Mitul A. Mehta

Methylphenidate Enhances Working Memory by Modulating Discrete Frontal and Parietal Lobe Regions in the Human Brain

The indirect catecholamine agonist methylphenidate (Ritalin) is the drug treatment of choice in attention deficit/hyperactivity disorder (AD/HD), one of the most common behavioral disorders of childhood (DSM-IV), although symptoms may persist into adulthood. Methylphenidate can enhance cognitive performance in adults and children diagnosed with AD/HD (Kempton et al., 1999; Riordan et al., 1999) and also in normal human volunteers on tasks sensitive to frontal lobe damage, including aspects of spatial working memory (SWM) performance (Elliott et al., 1997). The present study investigated changes in regional cerebral blood flow (rCBF) induced by methylphenidate during performance of a self-ordered SWM task to define the neuroanatomical loci of the beneficial effect of the drug. The results show that the methylphenidate-induced improvements in working memory performance occur with task-related reductions in rCBF in the dorsolateral prefrontal cortex and posterior parietal cortex. The beneficial effects of methylphenidate on working memory were greatest in the subjects with lower baseline working memory capacity. This is to our knowledge the first demonstration of a localization of a drug-induced improvement in SWM performance in humans and has relevance for understanding the treatment of AD/HD.

Distinct frontal systems for response inhibition, attentional capture, and error processing

Stopping an action in response to an unexpected event requires both that the event is attended to, and that the action is inhibited. Previous neuroimaging investigations of stopping have failed to adequately separate these cognitive elements. Here we used a version of the widely used Stop Signal Task that controls for the attentional capture of stop signals. This allowed us to fractionate the contributions of frontal regions, including the right inferior frontal gyrus and medial frontal cortex, to attentional capture, response inhibition, and error processing. A ventral attentional system, including the right inferior frontal gyrus, has been shown to respond to unexpected stimuli. In line with this evidence, we reasoned that lateral frontal regions support attentional capture, whereas medial frontal regions, including the presupplementary motor area (pre-SMA), actually inhibit the ongoing action. We tested this hypothesis by contrasting the brain networks associated with the presentation of unexpected stimuli against those associated with outright stopping. Functional MRI images were obtained in 26 healthy volunteers. Successful stopping was associated with activation of the right inferior frontal gyrus, as well as the pre-SMA. However, only activation of the pre-SMA differentiated stopping from a high-level baseline that controlled for attentional capture. As expected, unsuccessful attempts at stopping activated the anterior cingulate cortex. In keeping with work in nonhuman primates these findings demonstrate that successful motor inhibition is specifically associated with pre-SMA activation.

Opposite Effects of Δ-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology

Δ-9-tetrahydrocannabinol (Δ-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Δ-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Δ-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Δ-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Δ-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Δ-9-THC. Δ-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Δ-9-tetrahydrocannabinol. Δ-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBDs ability to block the psychotogenic effects of Δ-9-THC.

Salience network integrity predicts default mode network function after traumatic brain injury

Efficient behavior involves the coordinated activity of large-scale brain networks, but the way in which these networks interact is uncertain. One theory is that the salience network (SN)—which includes the anterior cingulate cortex, presupplementary motor area, and anterior insulae—regulates dynamic changes in other networks. If this is the case, then damage to the structural connectivity of the SN should disrupt the regulation of associated networks. To investigate this hypothesis, we studied a group of 57 patients with cognitive impairments following traumatic brain injury (TBI) and 25 control subjects using the stop-signal task. The pattern of brain activity associated with stop-signal task performance was studied by using functional MRI, and the structural integrity of network connections was quantified by using diffusion tensor imaging. Efficient inhibitory control was associated with rapid deactivation within parts of the default mode network (DMN), including the precuneus and posterior cingulate cortex. TBI patients showed a failure of DMN deactivation, which was associated with an impairment of inhibitory control. TBI frequently results in traumatic axonal injury, which can disconnect brain networks by damaging white matter tracts. The abnormality of DMN function was specifically predicted by the amount of white matter damage in the SN tract connecting the right anterior insulae to the presupplementary motor area and dorsal anterior cingulate cortex. The results provide evidence that structural integrity of the SN is necessary for the efficient regulation of activity in the DMN, and that a failure of this regulation leads to inefficient cognitive control.

Amygdala, hippocampal and corpus callosum size following severe early institutional deprivation: The English and Romanian Adoptees Study Pilot

The adoption into the UK of children who have been reared in severely deprived conditions provides an opportunity to study possible association between very early negative experiences and subsequent brain development. This cross-sectional study was a pilot for a planned larger study quantifying the effects of early deprivation on later brain structure. We used magnetic resonance imaging (MRI) to measure the sizes of three key brain regions hypothesized to be sensitive to early adverse experiences. Our sample was a group of adoptee adolescents (N = 14) who had experienced severe early institutional deprivation in Romania and a group of non-institutionalised controls (N = 11). The total grey and white matter volumes were significantly smaller in the institutionalised group compared with a group of non-deprived, non-adopted UK controls. After correcting for difference in brain volume, the institutionalised group had greater amygdala volumes, especially on the right, but no differences were observed in hippocampal volume or corpus callosum mid-sagittal area. The left amygdala volume was also related to the time spent in institutions, with those experiencing longer periods of deprivation having a smaller left amygdala volume. These pilot findings highlight the need for future studies to confirm the sensitivity of the amygdala to early deprivation.

Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease

Abstract  Rationale: The mesotelencephalic dopamine system has been implicated in cognitive processes dependent on an intact prefrontal cortex. Most previous research in humans has focused on dopaminergic agonists and their effects on tasks of working memory. Objectives: The present study was designed to investigate the cognitive and subjective effects of two doses (200 mg and 400 mg) of the dopaminergic D2 receptor antagonist, sulpiride on a broad range of well-validated neuropsychological tasks in a group of 34 young healthy male volunteers. Methods: Cognitive tasks were administered to subjects after ingestion of either drug or placebo within a double-blind, placebo-controlled, cross-over design. The cognitive tests included tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and were designed to assess visuospatial recognition memory, planning ability, working memory, strategy learning, sustained attention and attentional set-shifting. In addition, the National Adult Reading Test (NART) was used to assess verbal IQ, and visual analogue scales to assess subjective effects of the drug. Results: Subjects on sulpiride were impaired on the tasks of spatial recognition, spatial working memory (sequence generation), planning (one-touch Tower of London) and attentional set-shifting. Only the spatial working memory task demonstrated a dose dependent effect. The impairments were not due to generalised sedative or motoric influences of sulpiride. Conclusions: All of the tasks impaired following sulpiride are known to be sensitive to frontal lobe damage and the precise pattern of deficits seen is consistent with the anatomical distribution of central dopamine receptors. The results are discussed with particular reference to their close simulation of the impairments seen in idiopathic Parkinson’s disease.

Effects of Profound Early Institutional Deprivation: An Overview of Findings from a UK Longitudinal Study of Romanian Adoptees

A randomly selected sample of 165 children from Romania (of whom 144 had been reared in institutions) who were adopted by UK families, with placement before the age of 42 months, was studied at 4, 6, and 11 years of age. Comparisons were made with a sample of 52 non-institutionalized UK children adopted before the age of 6 months, who were studied in the same way. The paper briefly summarizes circumstances at the time of adoption and then reports findings at age 11, focusing on changes between 6 and 11. Marked catch-up in psychological functioning was evident following adoption, but significant problems continued in a substantial minority of the children placed after the age of 6 months. The theoretical implications of the findings are considered, and the policy implications are noted.

Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine- induced psychopathology

Preclinical studies suggest that ketamine-induced psychopathology is mediated, in part, by increased glutamate release, hypothesized to occur via inhibition of GABAergic interneurons. Using proton magnetic resonance spectroscopy (1H-MRS), we tested this hypothesis in healthy humans. Ketamine increased anterior cingulate cortex glutamate levels, which correlated with the degree of positive psychotic symptoms. Ketamine did not affect subcortical gamma-aminobutyric acid (GABA) levels.

Measuring fMRI reliability with the intra-class correlation coefficient.

The intra-class class correlation coefficient (ICC) is a prominent statistic to measure test-retest reliability of fMRI data. It can be used to address the question of whether regions of high group activation in a first scan session will show preserved subject differentiability in a second session. With this purpose, we present a method that extends voxel-wise ICC analysis. We show that voxels with high group activation have more probability of being reliable, if a subsequent session is performed, than typical voxels across the brain or across white matter. We also find that the existence of some voxels with high ICC but low group activation can be explained by stable signals across sessions that poorly fit the HRF model. At a region of interest level, we show that our voxel-wise ICC calculation is more robust than previous implementations under variations of smoothing and cluster size. The method also allows formal comparisons between the reliabilities of given brain regions; aimed at establishing which ROIs discriminate best between individuals. The method is applied to an auditory and a verbal working memory task. A reliability toolbox for SPM5 is provided at http://brainmap.co.uk.

Cognitive enhancement by drugs in health and disease

Attempts to improve cognitive function in patients with brain disorders have become the focus of intensive research efforts. A recent emerging trend is the use of so-called cognitive enhancers by healthy individuals. Here, we consider some of the effects – positive and negative – that current drugs have in neurological conditions and healthy people. We conclude that, to date, experimental and clinical studies have demonstrated relatively modest overall effects, most probably because of substantial variability in response both across and within individuals. We discuss biological factors that might account for such variability and highlight the need to improve testing methods and to extend our understanding of how drugs modulate specific cognitive processes at the systems or network level.