Jennifer F. Buckman

Time-dependent changes in striatal glutamate synapses following a 6-hydroxydopamine lesion

The goal of this study was to investigate changes in glutamatergic synapses in the striatum of rats at two different time-points following a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. One month following this lesion of the nigrostriatal pathway, there was an increase (70%) in the mean percentage of asymmetrical synapses within the dorsolateral striatum containing a discontinuous, or perforated, postsynaptic density, possibly suggesting an increase in glutamatergic activity. This was correlated, in the same brain region, with a decrease (44%) in the density of glutamate immunoreactivity within nerve terminals associated with all asymmetrical synapses and also with those terminals associated with a perforated postsynaptic density. These morphological changes were consistent with an increase (>two-fold) in the basal extracellular level of striatal glutamate, as measured by in vivo microdialysis. The density of GABA immunolabeling within symmetrical nerve terminals was increased (25%) at this one month time-period. Dopamine levels within the lesioned striatum were >99% depleted. However, at three months, while an increase in the mean percentage of striatal perforated synapses was maintained, a significant increase (50%) in the density of striatal nerve terminal glutamate immunolabeling within all asymmetrical synapses and those associated with a perforated postsynaptic density was observed. This was correlated with a small, but significant, decrease (32%) in the basal extracellular level of striatal glutamate. The density of GABA immunolabeling within nerve terminals associated with a symmetrical contact remained elevated at this three month time-period, while striatal dopamine levels remained depleted. While the density of nerve terminal GABA immunolabeling remained elevated at both the one and three month time-periods, there appeared to be a differential effect on glutamatergic synapses. The in vivo microdialysis data suggest that glutamate synapses were more active at a basal level at one month and become less active compared to the control group at the three month time-period. These data suggest that there are compensatory changes in glutamatergic synapses within the striatum following a 6-hydroxydopamine lesion that appear to be independent of the level of striatal dopamine or GABA. We propose that changes in the activity of the thalamo-cortico-striatal pathway may help to explain the differential time-course change in striatal glutamatergic synaptic activity.

MitoTracker labeling in primary neuronal and astrocytic cultures : influence of mitochondrial membrane potential and oxidants

MitoTracker dyes are fluorescent mitochondrial markers that covalently bind free sulfhydryls. The impact of alterations in mitochondrial membrane potential (Delta Psi(m)) and oxidant stress on MitoTracker staining in mitochondria in cultured neurons and astrocytes has been investigated. p-(Trifluoromethoxy) phenyl-hydrazone (FCCP) significantly decreased MitoTracker loading, except with MitoTracker Green in neurons and MitoTracker Red in astrocytes. Treatment with FCCP after loading increased fluorescence intensity and caused a relocalization of the dyes. The magnitude of these effects was contingent on which MitoTracker, cell type and dye concentration were used. H(2)O(2) pretreatment led to a consistent increase in neuronal MitoTracker Orange and Red and astrocytic MitoTracker Green and Orange fluorescence intensity. H(2)O(2) exposure following loading increased MitoTracker Red fluorescence in astrocytes. In rat brain mitochondria, high concentrations of MitoTracker dyes uncoupled respiration in state 4 and inhibited maximal respiration. Thus, loading and mitochondrial localization of the MitoTracker dyes can be influenced by loss of Delta Psi(m) and increased oxidant burden. These dyes can also directly inhibit respiration. Care must be taken in interpreting data collected using MitoTrackers dyes as these dyes have several potential limitations. Although MitoTrackers may have some value in identifying the location of mitochondria within cultured neurons and astrocytes, their sensitivity to Delta Psi(m) and oxidation negates their use as markers of mitochondrial dynamics in healthy cultures.

Cognitive impairment influences drinking outcome by altering therapeutic mechanisms of change.

Serious neuropsychological impairments are seen in a minority of addiction treatment clients, and, theoretically, these impairments should undermine behavioral changes targeted by treatment; however, little evidence supports a direct influence of impairment on treatment response. To address this paradox, the authors used structural equation modeling and Project MATCH data (N=1,726) to examine direct, mediated, and moderated paths between cognitive impairment, therapeutic processes, and treatment outcome. Mediated relations were found, wherein impairment led to less treatment compliance, lower self-efficacy, and greater Alcoholics Anonymous Involvement, which, in turn, more proximally predicted drinking. Impairment further moderated the effect of self-efficacy, making it a poor predictor of drinking outcomes in impaired clients, thereby suggesting that impaired and unimpaired clients traverse different pathways to addiction recovery.

Caudate Nucleus Volume and Cognitive Performance: Are they related in Childhood Psychopathology?

BACKGROUND Impaired neuropsychological test performance, especially on tests of executive function and attention, is often seen in children diagnosed with autism spectrum disorders (ASD). Structures involved in fronto-striatal circuitry, such as the caudate nucleus, may support these cognitive abilities. However, few studies have examined caudate volumes specifically in children with ASD, or correlated caudate volumes to cognitive ability. METHODS Neuropsychological test scores and caudate volumes of children with ASD were compared to those of children with bipolar disorder (BD) and of typically developing (TD) children. The relationship between test performance and caudate volumes was analyzed. RESULTS The ASD group displayed larger right and left caudate volumes, and modest executive deficits, compared to TD controls. While caudate volume inversely predicted performance on the Wisconsin Card Sorting Test in all participants, it differentially predicted performance on measures of attention across the ASD, BD and TD groups. CONCLUSIONS Larger caudate volumes were related to impaired problem solving. On a test of attention, larger left caudate volumes predicted increased impulsivity and more omission errors in the ASD group as compared to the TD group, however smaller volume predicted poorer discriminant responding as compared to the BD group.

A Role for Cognitive Rehabilitation in Increasing the Effectiveness of Treatment for Alcohol Use Disorders

Neurocognitive impairments are prevalent in persons seeking treatment for alcohol use disorders (AUDs). These impairments and their physical, social, psychological and occupational consequences vary in severity across persons, much like those resulting from traumatic brain injury; however, due to their slower course of onset, alcohol-related cognitive impairments are often overlooked both within and outside of the treatment setting. Evidence suggests that cognitive impairments can impede treatment goals through their effects on treatment processes. Although some recovery of alcohol-related cognitive impairments often occurs after cessation of drinking (time-dependent recovery), the rate and extent of recovery is variable across cognitive domains and individuals. Following a long hiatus in scientific interest, a new generation of research aims to facilitate treatment process and improve AUD treatment outcomes by directly promoting cognitive recovery (experience-dependent recovery). This review updates knowledge about the nature and course of cognitive and brain impairments associated with AUD, including cognitive effects of adolescent AUD. We summarize current evidence for indirect and moderating relationships of cognitive impairment to treatment outcome, and discuss how advances in conceptual frameworks of brain-behavior relationships are fueling the development of novel AUD interventions that include techniques for cognitive remediation. Emerging evidence suggests that such interventions can be effective in promoting cognitive recovery in persons with AUD and other substance use disorders, and potentially increasing the efficacy of AUD treatments. Finally, translational approaches based on cognitive science, neurophysiology, and neuroscience research are considered as promising future directions for effective treatment development that includes cognitive rehabilitation.

Risk for excessive alcohol use and drinking-related problems in college student athletes

There is compelling evidence that college student athletes engage in frequent episodes of heavy drinking and are prone to negative consequences resulting from such use. This study sought to identify risk and protective factors associated with student-athlete drinking and determine if student-athlete risk factors differed from those of non-athletes. Athletes compared to non-athletes reported more exaggerated perceptions of peer heavy drinking and lower sensation seeking and coping and enhancement motives for drinking, suggesting a risk profile distinct from non-athletes. In the overall sample, higher sensation seeking, overestimation of peer heavy drinking, non-use of protective behaviors while drinking, and higher enhancement and coping drinking motives were associated with greater frequency of heavy episodic drinking and more negative drinking consequences. In athletes compared to non-athletes, sensation seeking was more strongly associated with heavy episodic drinking and drinking to cope was more strongly associated with negative alcohol-related consequences. Overall, the results suggest that already proven brief intervention strategies, with minor adaptations related to the roles of sensation seeking and drinking to cope, may be helpful for student athletes.

Short-term neuropsychological recovery in clients with substance use disorders

BACKGROUND Cognitive impairments are frequently observed in clients who enter treatment programs for substance abuse. The potential for early recovery of cognitive abilities is suggested by previous research; however, the extent of improvement and risk factors that may help predict individual differences in rates of recovery remain unclear. This study is a 6-week follow-up and retest of an original sample of 197 men and women who had received a broad neuropsychological assessment at addiction treatment entry. The aim was to examine the potential clinical significance of changes in cognitive functioning and the extent to which differential recovery was predictable from client background information. METHODS Fifteen neuropsychological tests were readministered to 169 of 197 clients 6 weeks after treatment entry. Structural equation modeling was used to estimate separately the practice effects and recovery in four cognitive domains: executive function, memory, information processing speed, and verbal ability. Client background information included age, sex, education, substance use and consequences, psychopathology, medical problems, familial alcoholism history, and childhood behavior problems. RESULTS A four-factor model of latent neuropsychological ability that was previously identified at treatment entry was replicated at follow-up. Statistically significant increases in the means of the four latent abilities were found. Memory showed a medium effect size improvement. Executive function, verbal ability, and information processing speed, however, showed only small effect size improvements, suggesting limited clinical significance. Substance use between treatment entry and follow-up, antisocial personality disorder, negative use consequences, less education, and medical problems were modestly predictive of less recovery. CONCLUSION Cognitive recovery in the first 6 weeks of treatment is possible, but, with the possible exception of memory, improvement may be minor in terms of clinical relevance.

Activation of corticostriatal pathway leads to similar morphological changes observed following haloperidol treatment.

Treatment with haloperidol, a dopamine receptor D‐2 antagonist, for one month resulted in an increase in the mean percentage of asymmetric synapses containing a discontinuous, or perforated, postsynaptic density (PSD) [Meshul et al. (1994) Brain Res., 648:181–195] and a change in the density of striatal glutamate immunoreactivity within those presynaptic terminals [Meshul and Tan (1994) Synapse, 18:205–217]. We speculated that this haloperidol‐induced change in glutamate density might be due to an activation of the corticostriatal pathway. To determine if activation of this pathway leads to similar morphological changes previously described following haloperidol treatment, GABA (10−5 M, 0.5 μl) was injected into the thalamic motor (VL/VM) nuclei daily for 3 weeks. This treatment resulted in an increase in the mean percentage of striatal asymmetric synapses containing a perforated PSD and an increase in the density of glutamate immunoreactivity within nerve terminals of asymmetric synapses containing a perforated or non‐perforated PSD. Subchronic injections of GABA into the thalamic somatosensory nuclei (VPM/VPL) had no effect on the mean percentage of synapses with perforated PSDs but resulted in a small, but significant, increase in density of glutamate immunoreactivity. Using in vivo microdialysis, an acute injection of GABA (10−5 M, 15 μl) into VL/VM resulted in a prolonged rise in the extracellular level of striatal glutamate. The increase in asymmetric synapses with perforated PSDs and in glutamate immunoreactivity within nerve terminals of the striatum following either subchronic haloperidol treatment or GABA injections into VL/VM suggest that an increase in glutamate release may be a common factor in these two experiments. It is possible that the extrapyramidal side effects associated with haloperidol treatment may be due, in part, to an increase in release of glutamate within the corticostriatal pathway.

Risk factors and neuropsychological recovery in clients with alcohol use disorders who were exposed to different treatments.

Risk covariates of neuropsychological ability (NA) at treatment entry and neuropsychological recovery (NR) across 15 months were examined and replicated in 2 samples (Ns = 952 and 774) from Project MATCH, a multisite study of alcoholism treatments. NA at treatment entry was associated with age, education, and other covariates. Statistically significant mean increases in NA over time had small effect sizes, suggesting limited clinical significance of NR in the samples as a whole. However, initial NA and a combination of risk factors in direct and mediated pathways predicted a large proportion of individual differences in NR. Statistically significant but modest differential treatment effects on NR suggest that addiction treatments may need to be modified or developed to facilitate this important aspect of recovery.

Measurement of vascular tone and stroke volume baroreflex gain.

The arterial baroreflex system (BRS) consists of at least three closed-loop control systems: the heart rate (HR), vascular tone (VT), and stroke volume (SV) BRSs. Whereas HR-BRS gain is well studied, VT-BRS and SV-BRS gain are not. This study aimed to develop a method for quantifying VT-BRS and SV-BRS gain using an established HR-BRS gain measurement approach. ECG and beat-to-beat blood pressure (BP) were recorded in 31 young healthy participants during three tasks. Sequences of R-to-R wave intervals (RRI) of the ECG, pulse transit time (PTT), and SV were measured to assess HR-, VT-, and SV-BRS gain using the cross-spectral technique of computing the BP-RRI, BP-PTT, and BP-SV transfer functions. Gain in each BRS arch was measured in individuals with intact BRS functioning. Functional overlap and independence was noted in the BRS arches. The implications of the proposed method are discussed.