P. Simon Jones

Abnormal Brain Structure Implicated in Stimulant Drug Addiction

Nature or Drug Abuse? There are significant structural changes in striatal and prefrontal brain regions of stimulant drugdependent individuals. However, it is not clear if these brain abnormalities predate drug-taking, rendering individuals vulnerable for the development of dependence, or if these changes are the effect of many years of drug use. Ersche et al. (p. 601; see the Perpective by Volkow and Baler) investigated brain abnormalities in both drug-dependent individuals and in their biological siblings who have never taken drugs of abuse and compared them with matched healthy volunteers. The brain abnormalities in the sibling pairs were associated with significant impairments in the regulation of behavior; an ability known to be compromised in drug dependence. Because these neural changes were observed in family members who do not take drugs, the changes are likely to represent neurological markers of vulnerability to addiction rather than consequences of chronic drug abuse. A neurological marker of addiction vulnerability occurs in sibling pairs who do not take drugs. Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual’s health and social and personal life. We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.

Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence

A growing body of preclinical evidence indicates that addiction to cocaine is associated with neuroadaptive changes in frontostriatal brain systems. Human studies in cocaine-dependent individuals have shown alterations in brain structure, but it is less clear how these changes may be related to the clinical phenotype of cocaine dependence characterized by impulsive behaviours and compulsive drug-taking. Here we compared self-report, behavioural and structural magnetic resonance imaging data on a relatively large sample of cocaine-dependent individuals (n = 60) with data on healthy volunteers (n = 60); and we investigated the relationships between grey matter volume variation, duration of cocaine use, and measures of impulsivity and compulsivity in the cocaine-dependent group. Cocaine dependence was associated with an extensive system of abnormally decreased grey matter volume in orbitofrontal, cingulate, insular, temporoparietal and cerebellar cortex, and with a more localized increase in grey matter volume in the basal ganglia. Greater duration of cocaine dependence was correlated with greater grey matter volume reduction in orbitofrontal, cingulate and insular cortex. Greater impairment of attentional control was associated with reduced volume in insular cortex and increased volume of caudate nucleus. Greater compulsivity of drug use was associated with reduced volume in orbitofrontal cortex. Cocaine-dependent individuals had abnormal structure of corticostriatal systems, and variability in the extent of anatomical changes in orbitofrontal, insular and striatal structures was related to individual differences in duration of dependence, inattention and compulsivity of cocaine consumption.

How Reliable Is Perfusion MR in Acute Stroke?: Validation and Determination of the Penumbra Threshold Against Quantitative PET

Background and Purpose— Perfusion magnetic resonance imaging (pMR) is increasingly used in acute stroke, but its physiologic significance is still debated. A reasonably good correlation between pMR and positron emission tomography (PET) has been reported in normal subjects and chronic cerebrovascular disease, but corresponding validation in acute stroke is still lacking. Methods— We compared the cerebral blood flow (CBF), cerebral blood volume, and mean transit time (MTT) maps generated by pMR (deconvolution method) and PET (15O steady-state method) in 5 patients studied back-to-back with the 2 modalities at a mean of 16 hours (range, 7 to 21 hours) after stroke onset. We also determined the penumbra thresholds for pMR-derived MTT, time to peak (TTP), and Tmax against the previously validated probabilistic PET penumbra thresholds. Results— In all patients, the PET and pMR relative distribution images were remarkably similar, especially for CBF and MTT. Within-patient correlations between pMR and PET were strong for absolute CBF (average r2=0.45) and good for MTT (r2=0.35) but less robust for cerebral blood volume (r2=0.24). However, pMR overestimated absolute CBF and underestimated MTT, with substantial variability in individual slopes. Removing individual differences by normalization to the mean resulted in much stronger between-patient correlations. Penumbra thresholds of ≈6, 4.8, and 5.5 seconds were obtained for MTT delay, TTP delay, and Tmax, respectively. Conclusions— Although derived from a small sample studied relatively late after stroke onset, our data show that pMR tends to overestimate absolute CBF and underestimate MTT, but the relative distribution of the perfusion variables was remarkably similar between pMR and PET. pMR appears sufficiently reliable for clinical purposes and affords reliable detection of the penumbra from normalized time-based thresholds.

A wavelet method for modeling and despiking motion artifacts from resting-state fMRI time series

The impact of in-scanner head movement on functional magnetic resonance imaging (fMRI) signals has long been established as undesirable. These effects have been traditionally corrected by methods such as linear regression of head movement parameters. However, a number of recent independent studies have demonstrated that these techniques are insufficient to remove motion confounds, and that even small movements can spuriously bias estimates of functional connectivity. Here we propose a new data-driven, spatially-adaptive, wavelet-based method for identifying, modeling, and removing non-stationary events in fMRI time series, caused by head movement, without the need for data scrubbing. This method involves the addition of just one extra step, the Wavelet Despike, in standard pre-processing pipelines. With this method, we demonstrate robust removal of a range of different motion artifacts and motion-related biases including distance-dependent connectivity artifacts, at a group and single-subject level, using a range of previously published and new diagnostic measures. The Wavelet Despike is able to accommodate the substantial spatial and temporal heterogeneity of motion artifacts and can consequently remove a range of high and low frequency artifacts from fMRI time series, that may be linearly or non-linearly related to physical movements. Our methods are demonstrated by the analysis of three cohorts of resting-state fMRI data, including two high-motion datasets: a previously published dataset on children (N = 22) and a new dataset on adults with stimulant drug dependence (N = 40). We conclude that there is a real risk of motion-related bias in connectivity analysis of fMRI data, but that this risk is generally manageable, by effective time series denoising strategies designed to attenuate synchronized signal transients induced by abrupt head movements. The Wavelet Despiking software described in this article is freely available for download at www.brainwavelet.org.

Motor Imagery After Subcortical Stroke A Functional Magnetic Resonance Imaging Study

Background and Purpose— In recovered subcortical stroke, the pattern of motor network activation during motor execution can appear normal or not, depending on the task. Whether this applies to other aspects of motor function is unknown. We used functional MRI to assess motor imagery (MI), a promising new approach to improve motor function after stroke, and contrasted it to motor execution. Methods— Twenty well-recovered patients with hemiparetic subcortical stroke (14 males; mean age, 66.5 years) and 17 aged-matched control subjects were studied. Extensive behavioral screening excluded 8 patients and 4 control subjects due to impaired MI abilities. Subjects performed MI and motor execution of a paced finger–thumb opposition sequence using a functional MRI paradigm that monitored compliance. Activation within the primary motor cortex (BA4a and 4p), dorsal premotor, and supplementary motor areas was examined. Results— The pattern of activation during affected-hand motor execution was not different from control subjects. Affected-hand MI activation was also largely similar to control subjects, including involvement of BA4, but with important differences: (1) unlike control subjects and the nonaffected hand, activation in BA4a and dorsal premotor was not lower during MI as compared with motor execution; (2) the hemispheric balance of BA4p activation was significantly less lateralized than control subjects; and (3) ipsilesional BA4p activation positively correlated with motor performance. Conclusions— In well-recovered subcortical stroke, the motor system, including ipsilesional BA4, is activated during MI despite the lesion. It, however, remains disorganized in proportion to residual motor impairment. Thus, components of movement upstream from execution appear differentially affected after stroke and could be targeted by rehabilitation in more severely affected patients.

The neural correlates of inner speech defined by voxel-based lesion-symptom mapping.

The neural correlates of inner speech have been investigated previously using functional imaging. However, methodological and other limitations have so far precluded a clear description of the neural anatomy of inner speech and its relation to overt speech. Specifically, studies that examine only inner speech often fail to control for subjects’ behaviour in the scanner and therefore cannot determine the relation between inner and overt speech. Functional imaging studies comparing inner and overt speech have not produced replicable results and some have similar methodological caveats as studies looking only at inner speech. Lesion analysis can avoid the methodological pitfalls associated with using inner and overt speech in functional imaging studies, while at the same time providing important data about the neural correlates essential for the specific function. Despite its advantages, a study of the neural correlates of inner speech using lesion analysis has not been carried out before. In this study, 17 patients with chronic post-stroke aphasia performed inner speech tasks (rhyme and homophone judgements), and overt speech tasks (reading aloud). The relationship between brain structure and language ability was studied using voxel-based lesion–symptom mapping. This showed that inner speech abilities were affected by lesions to the left pars opercularis in the inferior frontal gyrus and to the white matter adjacent to the left supramarginal gyrus, over and above overt speech production and working memory. These results suggest that inner speech cannot be assumed to be simply overt speech without a motor component. It also suggests that the use of overt speech to understand inner speech and vice versa might result in misleading conclusions, both in imaging studies and clinical practice.

Distinctive Personality Traits and Neural Correlates Associated with Stimulant Drug Use Versus Familial Risk of Stimulant Dependence

Background Stimulant drugs such as cocaine and amphetamine have a high abuse liability, but not everyone who uses them develops dependence. However, the risk for dependence is increased for individuals with a family history of addiction. We hypothesized that individuals without a family history of dependence who have been using cocaine recreationally for several years but have not made the transition to dependence will differ in terms of personality traits and brain structure from individuals who are either dependent on stimulants or at risk for dependence. Methods We compared 27 individuals without a familial risk of dependence who had been using cocaine recreationally with 50 adults with stimulant dependence, their nondependent siblings (n = 50), and unrelated healthy volunteers (n = 52) who had neither a personal nor a family history of dependence. All participants underwent a magnetic resonance imaging brain scan and completed a selection of personality measures that have been associated with substance abuse. Results Increased sensation-seeking traits and abnormal orbitofrontal and parahippocampal volume were shared by individuals who were dependent on stimulant drugs or used cocaine recreationally. By contrast, increased levels of impulsive and compulsive personality traits and limbic-striatal enlargement were shared by stimulant-dependent individuals and their unaffected siblings. Conclusions We provide evidence for distinct neurobiological phenotypes that are either associated with familial vulnerability for dependence or with regular stimulant drug use. Our findings further suggest that some individuals with high sensation-seeking traits but no familial vulnerability for dependence are likely to use cocaine but may have relatively low risk for developing dependence.

Imaging of Brain Hypoxia in Permanent and Temporary Middle Cerebral Artery Occlusion in the Rat using 18F-Fluoromisonidazole and Positron Emission Tomography: A Pilot Study

In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. Previous human studies using 18F-fluoromisonidazole and positron emission tomography (18F-FMISO PET) have shown high tracer retention indicative of tissue hypoxia, which had normalized at repeat scan >48 h later. In the only validation study of 18F-FMISO, using ex vivo autoradiography in thread middle cerebral artery occluded (MCAo) rats, there was unexpected high uptake as late as 22 h after reperfusion, raising questions about the use of 18F-FMISO as a hypoxia tracer. Here we report a pilot study of 18F-FMISO PET in experimental stroke. Spontaneous hypertensive rats were subjected to distal clip MCAo. Three-hour dynamic PET was performed in 7 rats: 3 normals, 1 with permanent MCAo (two sessions: 30 mins and 48 h after clip), and 3 with temporary MCAo (45 mins, n = 1; 120 mins, n = 2; scanning started 30 mins after clip removal). Experiments were terminated by perfusion—fixation for standard histopathology. Late tracer retention was assessed by both compartmental modelling and simple side-to-side ratios. In the initial PET session of the permanent MCAo rat, striking trapping of 18F-FMISO was observed in the affected cortex, which had normalized 48 h later; histopathology revealed pannecrosis. In contrast, there was no demonstrable tracer retention in either temporary MCAo models, and histopathology showed ischemic changes only. These results document elevated 18F-FMISO uptake in the stroke area only in the early phase of MCAo, but not after early reperfusion nor when tissue necrosis has developed. These findings strongly support the validity of 18F-FMISO as a marker of viable hypoxic tissue/penumbra after stroke.

Watershed Infarcts in Transient Ischemic Attack/Minor Stroke With ≥50% Carotid Stenosis Hemodynamic or Embolic?

Background and Purpose— Watershed ischemia is a significant cause of stroke in severe carotid disease, but its pathophysiology is unsettled. Although hemodynamic compromise has long been regarded as the main mechanism—particularly with deep watershed infarction—there is some contradictory evidence from clinical and pathological studies for a role of microembolism, thought to result from plaque inflammation. However, no study so far has directly addressed these conflicting scenarios. Methods— In 16 consecutive patients with recent transient ischemic attack/minor stroke and ipsilateral 50% to 99% carotid stenosis, we prospectively obtained (1) plaque inflammation mapping with 18F fluorodeoxyglucose positron emission tomography; (2) brain MRI and perfusion MR; and (3) transcranial Doppler detection of microembolic signals (MES). Patients were excluded if on dual antiplatelets or with a potential cardiac source of emboli or contralateral MES. Results— We found the expected significant relationship between (1) degree of stenosis and severity of distal hemodynamic impairment in the watershed areas; and (2) degree of in vivo plaque inflammation and rate of MES/hr. Deep watershed infarcts were present in 8 patients and MES in 8 (3 with both). There was no systematic association between the presence of deep watershed infarcts and either hemodynamic impairment or MES, but deep watershed infarcts were present only when either hemodynamic impairment or MES was present (P=0.01). Conclusion— This pilot study supports the idea that in symptomatic carotid disease, deep watershed infarcts result either from hemodynamic impairment secondary to severe lumen stenosis or from microembolism secondary to plaque inflammation. There was no direct evidence that both mechanisms act in synergy.

A comparison of VLSM and VBM in a cohort of patients with post-stroke aphasia

Studies attempting to map post-stroke cognitive or motor symptoms to lesion location have been available in the literature for over 150 years. In the last two decades, two computational techniques have been developed to identify the lesion sites associated with behavioural impairments. Voxel Based Morphometry (VBM) has now been used extensively for this purpose in many different patient populations. More recently, Voxel-based Lesion Symptom Mapping (VLSM) was developed specifically for the purpose of identifying lesion–symptom relationships in stroke patients, and has been used extensively to study, among others functions, language, motor abilities and attention. However, no studies have compared the results of these two techniques so far. In this study we compared VLSM and VBM in a cohort of 20 patients with chronic post-stroke aphasia. Comparison of the two techniques showed overlap in regions previously found to be relevant for the tasks used, suggesting that using both techniques and looking for overlaps between them can increase the reliability of the results obtained. However, overall VBM and VLSM provided only partially concordant results and the differences between the two techniques are discussed.