Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning.

The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.

Characterizing Social Functioning in School-Age Children with Sensory Processing Abnormalities.

Children with sensory abnormalities (SAs) have a variety of social problems resulting in poorer social functioning than children with typical development (TD). We describe the relationship between SAs and social functioning in school-age children with SAs, children with TD and a clinical comparison sample of children with autism spectrum disorder (ASD). Children with SAs demonstrated impaired social functioning on standardized measures. Children with SAs demonstrated worse social functioning than children with TD and equivalent social functioning to children with ASD. Increased SAs were associated with poorer social functioning across all groups. The results suggest that children with SAs experience clinically significant problems with social functioning and future research is needed to develop interventions to support social functioning in this population.

Infants later diagnosed with autism have lower canonical babbling ratios in the first year of life.

BACKGROUND: Canonical babbling-producing syllables with a mature consonant, full vowel, and smooth transition-is an important developmental milestone that typically occurs in the first year of life. Some studies indicate delayed or reduced canonical babbling in infants at high familial likelihood for autism spectrum disorder (ASD) or who later receive an ASD diagnosis, but evidence is mixed. More refined characterization of babbling in the first year of life in infants with high likelihood for ASD is needed. METHODS: Vocalizations produced at 6 and 12 months by infants (n = 267) taking part in a longitudinal study were coded for canonical and non-canonical syllables. Infants were categorized as low familial likelihood (LL), high familial likelihood diagnosed with ASD at 24 months (HL-ASD) or not diagnosed (HL-Neg). Language delay was assessed based on 24-month expressive and receptive language scores. Canonical babble ratio (CBR) was calculated by dividing the number of canonical syllables by the number of total syllables. Generalized linear (mixed) models were used to assess the relationship between group membership and CBR, controlling for site, sex, and maternal education. Logistic regression was used to assess whether canonical babbling ratios at 6 and 12 months predict 24-month diagnostic outcome. RESULTS: No diagnostic group differences in CBR were detected at 6 months, but HL-ASD infants produced significantly lower CBR than both the HL-Neg and LL groups at 12 months. HL-Neg infants with language delay also showed reduced CBR at 12 months. Neither 6- nor 12-month CBR was significant predictors of 24-month diagnostic outcome (ASD versus no ASD) in logistic regression. LIMITATIONS: Small numbers of vocalizations produced by infants at 6 months may limit the reliability of CBR estimates. It is not known if results generalize to infants who are not at high familial likelihood, or infants from more diverse racial and socioeconomic backgrounds. CONCLUSIONS: Lower canonical babbling ratios are apparent by the end of the first year of life in ASD regardless of later language delay, but are also observed for infants with later language delay without ASD. Canonical babbling may lack specificity as an early marker when used on its own.

A voxel-wise assessment of growth differences in infants developing autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a phenotypically and etiologically heterogeneous developmental disorder typically diagnosed around 4 years of age. The development of biomarkers to help in earlier, presymptomatic diagnosis could facilitate earlier identification and therefore earlier intervention and may lead to better outcomes, as well as providing information to help better understand the underlying mechanisms of ASD. In this study, magnetic resonance imaging (MRI) scans of infants at high familial risk, from the Infant Brain Imaging Study (IBIS), at 6, 12 and 24 months of age were included in a morphological analysis, fitting a mixed-effects model to Tensor Based Morphometry (TBM) results to obtain voxel-wise growth trajectories. Subjects were grouped by familial risk and clinical diagnosis at 2 years of age. Several regions, including the posterior cingulate gyrus, the cingulum, the fusiform gyrus, and the precentral gyrus, showed a significant effect for the interaction of group and age associated with ASD, either as an increased or a decreased growth rate of the cerebrum. In general, our results showed increased growth rate within white matter with decreased growth rate found mostly in grey matter. Overall, the regions showing increased growth rate were larger and more numerous than those with decreased growth rate. These results detail, at the voxel level, differences in brain growth trajectories in ASD during the first years of life, previously reported in terms of overall brain volume and surface area.

Shape mapping of the hippocampus in young children with autism spectrum disorder.

BACKGROUND AND PURPOSE: We hypothesized the occurrence of characteristic hippocampal-shape alterations in young children with autistic spectrum disorder (ASD) who also exhibit deficits on neuropsychologic tests of medial temporal lobe (MTL) function. MATERIALS AND METHODS: Coronal 3D MR images were acquired from 3- to 4-year-old children with ASD (n = 45) and age-matched children with typical development (n = 13). Children with ASD were further subclassified into those with autism disorder (AD, n = 29) or pervasive developmental disorder-not otherwise specified (PDD-NOS) (n = 16). Variations in hippocampal shape were evaluated by using large-deformation high-dimensional brain mapping. RESULTS: Hippocampal shape measures distinguished children with ASD from those with typical development; within the ASD sample, children with AD were distinguished from those with PDD-NOS. Hippocampal-shape alterations in children with ASD were correlated with degree of mental retardation and performance deficits on tests of MTL function. CONCLUSIONS: Children with ASD exhibited an alteration of hippocampal shape consistent with inward deformation of the subiculum. This pattern of hippocampal-shape deformations in the children with ASD was accentuated in the more severely affected subgroup of children with AD and was associated with deficits on neuropsychologic tests of MTL but not prefrontal function. Hippocampal-shape deformation in the children with ASD was observed to be similar to a pattern of hippocampal shape deformation previously reported in adults with MTL epilepsy. Although the children with ASD, and those with AD in particular, PDD-NOS are at high risk for epilepsy as they enter adolescence, the specificity and causal relationship of this pattern of hippocampal-shape deformation to the development of seizures is not yet known.

Two-dimensional proton echo-planar spectroscopic imaging of brain metabolic changes during lactate-induced panic.

BACKGROUND: A fast, proton echo-planar spectroscopic imaging (PEPSI) technique, capable of simultaneously measuring metabolites from multiple brain regions, was used to investigate the anatomical distribution and magnitude of brain lactate responses to intravenous lactate infusion among subjects with panic disorder and control subjects. METHODS: Fifteen subjects with panic disorder and 10 control subjects were studied. All subjects were medication free and met DSM-IV criteria for panic disorder, or, for controls, no Axis I psychiatric disorder. Two-dimensional axial metabolite images having 1-cm3 spatial resolution were acquired at 61/2-minute intervals during 3 conditions: a 20-minute baseline, 20-minute 0.5-mol/L sodium lactate infusion, and 15-minute postinfusion period. RESULTS: Intravenous lactate infusion increased brain lactate levels throughout the axial brain section studied in all subjects. Panic-disordered subjects had significantly greater global brain lactate increases in response to lactate infusion. Lateralization of brain lactate response did not occur, nor were discrete regional loci of elevated lactate observed. Cerebrospinal fluid lactate changes corresponded to lactate changes in brain tissue. Severity of symptoms provoked by lactate infusion did not directly correlate with brain lactate response. CONCLUSIONS: Greater overall rises in brain lactate among subjects with panic disorder compared with controls occurred in response to lactate infusion. We were unable to detect a distinct regional pattern for magnitude differences in brain lactate rise by which to identify a specific neuroanatomical substrate underlying a lactate-induced panic response. The wide anatomical distribution of these brain lactate increases suggest metabolic and/or neurovascular mechanisms for the abnormal rise in subjects with panic disorder.

Magnetization transfer of fluoxetine in the human brain using fluorine magnetic resonance spectroscopy.

Fluorine magnetic resonance spectroscopy ((19)F MRS) measurements of fluoxetine and metabolite concentration in the human brain underestimate true drug levels because of a bound, MRS-"invisible" pool of drug molecules. Magnetization transfer (MT) spectroscopy may be a useful technique for characterizing this bound pool of fluoxetine in the brain. Six subjects on consistent daily doses of fluoxetine underwent (19)F MT spectroscopy on a 1.5-T scanner using a train of three preparation pulses at -3000 Hz off resonance with 0.5 W of peak power deposition in tissue. One subject was scanned at multiple time points after initiation of drug therapy. Magnetization transfer signal contrast was quantified using VARPRO-based time domain fitting software. Magnetization transfer signal contrast was quantifiable with mean MT signal depression of 12.5% (SD = 5.0, n = 6). An inverse relationship between brain concentration and the MT signal contrast of fluoxetine was found (r = -.82, Spearman coefficient =.007). This study is the first in vivo application of (19)F MT spectroscopy and the first to demonstrate a quantifiable MT effect for a psychotropic medication in the human brain. Findings suggest that fluoxetine is substantially bound in the brain and that individual differences, inversely related to brain concentration, can be detected in the magnitude of MT contrast.

Biological markers in panic states: lactate-induced panic and mitral valve prolapse.

Anxious patients, and more specifically, patients experiencing panic attacks, are thought to have a significant biological component to their illness. This study looks at two promising biological markers associated with this patient population-mitral valve prolapse and lactate-induced panic. We present our findings, which further characterize clinical and biological aspects of these two markers.

Characterization of human brain pharmacokinetics using a two-compartment model.

We developed a two-compartment pharmacokinetic model to systematically characterize 19F magnetic resonance spectroscopy (19F MRS) data on the concentration time course of psychotropic compounds measured in human brain. Using this model, brain volume of distribution and clearance were calculated for fluvoxamine as an index compound. Our interest in formalizing a multicompartment model was motivated by recent advances in the field of brain spectroscopy that allow the noninvasive characterization of brain uptake and elimination half-lives of fluorinated psychotropic compounds. Differences between central compartment single-dose and steady-state half-lives and the peripheral elimination half-life at steady state were used to formulate the model. Application of the model is illustrated using previously published data on the elimination half-lives of fluvoxamine from plasma and brain at steady state, along with the literature values for single-dose plasma elimination half-life. Applying the model, brain volume of distribution (1.12 L/kg +/- 0.2 SEM) and clearance (1.01 L/hour +/- 0.12 SEM) were calculated for fluvoxamine. The bioavailability of fluvoxamine to the brain from plasma was 1.85 +/- 0.23 SEM. The underlying multicompartment pharmacokinetics of fluvoxamine were reflected by the difference between brain and plasma elimination half-lives from steady state. This method to derive pharmacokinetic parameters using 19F MRS measurements of drug concentration in brain can be applied to characterize the pharmacokinetics of other fluorinated psychotropic compounds.

Response to lactate infusion in generalized anxiety disorder.

Intravenous sodium lactate infusion provokes symptoms of panic in patients with panic disorder at a significantly higher rate than in normal controls. Lactate sensitivity has been postulated to be specific for patients with panic attacks regardless of frequency of attacks or coexisting diagnoses. The authors present results of a pilot study of lactate infusions in patients with generalized anxiety disorder (GAD) without any history of panic attacks. Patients with GAD reacted more like panic disorder patients than like normal controls in anxiety and symptom scores during lactate infusion and in the rate of positive responses to lactate. Although preliminary, these findings raise questions regarding the specificity of lactate sensitivity and the relationship of GAD to panic disorder.

MRS detection of whole brain lactate rise during 1 M sodium lactate infusion in rats.

Proton magnetic resonance spectroscopy (1H MRS) performed in vivo on nine Sprague Dawley rats detected a threefold increase in whole brain lactate during intravenous 1 mol/L sodium lactate infusion. Significant increases in whole brain lactate were detected within 5 min after starting lactate infusion, progressively rose to a maximum level estimated at 3.2 +/- 1.5 mmol/L (all values +/- SD) immediately postinfusion, then decreased towards baseline levels during the next hr. Venous lactate concentration, increasing from 2.3 +/- 2.4 mmol/L to 43.0 +/- 8.0 mmol/L during the infusion, exhibited a steeper rise and then decreased more rapidly in comparison to changes in whole brain lactate. These data suggest MRS can be used in vivo to study acute changes in brain lactate associated with increasing blood lactate concentrations.

Lactate vulnerability after alprazolam versus placebo treatment of panic disorder.

Thirty-six patients with panic disorder underwent sodium lactate infusion before and after 8 weeks of treatment with alprazolam or placebo. With reinfusion, those patients panic-free with chronic alprazolam treatment displayed significantly decreased reactivity to lactate, as measured by subjective symptom ratings, duration of infusion before developing peak lactate-induced symptoms, and the proportion of patients experiencing lactate-induced anxiety or panic. Patients panic-free on placebo, as well as nonresponders to alprazolam treatment, displayed some, although less striking, decreases in reactivity to lactate with reinfusion. As a group, patients clinically unchanged with placebo treatment showed no systematic change in lactate response with reinfusion. Although the small numbers of patients in each treatment outcome group prohibit drawing definitive conclusions, these findings suggest that decreases in lactate-induced panic after successful alprazolam treatment of panic may result from a combination of changes in clinical state and direct effects of the medication.

Morning or evening bright light treatment of winter depression? The significance of hypersomnia.

In a randomized crossover design 19 patients with winter depression were treated with 7 days of bright morning light (6:00 to 8:00 AM) and 7 days of evening light (7:00 to 9:00 PM). Bright light in the morning reduced the Hamilton Depression Rating Scale score from 22.3 to 5.5; bright light in the evening decreased the Hamilton score from 21.0 to 12.2. Improvement in the depression as measured by the Hamilton Depression Rating scores was greater with morning light compared with evening lights. Hypersomnia was associated (p less than 0.05) with a superior response to morning light.

Central nervous system effects of lactate infusion in primates.

The concentration of total lactate in cisternal fluid increased threefold, from 12.3 +/- 2.1 to 37.6 +/- 8.9 mg/dl, during a 20-min intravenous infusion of 1 M racemic sodium lactate (10 mEq/kg) in 3 anesthetized, mechanically ventilated baboons. Rises in cisternal lactate lagged behind arterial lactate increases, but occurred during the time interval in which susceptible humans typically panic in response to lactate infusion. Subsequent to cisternal lactate increases, cisternal pH and HCO3- concentration progressively increased during a 105-min interval following lactate infusion. No consistent changes in cisternal pCO2 occurred during or subsequent to lactate infusion. These preliminary findings fail to support the hypothesis that lactate-induced panic is mediated by increasing central nervous system pCO2. Instead, these data demonstrate that lactate can rapidly increase in the central nervous system during lactate infusion, suggesting new lines of investigation for studying the mechanisms responsible for lactate-induced panic.

Effects of myo-inositol ingestion on human brain myo-inositol levels: a proton magnetic resonance spectroscopic imaging study.

BACKGROUND: Cerebrospinal fluid levels of myo-Inositol (m-Ino) are reported to be decreased in patients with affective disorder, and dietary supplements of m-Ino have been shown to reduce the symptoms of major depression. Myo-Inositol transport across the blood-brain barrier is mediated by a low capacity, saturable system. This study tests whether dietary m-Ino increases brain m-Ino or changes brain metabolism of m-Ino, possibly explaining the ability of this compound to alter mood. METHODS: Using proton magnetic resonance spectroscopic imaging, we measured m-Ino levels in occipital gray and parietal white matter of seventeen healthy subjects. Magnetic resonance spectroscopic imaging was performed twice at baseline as well as at day 4 and day 8 while subjects ingested 6 g of m-Ino twice a day. RESULTS: Following 4 days of m-Ino, m-Ino/Cr was 20% higher than baseline levels in occipital gray matter (p < 0.04) and 8% higher in parietal white matter (p = ns). By day 8, m-Ino/Cr ratios had returned to baseline values. CONCLUSIONS: Brain m-Ino levels initially increase during m-Ino administration and subsequently return to baseline levels. The time-limited increases observed for brain m-Ino may reflect homeostatic mechanisms, possibly associated with the role of m-Ino as a cerebral osmolyte, or with changes in brain phosphoinositide metabolism.

Lactate-induced panic in primary affective disorder.

Intravenous sodium lactate was given to seven patients with primary depression and secondary panic attacks and 26 patients with panic disorder or agoraphobia with panic attacks. The two groups had similar rates of panic response. These results challenge the diagnostic specificity of lactate-induced panic.

Differentiation of anxious patients by two-dimensional echocardiographic evaluation of the mitral valve.

Forty-four anxious patients with a history of panic attacks had a significantly higher prevalence of mitral valve abnormalities than 20 patients with generalized anxiety only. The higher number of mitral valve abnormalities was not correlated with the frequency of panic attacks.

Brain elimination half-life of fluvoxamine measured by 19F magnetic resonance spectroscopy.

OBJECTIVE: This study used fluorine-19 magnetic resonance spectroscopy (19F MRS) to characterize the elimination of fluvoxamine from the human brain after abrupt drug discontinuation. The elimination half-lives of fluvoxamine in brain and plasma were determined to assess their interdependence and the relationship of brain half-life to the clinical practice of drug holidays and reports of acute withdrawal symptoms. METHODS: Six subjects completing clinical treatment with fluvoxamine were enrolled in the study. Spectroscopic quantification of whole brain fluvoxamine concentrations and chromatographic determination of plasma fluvoxamine levels were performed serially for up to 10 days after drug withdrawal. Psychiatric evaluation to assess withdrawal symptoms was also done at each scanning session. RESULTS: Elimination of fluvoxamine in the brain and plasma was optimally described by first-order kinetics; the mean elimination half-lives were 58 hours and 26 hours, respectively. The mean ratio of fluvoxamine brain elimination half-life to plasma half-life was 2.4. Three of the six subjects experienced mild to moderate withdrawal symptoms between the third and fifth days of the study, which corresponded to between one and two brain half-lives of fluvoxamine. CONCLUSIONS: The brain elimination half-life for fluorinated psychotropic compounds can be measured noninvasively by 19F MRS. The elimination half-life of fluvoxamine was found to be substantially longer for the brain than for plasma. The time course of withdrawal symptom onset and the rationale for drug holidays with fluvoxamine appear to be well explained by the brain elimination half-life.

Relapse and rebound following discontinuation of benzodiazepine treatment of panic attacks: alprazolam versus diazepam.

The authors assessed the effects of partial tapering followed by abrupt discontinuation of alprazolam, diazepam, and placebo in 40 patients with panic attacks. The anxiety scores and frequency of panic attacks of the three groups did not differ at the end of the initial 2-week taper, but 1 week after abrupt discontinuation of the remaining medication, patients formerly taking alprazolam had greater increases in anxiety but no more panic attacks than did the other patients. Because of low statistical power, differences in benzodiazepine half-lives, absence of multiple ratings, and imbalances between groups in clinical characteristics, these findings must be viewed as preliminary.