Cortical inhibition and excitation in abstinent cocaine-dependent patients: a transcranial magnetic stimulation study

Prior transcranial magnetic stimulation studies showed that resting motor threshold is elevated in abstinent cocaine-dependent patients, suggesting a decrease in axonal excitability. In contrast, the increased incidence of seizures and psychosis in this group suggests increased excitability or decreased inhibition. Here, we studied long-interval intracortical facilitation and long-interval intracortical inhibition, paired-pulse transcranial magnetic stimulation measures that are more directly linked to glutamatergic cortical facilitation and GABAergic inhibition, respectively. Ten cocaine-dependent and 10 healthy controls were examined. Resting motor threshold, long-interval intracortical facilitation and long-interval intracortical inhibition were tested from the left motor cortex. The cocaine group showed an elevated resting motor threshold and an increased long-interval intracortical facilitation, whereas long-interval intracortical inhibition was normal. Although the increase in long-interval intracortical facilitation suggests exaggerated cortical glutamatergic excitability, the increase in resting motor threshold may signify a protective mechanism against seizures and psychosis.     

CSF CRH in abstinent cocaine-dependent patients

Alterations in stress responsivity may be important in the vulnerability to become cocaine dependent. Thus, an index of hypothalamic-pituitary-adrenal (HPA) axis function was examined in abstinent cocaine-dependent patients. Cerebrospinal fluid (CSF) concentrations of corticotropin releasing factor (CRH) were determined in 29 abstinent cocaine-dependent patients and 66 normal controls. The results showed that there was no significant difference between the abstinent cocaine-dependent patients and normal controls for CSF CRH. Also, CSF CRH concentrations were not related to cocaine-craving scores in a cue-elicited cocaine-craving procedure. Thus, these data suggest that after protracted abstinence from cocaine there is no marked dysregulation of CRH systems as measured by CSF CRH concentrations.     

Higher levels of CSF homovanillic acid in recently abstinent cocaine-dependent patients

OBJECTIVE: The authors examined an index of dopaminergic neurotransmission in recently abstinent cocaine-dependent patients. METHOD: CSF concentrations of the dopamine metabolite homovanillic acid (HVA) were determined in 30 recently abstinent cocaine-dependent patients and 69 healthy comparison subjects. RESULTS: The cocaine-dependent patients had a significantly higher mean concentration of CSF HVA than did the healthy comparison group. CONCLUSIONS: Recently abstinent cocaine-dependent patients may show dysregulation of the central dopaminergic system.     

Elevated central serotonin transporter binding availability in acutely abstinent cocaine-dependent patients

OBJECTIVE: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence.METHOD: Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography.RESULTS: Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups.CONCLUSIONS: These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.     

Prefrontal cortical dysfunction in abstinent cocaine abusers

The anterior cingulate cortex (ACC) and lateral prefrontal (LPFC) cortex are brain regions important to executive cognitive functions (ECF). We determined ACC and LPFC function in 23-day abstinent cocaine abusers using positron emission tomography (PET H(2)(15)O) during performance of a modified version of the Stroop Task. Cocaine abusers showed less activation than non-drug-using comparison subjects in the left ACC and the right LPFC and greater activation in the right ACC. Average amount of cocaine used per week was negatively correlated with activity in the rostral ACC and right LPFC. Disruption of ECF in substance abusers could interfere with attempts to stop drug use and undermine treatment. Since impairment in ECF may be a common feature of various neuropsychiatric disorders, these findings have applicability beyond the neurobiology of addiction.     

The ongoing balance of cortical excitation and inhibition during early development

Two papers recently published in Nature propose that the balance between excitation and inhibition is important for the maturation of cortical function. Their conclusions however, are contradictory; one study suggests that balance is established before hearing onset, whereas the other proposes that balance is established after hearing onset. We carefully examined the data and found that the differences between the two groups are less dramatic than they first appear. Despite their methodological differences, both studies provide evidence that an ongoing balance between cortical excitation/inhibition accounts for the maturation and refinement of cortical function during early development.     

Motor inhibition and excitation are independent effects of magnetic cortical stimulation.

We administered magnetic cortical stimulation (MCS) during voluntary contraction of intrinsic hand muscles to 8 patients with motor neuron disease (MND), 5 patients with pure lower motor neuron syndromes (LMN), a patient with severe subacute sensory neuropathy (SSN), and 10 healthy volunteers. Patients with MND had clinical evidence of upper MND and elevated thresholds for (3 patients) or absence of (5 patients) motor evoked potentials (MEPs). MCS during sustained contraction inhibited electromyographic activity in 6 of 8 patients with MND, without preceding MEPs. MCS had no effect on the electromyogram (EMG) of the other 2 patients with MND. In normal subjects and patients with LMN, inhibition of EMG was never seen without a preceding MEP, regardless of stimulus intensity. In the patient with SSN, MCS elicited normal MEPs and inhibited the EMG in a pattern similar to normal subjects, whereas supramaximal electrical stimulation of median and ulnar nerves failed to inhibit the EMG despite normal M and F responses. Our findings indicate that the inhibitory effects of MCS on EMG are not dependent solely on changes in afferent feedback caused by the muscle twitch produced by the MEP, or on Renshaw cell inhibition. We suggest that some of the inhibitory and excitatory effects of MCS on the motor system are mediated by distinct cortical elements, which may have different susceptibilities to pathophysiological processes in MND.     

Cholinergic excitation and inhibition in the visual thalamus of the cat--influences of cortical inactivation and barbiturate anesthesia

Neuronal responses to microiontophoretically applied pulses of acetylcholine (ACh) were recorded in the perigeniculate nucleus (PGN) and dorsal lateral geniculate nucleus (dLGN) of the cat. In the PGN, ACh inhibited 95% of the cells under N2O/O2-halothane anesthesia. Systemic application of sodium pentobarbitone did not abolish ACh inhibition. In the dLGN with N2O-halothane, ACh increased firing rates of neurons before (88%) and after (78%) interruption of their direct retinal inputs by photocoagulation of the receptive field area on the retina. Functional inactivation of the corticogeniculate loop by cooling of the ipsilateral visual cortex did not selectively influence ACh sensitivity in the retinally deafferented dLGN. It is concluded that ACh exerts a direct, excitatory action on geniculate neurons. Infusion of sodium pentobarbitone resulted in reduction of ACh firing rates to about 30% of the control values in 35% of the normally innervated cells (65% of that sample not being excited by ACh), whereas excitatory ACh responses after retinal deafferentation were completely blocked by the barbiturate. It is concluded that pentobarbitone influences direct ACh excitation, but not cholinergic disinhibition in the dLGN or ACh inhibition in the PGN. Possible differential effects of pentobarbitone on nicotinic and muscarinic types of ACh responses are discussed.     

Impaired inhibition of proactive interference in abstinent individuals with alcoholism

Cognitive impairment has been associated with higher risk of alcoholism and relapse. Recent theoretical refinements have separated inhibition of dominant response and inhibition of proactive interference. We assessed the latter using a directed-forgetting procedure in 38 recently detoxified individuals with alcoholism and in 26 controls. On this task, memory performance of letter trigrams was compared when presented alone, followed by a second trigram to be recalled, then a second trigram to be forgotten (directed-forgetting condition). Individuals with alcoholism recalled more letters to be forgotten and performed worse than controls in the directed-forgetting condition, which significantly correlated with the duration of alcoholism.     

Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia.

Transcranial magnetic stimulation has been used in a double pulse paradigm to investigate the excitability of intrinsic motor cortical circuits in 15 patients with focal task specific dystonia of the right hand and a group of eight age matched controls. The left hemisphere was examined in five patients; in the remainder, both hemispheres were tested. There was no significant difference in stimulation threshold between patients and controls nor between the left and right hemispheres in the patients. There was a significant decrease in early corticocortical suppression when comparing stimulation of the left hemisphere in the patients and controls at interstimulus intervals of 1-15 ms (P < 0.01). There was no difference in the amount of suppression in the right and left hemispheres of the patients. It is concluded that in focal task specific dystonia there is shift in the balance between excitation and inhibition in local circuits of the motor cortex which leads to a net decrease in the amount of short latency suppression. These changes reflect disturbed basal ganglia input to the motor cortex. Reduced excitability of cortical inhibitory circuits may be one factor which contributes to the excessive and inappropriate muscle contraction which occurs during fine motor tasks in patients with focal dystonia.     

Implications of cortical balanced excitation and inhibition,functional heterogeneity,and sparseness of neuronal activity in fMRI

Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies often report inconsistent findings, probably due to brain properties such as balanced excitation and inhibition and functional heterogeneity. These properties indicate that different neurons in the same voxels may show variable activities including concurrent activation and deactivation, that the relationships between BOLD signal and neural activity (i.e., neurovascular coupling) are complex, and that increased BOLD signal may reflect reduced deactivation, increased activation, or both. The traditional general-linear-model-based-analysis (GLM-BA) is a univariate approach, cannot separate different components of BOLD signal mixtures from the same voxels, and may contribute to inconsistent findings of fMRI. Spatial independent component analysis (sICA) is a multivariate approach, can separate the BOLD signal mixture from each voxel into different source signals and measure each separately, and thus may reconcile previous conflicting findings generated by GLM-BA. We propose that methods capable of separating mixed signals such as sICA should be regularly used for more accurately and completely extracting information embedded in fMRI datasets.     

Cocaine craving and attentional bias in cocaine-dependent schizophrenic patients

Cocaine craving has been implicated as a major factor underlying addiction and drug relapse. From a cognitive viewpoint, craving may reflect, in part, attentional processing biased in favor of drug-related cues and stimuli. Schizophrenic individuals (SZ), however, abuse cocaine in high numbers but typically manifest baseline cognitive deficits that impair their ability to selectively allocate their attentional resources. In this study, we examined the relationship between attentional bias and craving in patients with cocaine dependence (COC; n=20), schizophrenic patients comorbid for cocaine dependence (COC+SZ; n=23), as well as two other comparison groups using a modified version of the Stroop test to include cocaine-relevant words. Results revealed that only the COC patients demonstrated Stroop interference on the cocaine-related words. Moreover, COC patients' attentional processing biases were significantly associated with their cocaine craving severity ratings. COC+SZ patients, in contrast, did not demonstrate Stroop interference and manifested significantly fewer craving symptoms than their COC counterparts. These results suggest that COC+SZ patients' inability to selectively encode their drug-use experience may limit and shape their subjective experience of craving cocaine and motivation for cocaine use.     

Risk factors for cocaine-induced psychosis in cocaine-dependent patients

Cocaine consumption can induce transient psychotic symptoms, expressed as paranoia or hallucinations. Cocaine induced psychosis (CIP) is common but not developed in all cases. This is the first European study on the relationship between CIP, consumption pattern variables and personality disorders. We evaluated 173 cocaine-dependent patients over 18 years; mostly males, whose average age was 33.6 years (SD = 7.8). Patients attending an outpatient addictions department were enrolled in the study and subsequently systematically evaluated using SCID I and SCID II interviews for comorbid disorders, a clinical interview for psychotic symptoms and EuropASI for severity of addiction. A high proportion of cocaine dependent patients reported psychotic symptoms under the influence of cocaine (53.8%), the most frequently reported being paranoid beliefs and suspiciousness (43.9%). A logistic regression analysis was performed, finding that a model consisting of amount of cocaine consumption, presence of an antisocial personality disorder and cannabis dependence history had 66.2% sensitivity 75.8% specificity predicting the presence of CIP. In our conclusions, we discuss the relevance of evaluating CIP in all cocaine dependent-patients, and particularly in those fulfilling the clinical profile derived from our results. These findings could be useful for a clinical approach to the risks of psychotic states in cocaine-dependent patients.     

Abnormalities of cortical excitability and cortical inhibition in cervical dystonia

Cortical excitability and cortico-cortical inhibition were examined in twenty-one patients suffering from idiopathic rotational cervical dystonia. Polymyography of cervical muscles, somatosensory evoked potential recordings, and paired transcranial magnetic stimulation were used to assess the dystonic disorder. The results were compared with those obtained in a group of sixteen healthy age-matched volunteers. Statistically significant differences between the patient group and the control group were found when the amplitude values of the mean P22/N30 component measured at F [3, 4] and C[3, 4]' electrode positions were compared. The mean amplitude of P22/N30 in both of these electrode positions contralaterally to the direction of head deviation was significantly higher in the patient group (p ≤ 0.05). The mean side-to-side P22/N30 amplitude ratio was calculated in both groups in the F[3, 4] and C[3, 4]' electrode positions: there was a significant difference between the two groups. The mean ratio (calculated contralaterally/ipsilaterally in the patient group and left/right side in the control group) was significantly higher in the patient group (p ≤ 0.05). There were statistically significant differences between the two groups when the mean values of MEP amplitudes following paired stimuli at short and medium interstimulus intervals (ISI)) were compared. The percentage of amplitude reduction registered at short ISI was significantly lower in the patient group when both 3 ms ISI and 5 ms ISI were considered, and when the hemisphere contralateral to the direction of head deviation was stimulated. There was also a difference (with the short ISI) when the hemisphere ipsilateral to the direction of head deviation was stimulated, but this difference was not significant (p < 0.5). Almost all of the amplitude changes following the paired stimulus at the longer ISI, i. e. 10, 15, and 20 ms were significantly different when the patient group was compared with control group: when the ipsilateral hemisphere was stimulated, the amplitude of conditioned responses was significantly higher following all three paired stimuli (with 10, 15, and 20 ms ISI) at the p ≤ 0.05 significance level; when the contralateral hemisphere was stimulated, they were significantly higher following the 10 and 20 ms ISI paired stimuli (significance level p ≤ 0.05). The interhemispheric difference in the patient group was significant only for the paired stimuli using 3 and 5 ms (short) ISI and 15 and 20 ms (medium) ISI. There was a significantly decreased inhibition at 3 and 5 ms ISI when the hemisphere contralateral to the direction of head deviation was stimulated, as compared with the hemisphere ipsilateral (p ≤ 0.05). Similarly, there was a significantly increased facilitation at 15 and 20 ms when the hemisphere contralateral to the direction of head deviation was stimulated, as compared with the hemisphere ipsilateral (p ≤ 0.05). The results indicate that a disorder of both cortical excitability and intracortical inhibition exists in patients with cervical dystonia, and that this disorder is lateralized, i. e. it is located within the hemisphere contralateral to the direction of head deviation. Received: 5 March 2002, Received in revised form: 1 August 2002, Accepted: 2 August 2002 Correspondence to Doc. MUDr Petr Kaňovsky, CSc.     

Characteristics of cocaine-dependent patients who attempt suicide

OBJECTIVE: Although suicidal behavior is frequent among cocaine-dependent patients, it has been little studied. Therefore, the author examined the characteristics of cocaine-dependent patients who had attempted suicide. METHOD: Cocaine-dependent patients who had attempted suicide (N=84) were compared with cocaine-dependent patients who had never attempted suicide (N=130) on clinical, personality, psychiatric, and physical variables. RESULTS: Significantly more of the patients who had attempted suicide were female and had a family history of suicidal behavior; they reported significantly more childhood trauma and were significantly more introverted, neurotic, and hostile. They had also had significantly more comorbidity with alcohol and/or opiate dependence, major depression, and physical disorders. CONCLUSIONS: The clinical implications are that family, childhood, personality, psychiatric, and physical risk factors contribute to suicidal behavior in cocaine-dependent patients. Comorbidity appears to be an important determinant of suicidal behavior.     

Serum cholesterol, suicidal behavior and impulsivity in cocaine-dependent patients

Relationships between serum cholesterol and suicidal behavior have been reported. As suicidal behavior is common in cocaine dependence, we looked for a relationship with serum cholesterol. To do this, we compared 57 cocaine-dependent patients who had attempted suicide with 111 cocaine-dependent patients who had never attempted suicide for their admission total serum cholesterol levels. We found that there were no significant differences between cocaine-dependent patients who had or had not attempted suicide in their total serum cholesterol levels. Also, there were no significant correlations between total serum cholesterol levels and scores on the Barratt Impulsivity Scale. Thus, admission total serum cholesterol does not appear to be clinically useful in the assessment of suicidal behavior in cocaine-dependent patients.     

Learning and memory impairment in cocaine-dependent and comorbid schizophrenic patients

Impairments in verbal learning and memory functioning have been found to be cardinal features among individuals with schizophrenia as well as among non-schizophrenic cocaine abusers. Cognitive deficits in these areas, moreover, have been associated with poor treatment response and short-term outcome. Little is known, however, about the acute effects of cocaine abuse on schizophrenic patients' learning and memory functioning. Consequently, a potentially reversible and treatable source of cognitive impairment has been virtually ignored. The present study examined the extent of verbal learning and memory impairment in a group of cocaine-dependent schizophrenic patients (n=42) and a group of non-schizophrenic cocaine-dependent patients (n=21) within 72 h of the last cocaine use using the California Verbal Learning Test (CVLT). Schizophrenic patients (n=34) without any substance-use disorders were also tested in an identical time frame and served as a comparison group. Results revealed that all groups demonstrated significant learning and memory impairment relative to CVLT published age and gender corrected norms. Both cocaine-dependent and non-substance abusing schizophrenic groups presented a very similar pattern of impaired learning and recall performance across all CVLT task domains. Comorbid patients, in contrast, presented with marked deficits in their ability to learn and recall verbal information relative to either schizophrenic or cocaine-only groups. Moreover, the cocaine-abusing schizophrenic patients showed significant forgetfulness of the information that they did acquire during delayed recall conditions. The performance deficits exhibited by cocaine-abusing schizophrenic patients differed not only in relative severity of impairment, but also qualitatively in their increased rates of forgetfulness of acquired information. These results are interpreted in terms of the neurobiological substrates of learning and memory and the neurobiological impact of cocaine on schizophrenic patients' cognition during the early phase of inpatient hospitalization. These results suggest that comorbid patients should be targeted for specialized remediation efforts at the beginning phases of inpatient treatment.