Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers

BACKGROUND: Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood. OBJECTIVE: To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers. DESIGN: Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task. SETTING: Participants were recruited from the general community to a research center. PARTICIPANTS: Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women). MAIN OUTCOME MEASURES: Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum. RESULTS: Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity. CONCLUSIONS: Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.     

Glial dysfunction in abstinent methamphetamine abusers

Persistent neurochemical abnormalities in frontal brain structures are believed to result from methamphetamine use. We developed a localized ¹³C magnetic resonance spectroscopy (MRS) assay on a conventional MR scanner, to quantify selectively glial metabolic flux rate in frontal brain of normal subjects and a cohort of recovering abstinent methamphetamine abusers. Steady-state bicarbonate concentrations were similar, between 11 and 15 mmol/L in mixed gray-white matter of frontal brain of normal volunteers and recovering methamphetamine-abusing subjects (P>0.1). However, glial ¹³C-bicarbonate production rate from [1-¹³C]acetate, equating with glial tricarboxylic acid (TCA) cycle rate, was significantly reduced in frontal brain of abstinent methamphetamine-addicted women (methamphetamine 0.04 μmol/g per min (N=5) versus controls 0.11 μmol/g per min (N=5), P=0.001). This is equivalent to 36% of the normal glial TCA cycle rate. Severe reduction in glial TCA cycle rate that normally comprises 10% of total cerebral metabolic rate may impact operation of the neuronal glial glutamate cycle and result in accumulation of frontal brain glutamate, as observed in these recovering methamphetamine abusers. Although these are the first studies to define directly an abnormality in glial metabolism in human methamphetamine abuse, sequential studies using analogous ¹³C MRS methods may determine ‘cause and effect'' between glial failure and neuronal injury.     

Enlarged striatum in abstinent methamphetamine abusers: a possible compensatory response.

BACKGROUND: Little is known about structural brain abnormalities associated with methamphetamine (METH) abuse; therefore, we aimed: 1) to evaluate possible morphometric changes, especially in the striatum of recently abstinent METH-dependent subjects; 2) to evaluate whether morphometric changes are related to cognitive performance; and 3) to determine whether there are sex-by-METH interactions on morphometry. METHODS: Structural MRI was performed in 50 METH and 50 comparison subjects with the same age range and sex proportion; quantitative morphometric analyses were performed in the subcortical gray matter, cerebellum and corpus callosum. Neuropsychological tests were also performed in 44 METH and 28 comparison subjects. RESULTS: METH users showed enlarged putamen (left: + 10.3%, p = .0007; right: + 9.6%, p = .001) and globus pallidus (left: + 9.3%, p = .002; right: + 6.6%, p = .01). Female METH subjects additionally showed larger mid-posterior corpus callosum (+ 9.7%, p = .05). Although METH users had normal cognitive function, those with smaller striatal structures had poorer cognitive performance and greater cumulative METH usage. CONCLUSIONS: Since METH subjects with larger striatal structures had relatively normal cognitive performance and lesser cumulative METH usage, the enlarged putamen and globus pallidus might represent a compensatory response to maintain function. Possible mechanisms for the striatal enlargement include glial activation and inflammatory changes associated with METH-induced injury.     

Functional connectivity abnormalities underlying mood disturbances in male abstinent methamphetamine abusers

Anxiety and depression are the most common withdrawal symptoms of methamphetamine (METH) abuse, which further exacerbate relapse of METH abuse. To date, no effective pharmacotherapy exists for METH abuse and its withdrawal symptoms. Therefore, understanding the neuromechanism underlying METH abuse and its withdrawal symptoms is essential for developing clinical strategies and improving patient care. The aims of this study were to investigate brain network abnormalities in METH abusers (MAs) and their associations with affective symptoms. Forty‐eight male abstinent MAs and 48 age‐gender matched healthy controls were recruited and underwent resting state functional magnetic resonance imaging (fMRI). The severity of patient anxiety and depressive symptoms were measured by Hamilton anxiety and depression rating scales, which decreased across the duration of abstinence. Independent component analysis was used to investigate the brain network functional connectivity (FC) properties. Compared with healthy controls, MAs demonstrated hypo‐intra‐network FC in the cerebellar network and hyper‐intra‐network FC in the posterior salience network. A whole‐brain regression analysis revealed that FC strength of clusters located in the right rostral anterior cingulate cortex (rACC) within the ventromedial network (VMN) was associated with affective symptoms in the patients. Importantly, the intra‐network FC strength of the rACC in VMN mediated the association between abstinence duration and the severity level of affective symptoms. Our results demonstrate alterations in brain functional networks underlying METH abuse, and that the FC of rACC within VMN serve as a neural substrate in the association between abstinence length and affective symptom severity in the MAs.     

Dose-dependent frontal hypometabolism on FDG-PET in methamphetamine abusers

Objective

Although a lot of evidence from neuropsychological and neuroimaging studies supports the view that patients with substance dependence have abnormalities in the prefrontal cortex, functional deficits in the prefrontal cortex have not been fully investigated in methamphetamine (MA) dependent patients. This study was prepared to examine whether MA abusers have cerebral metabolic abnormalities and executive dysfunction.

Method

Twenty-four abstinent MA dependent patients and 21 age-matched control subjects underwent resting brain FDG-PET and completed computerized versions of the Wisconsin card sorting test (WCST). Resting brain PET images were obtained 30 min after an intravenous injection of 370 MBq of ¹⁸F-FDG. Significant differences in glucose metabolism were estimated for every voxel using t-statistics on SPM2 implemented in Matlab.

Results

Resting brain FDG-PET revealed significant hypometabolism in the left inferior frontal white matter (Talairach coordinates (x, y, z): −34, 7, 31) in MA dependent patients compared to the control subjects (corrected p = 0.001, peak Z = 5.37, voxel number 201). The nearest gray matter region was the left inferior frontal cortex (Brodmann area 9). There were negative correlations between the relative regional cerebral metabolism for glucose (rCMRglc) in the left inferior frontal white matter and the total cumulative dose of MA (r = −0.57, p < 0.01). MA dependent patients completed significantly fewer categories (3.8 ± 2.2) and made more perseveration errors (21.3 ± 11.8) and total errors (43.5 ± 19.5) on the WCST when compared to the control subjects (p < 0.01).

Conclusions

These data suggest that MA dependent patients have dose-dependent frontal hypometabolism and frontal executive dysfunction.     

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.     

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.     

Deficits in two versions of a sustained attention test in adolescents with cerebral palsy

Objective: To evaluate sustained attention in adolescents with cerebral palsy (CP). CP affects motor control as well as certain cognitive processes such as attention, but its influence on the latter remains largely unexplored.

Methods: Manual (Experiment 1) and oculomotor (Experiment 2) versions of the Continuous Performance Test were performed by adolescents with spastic CP and healthy age-matched controls (n?=?10 per group in each experiment).

Results: In both experiments, patients with CP showed more omissions and their reaction time was more variable than controls. In Experiment 2, patients also showed more commissions. This problem was not observed in Experiment 1, possibly because of the presence of a hand movement deficit in CP.

Conclusion: Taken together, the results show that sustained attention and inhibition capabilities are affected in CP. The present study also proposes that eye movements could constitute an interesting alternative for measuring sustained attention when hand movement is affected.     

Sustained attention deficits in nonpsychotic relatives of schizophrenic patients: a recurrence risk ratio analysis.

BACKGROUND: In nonpsychotic parents and siblings of schizophrenic patients, the recurrence risk ratios of sustained attention deficits, as measured by the continuous performance test (CPT), were examined with a series of cut-off points. METHODS: Among 116 parents and 95 siblings of 91 schizophrenic probands in northern Taiwan, both undegraded and degraded sessions of the CPT were administered. Subjects' signal detection sensitivity of CPT performance (d') was standardized against a community sample without (unadjusted z score) or with (adjusted z score) adjustment for age, gender, and educational level. RESULTS: Differences in the risk ratios between the parents and siblings that were based on the unadjusted z scores of CPT d' diminished markedly if the adjusted z scores were used. As the cut-off point in the adjusted z score decreased from -2.5 to -3.0, the risk ratio increased continually for both the undegraded (10.1-18.8 for parents, 10.0-16.7 for siblings) and degraded (12.4-102.7 for parents, 8.6-72.0 for siblings) test. CONCLUSIONS: Stringent cut-off criteria of CPT deficits with adjustment for demographic features leads to recurrence risk ratios greater than those based on schizophrenia alone in both parents and siblings of schizophrenic patients.     

Impairments of facial emotion recognition and theory of mind in methamphetamine abusers

Chronic use of methamphetamine is related to behavioral disturbances including depression, aggressive behavior, and social isolation. These alterations of social behavior may be attributable to impairments in social cognition. However, few studies have evaluated social cognition in methamphetamine (MA) abusers. Therefore, the aim of the present study was to investigate whether MA abusers exhibit social cognition deficits in terms of facial emotion recognition and theory of mind (ToM). We also assessed cognitive flexibility by using the Wisconsin Card Sorting Test (WCST) to evaluate the impact of this function on social cognition. Twenty-eight MA abusers and twenty-seven healthy subjects enrolled in this study. All participants performed the Facial Emotion Recognition Task and advanced ToM tasks such as the Eye Test and Hinting Task. The Korean Wechsler Adult Intelligence Scale—Revised and computerized versions of the WCST were also administrated. The performances of MA abusers on the Facial Emotion Recognition Task and Eyes Test were lower than those of healthy subjects. In the WCST, MA abusers completed significantly fewer categories and made more total and perseverative errors than healthy subjects did. In addition, impairments in cognitive flexibility are correlated with impairments in facial emotion recognition and ToM within MA abusers. These findings lend further support to the assertion that the capacity to identify emotions from facial expression and infer mental state of others is impaired in MA abusers. Therefore, treatment and rehabilitation for MA abusers must consider role of social cognition and include relearning social interactions and behaviors.     

Minor structural brain changes in young drug abusers

Twenty-three drug abusers and seventeen controls underwent clinical neurological examinations and magnetic resonance imaging (MRI) of the brain. The drug abuse encompassed cannabis, inhalants, opiates, psychedelics, amphetamines, and cocaine but not necessarily all drugs in all persons. The drug abuse was always combined with heavy alcohol consumption. One drug abuser had abnormal neurological findings which consisted of lower limb ataxia and 3 others had mild imbalance. MRI examinations did not show differences in width of the third, fourth or lateral ventricles nor the diameter of the cerebral aqueduct but the drug abusers had significantly smaller vermes cerebelli compared to controls. White matter changes also occurred more often in the drug abuser group. These findings are not consistent with known side-effects of the narcotic drugs but more probably a result of very high alcohol consumptions in parallel with drug abuse. Alcohol is clearly a much more potent brain toxic agent than are the most commonly abused narcotic drugs.     

Dopamine transporter dysfunction in Han Chinese people with chronic methamphetamine dependence after a short-term abstinence

Single-photon emission-computed tomography (SPECT) after the administration of ^99mTc-TRODAT-1 was performed on healthy subjects and subjects with methamphetamine (METH)dependence at time 1 (T1) after 24–48 h of abstinence, time 2 (T2) after 2 weeks of abstinence, and time 3 (T3) after 4 weeks of abstinence. In contrast to values in controls, the values of the striatal DAT specific uptake ratios (SURs) in subjects with METH dependence were significantly lower at T1 (n=25), T2 (n=9), and T3 (n=8); a mild increase in SURs was observed at T2 and T3, but values were still significantly lower than those in controls. In subjects with METH dependence, there was a trend for a negative correlation of striatal DAT SURs and craving for METH at T1. METH craving, anxiety and depression scores significantly decreased from T1 to T2 to T3. We conclude that Han Chinese people with METH dependence experience significant striatal DAT dysfunction, and that these changes may be mildly reversible after 4 weeks of abstinence, but that DAT levels still remain significantly lower than those in healthy subjects. The mild recovery of striatal DAT may parallel improvements in craving, anxiety and depression.     

连续操作测验检测持续性注意功能

连续操作测验（CPT）检测持续性注意功能在精神科临床广泛应用,本文介绍了持续注意功能的检测的方法,回顾CPT对一些疾病的注意力损害方面的诊断作用,对文献进行分析、归纳和综述,并简述现行CPT的不足之处和发展方向。     

The effect of methylphenidate on sustained attention among adolescents with attention-deficit hyperactivity disorder

Twenty-seven adolescents diagnosed as having attention-deficit hyperactivity disorder (ADHD) were tested twice with a computerized MATH-CPT (mathematics continuous performance test). In one administration, the participants took medication (methylphenidate, MPH) 1.5 hr before being tested. In another administration, the MATH-CPT was administered without the medication. Treatment with MPH improved the “overall attention level” and in measures of “reaction time” and “impulsivity.” MPH did not improve the performance in the four measures of sustained attention. Knowing that treatment with MPH does not improve sustained attention can be helpful in reaching a decision of whether or not a child should be treated with MPH.     

Tonic and phasic alertness training: a novel treatment for executive control dysfunction following mild traumatic brain injury

Many individuals with traumatic brain injury (TBI) suffer difficulty regulating fundamental aspects of attention (focus, sustained attention) and may also exhibit hypo- or hyper-states of alertness. Deficits in the state of attention may underlie or exacerbate higher order executive dysfunction. Recent studies indicate that computerized cognitive training targeting attentional control and alertness can ameliorate attention deficits evident in patients with TBI or acquired brain injury. The current study examined whether improvements in attentional state following training can also influence performance on higher-order executive function and mood in individuals with mild TBI (mTBI). The current study examined five patients with executive control deficits as a result of mTBI, with or without persistent anxiety. Three patients engaged in ~5 hours of an executive control training task targeting inhibitory control and sustained attention; two additional patients were re-tested following the same period of time. Performance on standard neuropsychological measures of attention, executive function, and mood were evaluated pre- and post-training. The results indicate that tonic and phasic alertness training may improve higher-order executive function and mood regulation in individuals with TBI.     

Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers

Drug abuse is a major problem worldwide. The incidence of drug-related deaths attributed to opiate abuse is increasing annually. Apart from routine examination, little is known of the neuropathology of drug abuse. We, and others, have shown previously that drug abuse is associated with microglial activation. We hypothesised that neuroinflammation might lead to premature neurodegeneration in drug abusers. We investigated the brains of young opiate abusers (n=34, all<40 years) for the presence of proteins associated with neurodegenerative diseases and compared them with the brains of age-matched, non-drug users (n=16) all of whom died suddenly. Detailed immunohistochemical analysis of the hippocampus, brainstem and basal ganglia for hyperphosphorylated tau, beta-amyloid, beta-amyloid precursor protein (betaAPP) and ubiquitin demonstrated an excess of AT 8-positive neurofibrillary tangles (NFT) in the drug abusers. These were not only more prevalent in the drug abusers than in controls (44%vs. 19%) but also involved more brain areas. In controls NFT were confined to the entorhinal cortex whereas in drug users they were also found in the subiculum, temporal neocortex, nucleus basalis of Meynert and the locus coeruleus. Virtually no amyloid plaques were present but betaAPP positivity was again much more common in drug abusers than controls (73%vs. 20% in the brainstem and 59%vs. 23% in the temporal lobe). There is no suggestion that these drug abusers had displayed major cognitive impairment although detailed neuropsychological assessment is difficult in this subject group. Likely causes of hyperphosphorylated tau deposition in drug abuse include hypoxic-ischaemic injury, microglial-associated cytokine release and possibly drug-associated neurotoxicity or hepatitis. Head injury, which is another major risk factor, does not appear to have contributed to our findings. Genetic factors also merit consideration. It is unclear at present how much of the hyperphosphorylated tau detected in these young drug abusers represents a transitory phenomenon.     

Measurement of development of cognitive and attention functions in children using continuous performance test

Aim:  The development of attention function in children is still not sufficiently clear. Although it is difficult to objectively assess attention function, continuous performance tests (CPT) can be used to objectively assess cognitive function along with attention. The development of cognitive and attention functions was examined in children using a CPT.
Methods:  A total of 541 healthy girls aged 5–12 years participated. Ten parameters were calculated: numbers of cancellations for either target stimuli (T-cancel) or non-target stimuli (N-cancel), numbers of omission errors (Omission) and commission errors (Commission), hit rate (Hit), false alarm rate (False), mean reaction time for correct response (RT), coefficient of variance for mean reaction time (CVRT), sensitivity index (d'), and lnβ.
Results:  The parameters were divided into three types based on pattern of change. T-cancel, False, and Commission, which are related to inhibition of response, N-cancel, Hit, and Omission, which are related to inattention to stimuli, and CVRT, which is related to stability of processing time, exhibited significant change until 5 or 6 years of age. d', which is related to ability to discriminate between target or non-target, exhibited significant change until 8 years of age. RT, which is related to processing time, exhibited significant change until 11 years of age. lnβ exhibited no significant differences among age groups.
Conclusions:  These findings indicate that inhibition function, inattention to stimuli, and stability of processing time develop first. Discrimination ability subsequently increases based on these developments, and finally processing time is reduced.     

Sustained attention is associated with right superior longitudinal fasciculus and superior parietal white matter microstructure in children

Sustained attention develops during childhood and has been linked to the right fronto‐parietal cortices in functional imaging studies; however, less is known about its relation to white matter (WM) characteristics. Here we investigated whether the microstructure of the WM underlying and connecting the right fronto‐parietal cortices was associated with sustained attention performance in a group of 76 typically developing children aged 7–13 years. Sustained attention was assessed using a rapid visual information processing paradigm. The two behavioral measures of interest were the sensitivity index d′ and the coefficient of variation in reaction times (RT_CV). Diffusion‐weighted imaging was performed. Mean fractional anisotropy (FA) was extracted from the WM underlying right dorsolateral prefrontal (DLPFC) and parietal cortex (PC), and the right superior longitudinal fasciculus (SLF), as well as equivalent anatomical regions‐of‐interest (ROIs) in the left hemisphere and mean global WM FA. When analyzed collectively, right hemisphere ROIs FA was significantly associated with d′ independently of age. Follow‐up analyses revealed that only FA of right SLF and the superior part of the right PC contributed significantly to this association. RT_CV was significantly associated with right superior PC FA, but not with right SLF FA. Observed associations remained significant after controlling for FA of equivalent left hemisphere ROIs or global mean FA. In conclusion, better sustained attention performance was associated with higher FA of WM in regions connecting right frontal and parietal cortices. Further studies are needed to clarify to which extent these associations are driven by maturational processes, stable characteristics and/or experience. Hum Brain Mapp 34:3216–3232, 2013. © 2012 Wiley Periodicals, Inc.