of motor, affective, and cognitive behaviors. Importantly, the outcome is highly dependent upon the timing of glucocorticoid overexposure.

Parametric control of fingertip forces during precision grip lifts in children with DCD (developmental coordination disorder) and DAMP (deficits in attention motor control and perception)

Twenty boys with developmental coordination disorder (DCD), 11 of whom had associated attention deficit disorder (ADD), were compared with an age-matched control group of 12 boys to examine mechanisms that adapt the grip force at the digit-object interface in a precision grip task. An experimental grip object equipped with pressure transducers registered the grip forces (normal to the surface) and the load force (tangential to the surface) generated by the fingertips. The surface of the object was changed to vary the frictional properties. Both study groups exhibited disturbances of the basic coordination of forces in the initial phase of the movement, manifested by longer time latencies and higher force levels than the control group. All subjects were able to adapt the force output in response to the friction at the digit-object interface. Higher grip forces and safety margins were documented for the DCD group in comparison to the controls. Furthermore, there was greater variation in the parametric control of the grip force in the DCD group. The results suggest that the control of the grip force is similar in children with DCD, regardless of whether they have associated ADD or not, but it is impaired in comparison to that of controls.

Motor inhibitory role of dopamine D1 receptors: implications for ADHD.

Dysregulation of dopamine (DA) neurotransmission in frontal-striatal circuitry has been hypothesized to underlie several neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD). The actions of DA are mediated by five distinct receptor subtypes that belong to the G-protein-coupled receptor super-family and are divided into two major classes, D1-like (D1 and D5) and D2-like (D2, D3, and D4). Accumulating evidence implicates the D1 receptor subtype (D1R) in the regulation of motor and cognitive processes. It is generally assumed that D1R is linked to motor activity in a stimulatory fashion. However, recent findings in rodents suggest a potential role of D1R on motor inhibition, which emerges during late postnatal development. Several lines of evidence indicate that the locus of the inhibitory effects involve subregions of the prefrontal cortex (PFC). These results may be relevant for understanding the neurobiology of ADHD.