The effect of methadone dose regimen on neonatal abstinence syndrome.

OBJECTIVES: To evaluate the effects of a multiple daily dose methadone regimen in pregnancy on neonatal outcomes. METHODS: Although methadone maintenance has been the standard for the treatment of opioid dependence in pregnancy, there is no consensus on proper dosing. Single daily dosing is the most common strategy. Because of accelerated metabolism of methadone in pregnancy, this regimen may expose mother and fetus to daily episodes of withdrawal and possibly contribute to more severe Neonatal Abstinence Syndrome (NAS). This study reports on a protocol that increased both methadone dose and dose frequency in response to maternal reports of withdrawal. RESULTS: Treatment of NAS was needed in 29% of neonates, compared to a published rate of 60% to 80%. The mean methadone dose was 152 mg at delivery, divided into 2 to 6 doses per day. Ninety-two percent of mothers were free of illicit drug use at delivery. There was no relationship between methadone dose and treatment of NAS. Female babies had a treatment rate of 16% versus 38% for male babies. Beyond abstinence symptoms, cohort outcomes in terms of gestational age, birth weight, prematurity, Caesarian sections, and breastfeeding equaled or approximated US population norms. CONCLUSIONS: The protocol was associated with low rates of treatment of NAS and high rates of maternal recovery. High rates of treatment for NAS reported in methadone-exposed neonates might relate in part to iatrogenic factors and be reduced through the use of divided daily doses and protocols that minimize maternal withdrawal.

Reaction time variability and related brain activity in methamphetamine psychosis.

BACKGROUND: This study investigated the dynamics of cognitive control instability in methamphetamine (MA) abuse, as well its relationship to substance-induced psychiatric symptoms and drug use patterns. METHODS: We used an ex-Gaussian reaction time (RT) distribution to examine intraindividual variability (IIV) and excessively long RTs (tau) in an individual's RT on a Stroop task in 30 currently drug-abstinent (3 months to 2 years) MA abusers compared with 27 nonsubstance-abusing control subjects. All subjects underwent functional magnetic resonance imaging while performing the Stroop task, which allowed us to measure the relationship between IIV and tau to functional brain activity. RESULTS: Elevated IIV in the MA compared with the control group did not reach significance; however, when the MA group was divided into those subjects who had experienced MA-induced psychosis (MAP+) (n = 19) and those who had not (n = 11), the MAP+ group had higher average IIV compared with the other groups (p < .03). In addition, although control subjects displayed a relationship between IIV and conflict-related brain activity in bilateral prefrontal cortex such that increased IIV was associated with increased activity, the MAP+ group displayed this relationship in right prefrontal cortex only, perhaps reflecting elevated vigilance in the MAP+ group. Greater IIV did not correlate with severity of use or months MA abstinent. No group differences emerged in tau values. CONCLUSIONS: These results suggest increased cognitive instability in those MA-dependent subjects who had experienced MA-induced psychosis.

Predictors of methamphetamine psychosis: history of ADHD-relevant childhood behaviors and drug exposure.

The goal of this study was to extend our previous research that reported a significant association between Attention Deficit Hyperactivity Disorder (ADHD)-relevant childhood behaviors and the frequency of methamphetamine (MA)-induced psychotic symptoms in an expanded sample. 190 participants who met DSM-IV criteria for MA dependence were administered the Methamphetamine Experience Questionnaire that assessed MA-induced psychosis. Data related to MA exposure, comorbid drug use, education, familial psychiatric history and assessments of ADHD-relevant childhood behaviors as measured by the Wender Utah Rating Scale (WURS) were collected. Although WURS scores did not differ between 145 MAP+ and 45 MAP- subjects, MAP+ subjects with higher WURS scores were significantly more likely to report more frequent psychosis. Although mean daily MA dosage did not differ between the MAP+ and MAP- subjects, MAP+ subjects who consumed larger doses of MA were significantly more likely to experience frequent psychosis. These data suggest that ADHD-relevant childhood behaviors may interact with MA exposure to reflect a neurobiological vulnerability related to the emergence of frequent MA-induced psychotic symptoms. These results may elucidate factors that contribute to the psychiatric sequelae of MA abuse.

Behavioral regulation in methamphetamine abusers: an fMRI study.

The goal of this study was to extend our previous findings of abnormal prefrontal function in methamphetamine (MA) abusers and controls and to link the imaging data to behavioral, demographic and drug use variables. We used a fast event-related functional magnetic resonance imaging (fMRI) design to examine trial-to-trial reaction time (RT) adjustments in 30 MA abusers and 30 controls. A variant of the Stroop task was employed to measure influence of response conflict on RT, including the level of trial-to-trial RT adjustments seen after conflict trials. Compared to control subjects, MA abusers exhibited reduced RT adjustments and reduced activation in the prefrontal cortex (PFC) after conflict trials. RT adjustment correlated negatively with PFC brain activity in the MA group, while a trend for a positive correlation was observed in controls. No correlations were observed between task performance or brain activity and age, education or drug use variables. These data support our previous findings that the ability to adapt a behavioral response based on prior experience is compromised in MA abusers. Interestingly, these impairments do not appear to be linked to drug use patterns or to educational levels.

Structural, functional and spectroscopic MRI studies of methamphetamine addiction.

This chapter reviews selected neuroimaging findings related to long-term amphetamine and methamphetamine (MA) use. An overview of structural and functional (fMRI) MR studies, Diffusion Tensor Imaging (DTI), Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) studies conducted in long-term MA abusers is presented. The focus of this chapter is to present the relevant studies as tools to understand brain changes following drug abstinence and recovery from addiction. The behavioral relevance of these neuroimaging studies is discussed as they relate to clinical symptoms and treatment. Within each imaging section this chapter includes a discussion of the relevant imaging studies as they relate to patterns of drug use (i.e., duration of MA use, cumulative lifetime dose and time MA abstinent) as well as an overview of studies that link the imaging findings to cognitive measures. In our conclusion we discuss some of the future directions of neuroimaging as it relates to the pathophysiology of addiction.

Overlapping cognitive patterns in schizophrenia and methamphetamine dependence.

OBJECTIVE: To examine whether overlapping cognitive deficits exist in currently drug-abstinent chronic methamphetamine (MA) abusers and schizophrenia (SZ) patients. BACKGROUND: Both SZ and chronic MA abuse are associated with frontostriatal disruption as well as deficits in cognitive control, such as selective attention. To identify overlapping cognitive profiles, we compared performance of the 2 groups on the Stroop attention task. METHODS: Data were analyzed from 69 MA abusers who had been MA-abstinent for differing periods of time and from 23 SZ patients and 38 non-substance-abusing controls. RESULTS: The MA abusers in early abstinence displayed more Stroop interference than the SZ patients (P=0.004), long-term abstinent MA abusers (P=0.009), and controls (P=0.002). In the MA abusers, the magnitude of Stroop interference correlated positively with longer drug use (P=0.01) and negatively with longer drug abstinence (P=0.04). No correlations were found between psychotic symptoms and task performance. CONCLUSIONS: On this task of attentional selection, only the MA abusers in early stages of abstinence showed performance deficits compared with controls. More research is needed to further elucidate overlapping patterns between MA abuse and SZ.

Distributed attentional deficits in chronic methamphetamine abusers: evidence from the Attentional Network Task (ANT).

OBJECTIVE: The goal of the present study was to examine distributed attentional functions in long-term but currently abstinent methamphetamine (MA) abusers using a task that measures attentional alertness, orienting, and conflict resolution. METHODS: Thirty currently abstinent MA abusers (1 month-5 years) and 22 healthy non-substance using adults were administered a multimodal version of the Attentional Network Task (ANT-I). In this task subjects identified the direction of a centrally presented arrow using a key press. Analyses examined the interaction between alerting tones, location cueing and congruency between the target arrows and flanking distractor stimuli. RESULTS: All participants were faster when an auditory tone preceded the trial onset (p<0.001), on trials in which a valid cue preceded the location of the target arrow (p<0.001), and on congruent trials (i.e., when all display arrows faced in the same direction) (p<0.001). Of primary interest was the finding that MA abusers were more influenced by the conflict between the peripheral arrows and the central target arrow (p=0.009). There were also correlations between length of drug sobriety and executive function as well as between drug-induced psychiatric symptoms and alertness. CONCLUSIONS: These results suggest that chronic MA abusers display cognitive deficits that may reflect a specific vulnerability to distraction on a task of executive function. These findings are consistent with other studies that have reported deficits in anterior attentional systems and top-down cognitive control.

Extended findings of brain metabolite normalization in MA-dependent subjects across sustained abstinence: a proton MRS study.

OBJECTIVE: The goal of the present study was to extend our previous findings on long-term methamphetamine (MA) use and drug abstinence on brain metabolite levels in an expanded group of MA-dependent individuals. METHODS: Seventeen MA abusers with sustained drug abstinence (1-5 years), 30 MA abusers with short-term drug abstinence (1-6 months) and 24 non-substance using controls were studied using MR spectroscopy (MRS). MRS measures of NAA/Cr, Cho/Cr and Cho/NAA were obtained in the anterior cingulate cortex (ACC) and in the primary visual cortex (PVC). RESULTS: ACC-Cho/NAA values were abnormally high in the short-term abstinent group compared to controls [F(1,52) = 18.76, p < 0.0001]. No differences were observed between controls and the long-term abstinent group [F(1,39) = 0.97, p = 0.97]. New evidence of lower ACC-NAA/Cr levels were observed in the short-term abstinent MA abusers compared to controls [F(1,52) = 23.05, p < 0.0001] and long-term abstinent MA abusers [F(1,45) = 7.06, p = 0.01]. No differences were observed between long-term abstinent MA abusers and controls [F(1,39) = 0.48, p = 0.49]. CONCLUSIONS: The new findings of relative NAA/Cr normalization across periods of abstinence suggest that adaptive changes following cessation of MA abuse may be broader than initially thought. These changes may contribute to some degree of normalization of neuronal function in the ACC.

Psychiatric comorbidity in methamphetamine dependence.

The primary aim of the present study was to assess the prevalence of psychiatric comorbidity in a large sample of methamphetamine (MA)-dependent subjects using a validated structured clinical interview, without limitation to sexual orientation or participation in a treatment program. The secondary aim was to assess whether the prevalence of psychiatric comorbidities varied by gender. Structured clinical interviews (SCIDs) were administered to 189 MA-dependent subjects and lifetime prevalence of DSM-IV diagnoses was assessed. Across the sample, 28.6% had primary psychotic disorders, 23.8% of which were substance-induced; 13.2% had MA-induced delusional disorders and 11.1% had MA-induced hallucinations. A substantial number of lifetime mood disorders were identified that were not substance-induced (32.3%), whereas 14.8% had mood disorders induced by substances, and 10.6% had mood disorders induced by amphetamines. Of all participants, 26.5% had anxiety disorders and 3.7% had a substance-induced anxiety disorder, all of which were induced by MA. Male subjects reported a higher percentage of MA-induced delusions compared to female abusers. Given the impact of MA psychosis and other drug-induced symptoms on hospitals and mental health services, the description and characterization of comorbid psychiatric symptoms associated with MA use is of paramount importance.

Methamphetamine and paranoia: the methamphetamine experience questionnaire.

Paranoia in methamphetamine (MA) users is not well characterized or understood. To investigate this phenomenon, we created the Methamphetamine Experience Questionnaire (MEQ), and tested its reliability and validity in assessing MA-induced paranoia. We administered the MEQ to 274 MA-dependent subjects. Of the total subjects, 45% (123) first experienced paranoia with MA use; 55% did not. Obtaining or using a weapon while paranoid was common (37% and 11% of subjects with MA-induced paranoia, respectively). Test-retest and inter-rater reliability for MA-induced paranoia showed substantial agreement (kappa = .77, p < .05 and kappa = .80, p < .05, respectively). First episodes of paranoia occurred more often with intravenous use of MA, and subsequent episodes at higher doses. There was modest correlation between paranoia on the MEQ and the Brief Symptom Inventory (BSI) paranoid ideation scale (rho = .27, p < .05). As expected, there was a poor correlation between paranoia on the MEQ and the BSI depression scale (rho = .14, p = .07). The MEQ provides useful information on drug use variables that contribute to paranoia commonly associated with MA use. (Am J Addict 2010;00:1-14).

Drug abstinence and cognitive control in methamphetamine-dependent individuals.

Chronic methamphetamine (MA) abuse is associated with disruption of frontostriatal function as well as deficits in cognitive control. To examine the relationship between drug use patterns and cognitive deficits, we pooled previously published behavioral data with new data collected using the Stroop Attention Test. Subject groups are composed of 38 MA-abusing individuals who recently initiated abstinence (36.1 +/- 8.8 years of age), 27 MA-abusing individuals who had initiated abstinence more than 1 year prior to study (38.7 +/- 7.7 years of age), and 33 non-substance-abusing controls (33.9 +/- 8.5 years of age). The recently abstinent MA-abusing individuals exhibited greater Stroop reaction time (RT) interference compared with both the control group (p = .001) and the long-term abstinent MA-abusing individuals (p = .01). No difference was seen between long-term abstinent MA-abusing individuals and controls (p = .87). Stroop RT interference correlated positively with both duration of drug use (p = .003) and drug abstinence (p = .05). The data in the current study provide evidence that cognitive function may improve with protracted drug abstinence.

Impaired prefrontal cortical function and disrupted adaptive cognitive control in methamphetamine abusers: a functional magnetic resonance imaging study.

BACKGROUND: Methamphetamine (MA) abuse is associated with neurotoxicity to frontostriatal brain regions with deleterious effects on cognitive processes. Deficits in behavioral control are thought to be one contributing factor to the sustainment of addictive behaviors in MA abuse. METHODS: In order to examine patterns of behavioral control relevant to addiction, we employed a fast-event-related functional magnetic resonance imaging design to examine trial-to-trial reaction time (RT) adjustments in 12 MA-dependent subjects and 16 non-substance-abusers. A variant of the Stroop task was employed to contrast the groups on error rates, RT conflict, and the level of trial-to-trial adjustments seen after incongruent trials. RESULTS: The MA abusers exhibited reduced RT adjustments and reduced activation in the right prefrontal cortex compared to controls on conditions that measured the ability to use exposure to conflict situations (i.e., conflict trials) to regulate behavior. The groups did not differ on accuracy rates or within-trial Stroop conflict effects. CONCLUSIONS: The observed deficits in trial-to-trial RT adjustments suggest that the ability to adapt a behavioral response based on prior experience may be compromised in MA abusers. These failures to modify behavior based on prior events may reflect a deficit that contributes to drug-seeking behavior.

Cognitive control and white matter callosal microstructure in methamphetamine-dependent subjects: a diffusion tensor imaging study.

BACKGROUND: Methamphetamine (MA) abuse causes damage to structures within the human cerebrum, with particular susceptibility to white matter (WM). Abnormalities have been reported in anterior regions with less evidence of changes in posterior regions. Methamphetamine abusers have also shown deficits on attention tests that measure response conflict and cognitive control. METHODS: We examined cognitive control with a computerized measure of the Stroop selective attention task and indices of WM microstructure obtained from diffusion tensor imaging (DTI) in the callosal genu and splenium of 37 currently abstinent MA abusers and 17 non-substance abusing control subjects. Measurements of fractional anisotropy (FA), apparent diffusion coefficient (ADC) of callosal fibers, and diffusion tensor eigenvalues were obtained in all subjects. RESULTS: The MA abusers exhibited greater Stroop reaction time interference (i.e., reduced cognitive control) (p = .04) compared with control subjects. After correcting for multiple comparisons, FA within the genu correlated significantly with measures of cognitive control in the MA abusers (p = .04, Bonferroni corrected) but not in control subjects (p = .26). Group differences in genu but not splenium FA were trend significant (p = .09). CONCLUSIONS: Methamphetamine abuse seems to alter anterior callosal WM microstructure with less evidence of change within posterior callosal WM microstructure. The DTI indices within the genu but not splenium correlated with measures of cognitive control in chronic MA abusers.

Preliminary evidence of behavioral predictors of recurrent drug-induced psychosis in methamphetamine abuse.

The goal of this study was to examine behavioral characteristics of currently drug-abstinent methamphetamine (MA)-dependent subjects (n=39) who experienced psychotic symptoms associated with MA abuse. All participants completed the Wender Utah Rating Scale (WURS), which retrospectively assesses Attention Deficit Hyperactivity Disorder-relevant childhood behaviors. The results suggest the existence of possible behavioral markers reflecting an early cognitive vulnerability to the development of frequent MA-induced psychotic symptoms as well as increased vulnerability associated with a family history of psychiatric illness.

Findings of preserved implicit attention in methamphetamine dependent subjects.

Long-term methamphetamine (MA) abuse is associated with a wide range of deficits on explicit tasks of selective attention. Less is known however about the effects of MA abuse on implicit measures of attention. Accordingly, we used a computerized spatial priming task to assess implicit attentional processes in 54 MA dependent subjects (mean age=37.04+/-8.9 years) and 32 healthy controls without history of any form of substance abuse (mean age=33.63+/-7.05 years). The MA dependent subjects had been drug-abstinent a minimum of 3 weeks with a mean duration of MA use of 13.27+/-7.75 years. The MA dependent subjects did not differ significantly from controls on either inhibitory priming [p=.37] or facilitory priming) [p=.69]. This result comports with our earlier findings of intact object-based priming in MA dependent individuals and suggests that intact priming effects extend across spatial domains. Further, this pattern of sparing suggests that cortical brain systems typically supporting implicit attentional functioning are relatively intact in long-term MA dependent individuals whereas brain systems supporting explicit attentional processes are affected.

Is filtering difficulty the basis of attentional deficits in schizophrenia?

The distractibility that schizophrenia patients display may be the result of a deficiency in filtering out irrelevant information. The aim of the current study was to assess whether patients with schizophrenia exhibit greater difficulty when task-irrelevant features change compared to healthy participants. Thirteen medicated outpatients with a diagnosis of schizophrenia and thirteen age- and parental education-matched controls performed a target selection task in which the task-relevant letter or the task-irrelevant features of color, and/or location repeated or switched. Participants were required to respond by pressing the appropriate key associated with the target letter. These patients with schizophrenia were slower when the task-relevant target letter switched than when it repeated. In contrast, schizophrenia patients performed similarly to controls when task-irrelevant information changed. Thus, we found no evidence that patients with schizophrenia were impaired in inhibiting irrelevant perceptual features. In contrast, changes in task-relevant features were problematic for patients relative to control participants. These results suggest that medicated outpatients who are mild to moderately symptomatic do not exhibit global impairments of feature processing. Instead, impairments are restricted to situations when task-relevant features vary. The current findings also suggest that when a course of action is not implied by an irrelevant feature, outpatients' behavior is not modulated by extraneous visual information any more than in healthy controls.

Attentional control and brain metabolite levels in methamphetamine abusers.

BACKGROUND: Methamphetamine abuse is associated with neurotoxicity to frontostriatal brain regions with concomitant deleterious effects on cognitive processes. METHODS: By using a computerized measure of selective attention and single-voxel proton magnetic resonance spectroscopy, we examined the relationship between attentional control and brain metabolite levels in the anterior cingulate cortex (ACC) and primary visual cortex (PVC) in 36 currently abstinent methamphetamine abusers and 16 non-substance-using controls. RESULTS: The methamphetamine abusers exhibited reduced attentional control (i.e., increased Stroop interference) compared with the controls (p = .04). Bonferroni-adjusted comparisons revealed that ACC levels of N-acetyl aspartate (NAA)-creatine and phosphocreatine (Cr) were lower and that levels of choline (Cho)-NAA were higher in the methamphetamine abusers compared with the controls, at the adjusted p value of .0125. Levels of NAA-Cr, but not of Cho-NAA, within the ACC correlated with measures of attentional control in the methamphetamine abusers (r = -.41; p = .01) but not in controls (r = .22; p = .42). No significant correlations were observed in the PVC (methamphetamine abusers, r = .19; p = .28, controls, r = .38; p = .15). CONCLUSIONS: Changes in neurochemicals within frontostriatal brain regions including ACC may contribute to deficits in attentional control among chronic methamphetamine abusers.

Methamphetamine users in sustained abstinence: a proton magnetic resonance spectroscopy study.

BACKGROUND: Abnormal patterns of metabolite levels have been detected by magnetic resonance spectroscopy in frontostriatal regions of individuals meeting DSM-IV criteria for methamphetamine dependence, but less is known about the effects of drug abstinence on metabolite levels. OBJECTIVE: To assess the effects of long-term methamphetamine use and drug abstinence on brain metabolite levels. DESIGN: To assess regional specific metabolite levels using magnetic resonance spectroscopy imaging techniques in 2 groups of currently abstinent methamphetamine users: methamphetamine users who recently initiated abstinence and methamphetamine users who had initiated abstinence more than 1 year prior to study. SETTING: Participants were recruited from outpatient substance abuse treatment centers. PARTICIPANTS: Eight methamphetamine users with sustained abstinence (1 year to 5 years) and 16 recently abstinent methamphetamine users (1 month to 6 months) were compared with 13 healthy, non-substance-using controls. MAIN OUTCOME MEASURES: Magnetic resonance spectroscopy measures of N-acetylaspartate-creatine and phosphocreatine (NAA/Cr), choline-creatine and phosphocreatine (Cho/Cr), and choline-N-acetylaspartate (Cho/NAA) ratios were obtained in the anterior cingulate cortex as well as in the primary visual cortex, which served as a control region. RESULTS: The absolute values of Cr did not differ between controls and methamphetamine users. Methamphetamine users had abnormally low NAA/Cr levels within the anterior cingulate cortex, regardless of the time spent abstinent (F(2,34) = 12.61; P<.001). No NAA/Cr group differences were observed in the primary visual cortex (F(2,33) = 0.29; P = .75). The Cho/NAA values for the anterior cingulate cortex were abnormally high in the methamphetamine users who recently initiated abstinence but followed a normal pattern in the methamphetamine users who had initiated abstinence more than 1 year prior to study (F(2,34) = 7.31; P = .002). CONCLUSIONS: The relative choline normalization across periods of abstinence suggests that following cessation of methamphetamine use, adaptive changes occur, which might contribute to some degree of normalization of neuronal structure and function in the anterior cingulum. More research is needed to elucidate the mechanisms underlying these adaptive changes.

A dissociation in attentional control: evidence from methamphetamine dependence.

BACKGROUND: Selective attention comprises multiple, dissociable component processes, including task shifting and selective inhibition. The goal of this study was to test whether task-shifting, selective inhibition, or both processes were impaired in long-term but currently abstinent methamphetamine-dependent individuals. METHODS: Participants were 34 methamphetamine-dependent subjects and 20 nonsubstance abusing controls who were tested on an alternating-runs switch task with conflict sequences that required subjects to switch tasks on every second trial (AABBAABB). RESULTS: Methamphetamine-dependent individuals committed more errors on trials that required inhibition of distracting information compared with controls (methamphetamine = 17%; controls = 13%; p = .02). By contrast, error rates did not differ between the groups on switch trials (methamphetamine = 7%; controls = 6%; p = .68). CONCLUSIONS: These results indicate that selective inhibition, but not task switching, is selectively compromised by methamphetamine.

Schizophrenia and the stroop effect.

Conflict between irrelevant words and relevant colors in the Stroop task creates interference, long considered a measure of how well individuals focus attention. In the traditional card version of the Stroop task, schizophrenia patients exhibit increased interference, consistent with the distractibility they exhibit in everyday life. In contrast, on other versions of the Stroop task they show augmented facilitation (faster responding to congruent than to neutral trials). We suggest that schizophrenia patients possess adequate attentional resources to avoid interference when each letter string is presented individually but face difficulty when delays are imposed and multiple attentional demands appear. Although psychiatric symptomatology may contribute to different patterns of performance, there is no evidence that medication modulates this.