Examining the effect of cerebral perfusion abnormality magnitude on cognitive performance in recently abstinent chronic cocaine abusers.

BACKGROUND AND PURPOSE: Cerebral perfusion abnormalities and neuropsychological impairment are common sequelae of chronic cocaine abuse. While perfusion abnormalities have been shown to relate to cognitive deficits in this substance abuse population, the relationship between cognitive performance and the magnitude of perfusion abnormality has yet to be fully determined. METHODS: Thirty-seven abstinent cocaine abusers and 13 normal controls were administered resting 99m-Tc-HMPAO single photon emission computed tomography (SPECT) scans followed by a neuropsychological assessment battery tapping executive skills, attention, memory, and motor performance. Statistical parametric mapping (SPM99) techniques were used to analyze the SPECT data to detect significant regional perfusion abnormalities in the cocaine group relative to normal controls, and resulting abnormal SPECT counts were employed for comparison with the assessment measures to examine the relationship between cocaine-induced perfusion abnormalities and cognitive performance. RESULTS: SPECT data analysis revealed significant regional perfusion abnormalities in the cocaine abuse sample relative to controls and significant differences in neuropsychological functioning on measures of executive functioning, complex attention, memory, and manual dexterity. For chronic cocaine abusers, however, within-group comparisons of the magnitude of abnormal perfusion and neuropsychological performance were largely nonsignificant, with the exception of complex attention and motor speed. CONCLUSIONS: Perfusion abnormalities and neuropsychological impairments readily distinguished cocaine abusers from normal controls. However, when the magnitude of cocaine-induced perfusion abnormalities is examined in relation to cognitive performance, motor speed and complex attention appear to be the best behaviorial indicants of the severity of perfusion dysfunction within this substance abuse population.

Cerebral perfusion defects in combined cocaine and alcohol dependence.

BACKGROUND: Cocaine abuse has been associated with widely distributed areas of significant cerebral blood flow (CBF) reductions or hypo-perfusion as well as CBF hyper-perfusion, but these perfusion abnormalities have not been examined using newer technologies such as statistical parametric mapping (SPM). These areas of abnormal CBF may be more likely among those who abuse cocaine and alcohol together. METHODS: Using SPECT with HMPAO for CBF we compared proportional scaling (PS) to histogram normalization (HEQ) in SPM among 20 controls and 32 recently abstinent cocaine abusers. We then separated the cocaine abusers into two groups (12 cocaine plus alcohol abusers and 20 cocaine alone abusers) and compared both groups to the 20 controls for brain areas of hypo- and hyper-perfusion. RESULTS: Sensitivity to hypo-perfusion was greater with HEQ than PS. Hypo-perfused areas were more likely in the 12 alcohol plus cocaine abusers than in the 20 cocaine alone abusers or 20 controls, and hyper-perfused areas were significantly more likely among the cocaine abusers than controls. The type of CBF abnormality varied by brain location with hypo-perfusion significantly more likely in occipital and temporal cortex or cerebellum and hyper-perfusion more likely in frontal and parietal cortex. CONCLUSIONS: These abnormalities in brain perfusion are consistent with previous non-SPM approaches that showed more hypo-perfusion in cocaine abusers than controls and appear to reflect vasospasm and potential compensations in cerebral blood flow.

Isradipine enhancement of cerebral blood flow in abstinent cocaine abusers with and without chronic perfusion deficits.

Nine cocaine abusers with cerebral blood flow (CBF) deficits (hypo-perfused areas) on HMPAO SPECT scans were compared to six without these deficits after six doses of isradipine (5 mg TID). When comparing the scan before isradipine to that after using SPM analysis, the ratio of hypo- to hyper-fusion showed a 16% increase in the maximum Z scores and 30% fewer areas of hypo-perfusion among those cocaine abusers with deficits. These deficits may represent segmental cerebral vasospasm that was reversed by this vasodilating agent in cocaine abusers with areas of hypo-perfusion (deficits) as baseline.

Current concepts in pharmacotherapy of substance abuse.

The cost to society of alcohol, tobacco, and illicit drug dependence is enormous. Although the importance of treatment for substance abuse to public health is increasingly acknowledged, pharmacotherapy is generally underutilized. However, the selection of medications for clinical testing is increasingly guided by the rapidly evolving science of addictive drugs and behavior. The benefit of medication for smoking cessation is firmly established, particularly for nicotine replacement and antidepressant therapy. Naltrexone is an important addition to the pharmacopoeia, and acamprosate may soon be approved as well. Although no new medications are approved for cocaine and amphetamine abuse, a variety of candidate treatments have shown promise in ongoing studies. Opiate substitution therapy is highly effective for rehabilitation of heroin addiction, and several alternative forms will soon be available; alternative forms of opiate detoxification have also received attention. Overall, there is increasing recognition that physicians have an obligation to identify and treat all forms of substance dependence, although knowledge of the efficacy of the available treatments is steadily increasing.

Pharmacotherapy of stimulant dependence: one of Japan's greatest public health challenges.

Stimulant dependence has become a major public health problem in the world over the last 15 years, and pharmacotherapies have been evolved based on our understanding of the neurobiological alterations induced by these drugs. Among the stimulants cocaine and amphetamine are the most common dependencies, and they share several common pathophysiologies in producing disease and in guiding medication approaches to treatment--neurotransmitter re-normalization, reversal of cerebral perfusion abnormalities and peripheral cocaine blockers. First is neurotransmitter re-normalization. A relative catecholamine deficiency occurs following prolonged abuse of cocaine and amphetamine due to transporter upregulation and receptor downregulation. This abnormality in dopamine and serotonin neurotransmission appears to be associated with depression and has supported antidepressant treatments to re-normalize neurotransmission. Dopaminergic and serotonergic agonists have also been given to re-normalize neurotransmission, but in contrast to substitution therapies such as methadone, LAAM or buprenorphine for opioids, these approaches have had limited success in unselected cocaine dependent patients. As a correlary approach to substitution, however, aspects of dopamine function can be augmented by dopamine beta hydroxylase inhibitors such as disulfiram to increase the aversive properties of stimulants and decrease their abuse. The second medication approach relates to cerebral perfusion defects and associated cognitive deficits due to vasoconstriction and abnormalities in platelets, which can respond to antiplatelet therapies as well as excitatory amino acid (EAA) antagonists. These EAA antagonists can prevent neuronal damage that is due to the release of EAA during cerebral ischemia induced by stimulant use. Finally, peripheral blockade treatment for cocaine may be possible using a newly developed active vaccine that blocks the uptake of cocaine from the bloodstream into the brain. Its potential efficacy has been shown in rodents that decrease their self-administration of cocaine when immunized with this vaccine, and preliminary human studies support its safety and immunogenicity. In summary, stimulant pharmacotherapy has made great progress in developing treatments based on understanding the neurobiology of these abused drugs, but these pharmacotherapies must be delivered in the context of appropriate behavioral and cognitive psychotherapies, which are also rapidly evolving.