Altered neurometabolites and motor integration in children exposed to methamphetamine in utero

Abstract

Methamphetamine (METH) is a neurotoxic drug. This study aimed to evaluate brain metabolite levels and cognitive function in young children with prenatal METH-exposure. 101 children ages 3-4 years were evaluated with neuropsychological tests and underwent proton magnetic resonance spectroscopy (1H-MRS) without sedation. Complete datasets from 49 METH-exposed and 49 controls who completed the neuropsychological test battery, and 38 METH-exposed and 37 controls with high-quality MR spectra are reported here. Despite similar physical characteristics (including head circumference), global cognitive function (on Stanford-Binet), parental education, intelligence, mood, and socioeconomic status, METH-exposed children had higher total creatine (tCr: +7%, p=0.003), N-acetyl compounds (NA: +4.3%, p=0.004) and glutamate+glutamine (GLX: +9.6%, p=0.02) concentrations in the frontal white matter, but lower myoinositol (MI: -7%, p=0.01) and MI/tCr (-7.5%, p=0.03) in the thalamus, than control children. The higher frontal white matter NA in the METH exposed children were due to the higher NA in the METH-exposed girls (+10.2%, p=0.0027), but not the boys (+0.8%) compared to sex-matched controls. Furthermore, the METH-exposed children had poorer performance on a visual motor integration (VMI) task, which correlated with lower MI in the thalamus (r=0.26, p=0.03). The higher NA, tCr and GLX concentrations suggest higher neuronal density or cellular compactness in the white matter, especially in the girls, whereas the lower MI suggests lower glial content in the thalamus of these METH-expose children. These findings combined with their poorer performance on VMI also suggest accelerated but aberrant neuronal and glial development in these brain regions.

Long-term effects of methamphetamine exposure on cognitive function and muscarinic acetylcholine receptor levels in mice

“…Exposure to MA during brain development causes long-term cognitive impairments in humans and rodents (Struthers and Hansen 1992; Vorhees et al , 2000; Williams et al , 2002., 2003a,b; Chang et al , 2004., 2009; Acevedo et al , 2007, 2008a; Vorhees et al , 2007.). Consistent with these findings, here we show that mice expressing human apoE3 or apoE4 have long-term cognitive impairments following MA exposure during hippocampal development.…”

“…MA exposure has also been shown to cause physiological and cognitive impairments in infants that persist into adolescence (Struthers and Hansen 1992; Chang et al , 2004; Smith et al , 2008). Children exposed to MA in utero show reduced spatial memory (Acevedo et al , 2008a), visual motor integration, attention, and verbal memory (Chang et al , 2004, 2009). …”

Frontostriatal Connectivity in Children during Working Memory and the Effects of Prenatal Methamphetamine, Alcohol, and Polydrug Exposure

“…Consistent with rodent models, the neuroimaging literature shows prominent effects on dopamine-rich frontostriatal circuits, including volume reductions in the globus pallidus and putamen [36] and in two subregions of the caudate [38], volume increases in the anterior cingulate and inferior frontal gyrus [38], and lower diffusion in frontal white matter [39]. Metabolic abnormalities have also been reported in the striatum [40] and the frontal white matter [35]. …”

“…In humans, prenatal exposure to methamphetamine leads to signs of motor abnormalities [30,31,32], restricted fetal growth [33,34], underarousal and increased stress [30,32], impaired visual motor integration [35,36], reduced attention and decreased verbal and spatial memory [36], and pronounced deficits in parentally rated executive functioning [37]. Consistent with rodent models, the neuroimaging literature shows prominent effects on dopamine-rich frontostriatal circuits, including volume reductions in the globus pallidus and putamen [36] and in two subregions of the caudate [38], volume increases in the anterior cingulate and inferior frontal gyrus [38], and lower diffusion in frontal white matter [39].…”

Neonatal (+)-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists

“…Effects in exposed children documented thus far include reduced birth weight, height and head circumference (Chomchai et al 2004; Dixon & Bejar, 1989; Little et al 1988; Smith et al 2008) and withdrawal symptoms shortly after birth (Chomchai et al 2004; Dixon, 1989; Oro & Dixon, 1987). Later changes include growth reduction (Smith et al 2003), neuroanatomical changes shown with magnetic resonance imaging (Chang et al 2004; Cloak et al 2009), elevated physiological stress (Smith et al 2008) and learning and memory deficits (Chang et al 2009; Struthers & Hansen, 1992). …”