The ICCAM platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part B: fMRI description.

OBJECTIVES: We aimed to set up a robust multi-centre clinical fMRI and neuropsychological platform to investigate the neuropharmacology of brain processes relevant to addiction - reward, impulsivity and emotional reactivity. Here we provide an overview of the fMRI battery, carried out across three centres, characterizing neuronal response to the tasks, along with exploring inter-centre differences in healthy participants. EXPERIMENTAL DESIGN: Three fMRI tasks were used: monetary incentive delay to probe reward sensitivity, go/no-go to probe impulsivity and an evocative images task to probe emotional reactivity. A coordinate-based activation likelihood estimation (ALE) meta-analysis was carried out for the reward and impulsivity tasks to help establish region of interest (ROI) placement. A group of healthy participants was recruited from across three centres (total n=43) to investigate inter-centre differences. Principle observations: The pattern of response observed for each of the three tasks was consistent with previous studies using similar paradigms. At the whole brain level, significant differences were not observed between centres for any task. CONCLUSIONS: In developing this platform we successfully integrated neuroimaging data from three centres, adapted validated tasks and applied whole brain and ROI approaches to explore and demonstrate their consistency across centres.

Differences in Regional Brain Responses to Food Ingestion After Roux-en-Y Gastric Bypass and the Role of Gut Peptides: A Neuroimaging Study.

OBJECTIVE: Improved appetite control, possibly mediated by exaggerated gut peptide responses to eating, may contribute to weight loss after Roux-en-Y gastric bypass (RYGB). This study compared brain responses to food ingestion between post-RYGB (RYGB), normal weight (NW), and obese (Ob) unoperated subjects and explored the role of gut peptide responses in RYGB. RESEARCH DESIGN AND METHODS: Neuroimaging with [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography was performed in 12 NW, 21 Ob, and 9 RYGB (18 ± 13 months postsurgery) subjects after an overnight fast, once FED (400 kcal mixed meal), and once FASTED, in random order. RYGB subjects repeated the studies with somatostatin infusion and basal insulin replacement. Fullness, sickness, and postscan ad libitum meal consumption were measured. Regional brain FDG uptake was compared using statistical parametric mapping. RESULTS: RYGB subjects had higher overall fullness and food-induced sickness and lower ad libitum consumption. Brain responses to eating differed in the hypothalamus and pituitary (exaggerated activation in RYGB), left medial orbital cortex (OC) (activation in RYGB, deactivation in NW), right dorsolateral frontal cortex (deactivation in RYGB and NW, absent in Ob), and regions mapping to the default mode network (exaggerated deactivation in RYGB). Somatostatin in RYGB reduced postprandial gut peptide responses, sickness, and medial OC activation. CONCLUSIONS: RYGB induces weight loss by augmenting normal brain responses to eating in energy balance regions, restoring lost inhibitory control, and altering hedonic responses. Altered postprandial gut peptide responses primarily mediate changes in food-induced sickness and OC responses, likely to associate with food avoidance.

The Imperial College Cambridge Manchester (ICCAM) platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part A: Study description.

Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs.

Regional cerebral blood flow and FDG uptake in asymptomatic HIV-1 men.

Despite advances in the treatment of patients with human immunodeficiency virus (HIV), HIV-associated neurocognitive disorder occurs in 15-50% of HIV-infected individuals, and may become more apparent as ageing advances. In the present study we investigated regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose uptake (rCMRglc) in medically and psychiatrically stable HIV-1-infected participants in two age-groups. Positron emission tomography (PET) and magnetic resonance imaging (MRI)-based arterial spin labeling (ASL) were used to measure rCMRglc and rCBF, respectively, in 35 HIV-infected participants and 37 HIV-negative matched controls. All participants were currently asymptomatic with undetectable HIV-1 viral loads, without medical or psychiatric comorbidity, alcohol or substance misuse, stable on medication for at least 6 months before enrolment in the study. We found significant age effects on both ASL and PET with reduced rCBF and rCMRglc in related frontal brain regions, and consistent, although small, reductions in rCBF and rCMRglc in the anterior cingulate cortex (ACC) in HIV, a finding of potential clinical significance. There was no significant interaction between HIV status and the ageing process, and no significant HIV-related changes elsewhere in the brain on PET or ASL. This is the first paper to combine evidence from ASL and PET method in HIV participants. These finding provide evidence of crossvalidity between the two techniques, both in ageing and a clinical condition (HIV).

Endogenous opioid release in the human brain reward system induced by acute amphetamine administration.

BACKGROUND: We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in the living human brain by evaluating the effects of amphetamine administration on [(11)C]carfentanil binding with positron emission tomography (PET). METHODS: Twelve healthy male volunteers underwent [(11)C]carfentanil PET before and 3 hours after a single oral dose of d-amphetamine (either a "high" dose, .5 mg/kg, or a sub-pharmacological "ultra-low" dose, 1.25 mg total dose or approximately .017 mg/kg). Reductions in [(11)C]carfentanil binding from baseline to post-amphetamine scans (ΔBP(ND)) after the "high" and "ultra-low" amphetamine doses were assessed in 10 regions of interest. RESULTS: [(11)C]carfentanil binding was reduced after the "high" but not the "ultra-low" amphetamine dose in the frontal cortex, putamen, caudate, thalamus, anterior cingulate, and insula. CONCLUSIONS: Our findings indicate that oral amphetamine administration induces endogenous opioid release in different areas of human brain, including basal ganglia, frontal cortex areas, and thalamus. The combination of an amphetamine challenge and [(11)C]carfentanil PET is a practical and robust method to probe the opioid system in the living human brain.

Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin.

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.

The response to rapid infusion of fentanyl in the human brain measured using pulsed arterial spin labelling.

OBJECTIVE: We evaluated the sensitivity of pulsed Arterial Spin Labelling (pASL) for the detection of changes in regional cerebral blood perfusion (CBP) during and after intra-venous (i.v.) infusion of an opioid agonist (fentanyl) and an opioid antagonist (naloxone). MATERIALS AND METHODS: Twenty-three subjects were scanned four times, receiving i.v. infusion of fentanyl, naloxone, placebo and a second fentanyl administration, in four separate scanning sessions in randomised order. End-tidal CO(2), respiration rate and heart rate were recorded continuously throughout each scan. pASL time series were collected using single shot EPI for 15 min (including 5 min of baseline prior to infusion). RESULTS: Significant increases in CBP were detected during and after administration of fentanyl, (when compared to placebo and naloxone), in most areas of high concentration of mu-opioid receptors (thalamus, lingual gyrus, para-hippocampal gyrus, and insula); near-significant increases were also observed in the insula. No increases in perfusion were observed during or after naloxone infusion. No correlation was found between regional rCBF changes and end-tidal CO(2), respiration rate or heart rate. Good reliability was found between the first and second fentanyl sessions but the regions of high reliability did not overlap completely with those of highest perfusion change. CONCLUSION: pASL is a suitable method for examining rapid, dynamic effects of opioid administration on brain physiology.

GABAB receptors in addiction and its treatment.

The GABA(B) receptor plays an important role in the control of neurotransmitter release, and experiments using preclinical models have shown that modulation of this receptor can have profound effects on the reward process. This ability to affect the reward process has led to clinical investigations into the possibility that this could be a viable target in the treatment of addiction. Presented here is an overview of a number of studies testing this hypothesis in different drug dependencies. The studies reviewed have used the GABA(B) receptor agonist baclofen, which is currently the only GABA(B) agonist for use in humans. In addition, studies using the non-specific GABA(B) receptor agonists vigabatrin and tiagabine have been included. In some of the studies these were found to have efficacy in the initiation and maintenance of abstinence, as an anti-craving treatment and alleviation of withdrawal syndromes, while in other studies showing limited effects. However, there is enough evidence to suggest that modulators of the GABA(B) receptor have potential as adjunct treatments to aid in the initiation of abstinence, maintenance of abstinence, and prevention of cue-related relapse in some addictions. This potential is at present poorly understood or studied and warrants further investigation.

Evolution and resolution of human brain perfusion responses to the stress of induced hypoglycemia.

The relationship between the human brain response to acute stress and subjective, behavioural and physiological responses is poorly understood. We have examined the human cerebral response to the intense interoceptive stressor of hypoglycemia, controlling plasma glucose at either normal fasting concentrations (5 mmol/l, n=7) or at hypoglycemia (2.7 mmol/l, n=10) for 1 h in healthy volunteers. Hypoglycemia was associated with symptomatic responses, counterregulatory neuroendocrine responses and a sequential pattern of brain regional engagement, mapped as changes in relative cerebral perfusion using [(15)O]-H(2)O water positron emission tomography. The early cerebral response comprised activation bilaterally in anterior cingulate cortex (ACC) and thalamic pulvinar, with deactivation in posterior parahippocampal gyrus. Later responses (>20 min) engaged bilateral anterior insula, ventral striatum and pituitary. Following resolution of hypoglycemia, the majority of responses returned to baseline, save persistent engagement of the ACC and sustained elevation of growth hormone and cortisol. Catecholamine responses correlated with increased perfusion in pulvinar and medial thalamus, ACC and pituitary, while growth hormone and cortisol responses showed no correlation with thalamic activation but did show additional correlation with the hypothalamus and ventral striatum bilaterally. These data demonstrate complex dynamic responses to the stressor of hypoglycemia that would be expected to drive physiological and behavioural changes to remedy the state. Further, these data show that sustained stress and its aftermath engage distinct sets of brain regions, providing a neural substrate for adaptive or 'allostasic' responses to stressors.

Nicotine dependence is characterized by disordered reward processing in a network driving motivation.

BACKGROUND: Drug addiction is characterized by an unhealthy priority for drug consumption with a compulsive, uncontrolled drug-intake pattern due to a disordered motivational system. However, only some individuals become addicted, whereas others maintain regular but controlled drug use. Whether the transition occurs might depend on how individuals process drug relative to nondrug reward. METHODS: We applied functional magnetic resonance imaging to measure mesocorticolimbic activity to stimuli predicting monetary or cigarette reward, together with behavioral assessment of subsequent motivation to obtain the respective reward on a trial-by-trial basis, in 21 nicotine-dependent and 21 nondependent, occasional smokers. RESULTS: Occasional smokers showed increased reactivity of the mesocorticolimbic system to stimuli predicting monetary reward relative to cigarette reward and subsequently spent more effort to obtain money. In the group of dependent smokers, we found equivalent anticipatory activity and subsequent instrumental response rates for both reward types. Additionally, anticipatory mesocorticolimbic activation predicted subsequent motivation to obtain reward. CONCLUSIONS: This imbalance in the incentive salience of drug relative to nondrug reward-predicting cues, in a network that drives motivation to obtain reward, could represent a central mechanism of drug addiction.

Hemisphere-specific episodic memory networks in the human brain: a correlation study between intracarotid amobarbital test and [(18)F]FDG-PET.

The purpose of the present study was to explore the brain regions involved in human episodic memory by correlating unilateral memory performance estimated by the intracarotid amobarbital test (IAT) and interictal cerebral metabolism measured by [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET). Using this method, regional alterations of cerebral metabolism associated with epilepsy pathophysiology are used to predict hemisphere-specific episodic memory function, hence, investigate the differential distribution of memory in each hemisphere. Sixty-two patients with unilateral temporal lobe epilepsy (35 left and 27 right) were studied using [(18)F]FDG-PET with complementary voxel-based statistical parametric mapping (SPM) and region-of-interest (ROI) methods of analysis. Positive regression was analyzed in SPM with a series of different thresholds (p = .001, .01 or .05) with a correction to 100 voxels. IAT memory performance in which left hemisphere was tested by right-sided injection of amobarbital correlated with [(18)F]FDG uptake in left lateral and medial temporal regions, and in the left ventrolateral frontal cortex. Right IAT memory performance correlated with [(18)F]FDG uptake in the right inferior parietal lobule, right dorsolateral frontal cortex, right precentral gyrus, and caudal portion of the right anterior cingulate cortex. ROI analysis corroborated these results. Analyses carried out separately in patients with left (n = 50) and nonleft (n = 12) dominance for language showed that in the nonleft dominant group, right IAT scores correlated with right fronto-temporal regions, whereas left total memory scores correlated with left lateral and medial temporal regions. The findings indicate that (i) episodic memory is subserved by more widespread cortical regions beyond the core mesiotemporal lobe memory structures; (ii) there are different networks functional in the two hemispheres; and (iii) areas involved in memory may be different between patients with left and nonleft dominance for language, particularly in the right hemisphere.

Attenuation of amydgala and frontal cortical responses to low blood glucose concentration in asymptomatic hypoglycemia in type 1 diabetes: a new player in hypoglycemia unawareness?

OBJECTIVE: Loss of ability to recognize hypoglycemia (hypoglycemia unawareness) increases risk of severe hypoglycemia threefold in insulin-treated diabetes. We set out to investigate the cerebral correlates of unawareness in type 1 patients. RESEARCH DESIGN AND METHODS: Regional changes in brain glucose kinetics were measured using [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), in 13 men with type 1 diabetes--6 with hypoglycemia awareness and 7 with hypoglycemia unawareness--at euglycemia (5 mmol/l) and hypoglycemia (2.6 mmol/l), in random order. RESULTS: Epinephrine responses to hypoglycemia were reduced in hypoglycemia unawareness (P < 0.0003), as were symptoms. Statistical parametric mapping (SPM) of FDG uptake using SPM2 at a statistical threshold of P < 0.005 showed increased FDG uptake in left amygdala in hypoglycemia awareness, but not in hypoglycemia unawareness (region of interest analysis -0.40 +/- 1.03 vs. 3.66 +/- 0.42, respectively; P = 0.007), and robust increase in bilateral ventral striatum during hypoglycemia (region of interest analysis hypoglycemia unawareness 3.52 +/- 1.02 vs. awareness 6.1 +/- 0.53; P = 0.054). Further analysis at the statistical threshold of P < 0.01 showed bilateral attenuated activation of brain stem regions and less deactivation in lateral orbitofrontal cortex in hypoglycemia unawareness. CONCLUSIONS: Ventral striatal, amygdala, brain stem, and orbitofrontal responses to hypoglycemia indicate engagement of appetitive motivational networks, associated with integrated behavioral responses to hypoglycemia. Reduced responses in these networks in hypoglycemia unawareness, particularly failure of amygdala and orbifrontal cortex responses, suggest habituation of higher behavioral responses to hypoglycemia as a basis for unawareness. New approaches may be needed to restore awareness effectively in practice.

Comparison of buprenorphine and methadone in the treatment of opiate withdrawal: possible advantages of buprenorphine for the treatment of opiate-benzodiazepine codependent patients?

The study is a preliminary investigation to compare the effectiveness of buprenorphine and methadone as opiate detoxification treatments. The sample comprised 123 drug misusers who were dependent upon opiates only or who were codependent upon opiates and benzodiazepines. Drug misusers dependent upon methadone doses up to 70 mg were eligible for the study. Detoxification took place within a specialist inpatient drug-dependence unit. Withdrawal symptom severity was assessed on a daily basis by means of the Short Opiate Withdrawal Scale. Outcome was assessed for reductions in severity of withdrawal symptoms, treatment retention, and treatment completion. Buprenorphine detoxification was associated with less severe opiate withdrawal symptoms than methadone. Opiate/Benzodiazepine codependent patients reported less severe withdrawal symptoms during treatment with buprenorphine than with methadone and were also more likely to complete detoxification when treated with buprenorphine.

Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome?

The rising prevalence of obesity and type 2 diabetes is a global challenge. A possible mechanism linking insulin resistance and weight gain would be attenuation of insulin-evoked responses in brain areas relevant to eating in systemic insulin resistance. We measured brain glucose metabolism, using [(18)F]fluorodeoxyglucose positron emission tomography, in seven insulin-sensitive (homeostasis model assessment of insulin resistance [HOMA-IR] = 1.3) and seven insulin-resistant (HOMA-IR = 6.3) men, during suppression of endogenous insulin by somatostatin, with and without an insulin infusion that elevated insulin to 24.6 +/- 5.2 and 23.2 +/- 5.8 mU/l (P = 0.76), concentrations similar to fasting levels of the resistant subjects and approximately threefold above those of the insulin-sensitive subjects. Insulin-evoked change in global cerebral metabolic rate for glucose was reduced in insulin resistance (+7 vs. +17.4%, P = 0.033). Insulin was associated with increased metabolism in ventral striatum and prefrontal cortex and with decreased metabolism in right amygdala/hippocampus and cerebellar vermis (P < 0.001), relative to global brain. Insulin's effect was less in ventral striatum and prefrontal cortex in the insulin-resistant subjects (mean +/- SD for right ventral striatum 3.2 +/- 3.9 vs. 7.7 +/- 1.7, P = 0.017). We conclude that brain insulin resistance exists in peripheral insulin resistance, especially in regions subserving appetite and reward. Diminishing the link be-tween control of food intake and energy balance may contribute to development of obesity in insulin resistance.

Correlations of regional cerebral metabolism with memory performance and executive function in patients with herpes encephalitis or frontal lobe lesions.

Cerebral [18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) data from patients suffering amnesia following herpes encephalitis (n=7) or frontal lobe pathology (n=14) were compared with data from age-matched nonamnesic subjects (n=10). All subjects received structural MRI, resting 18FDG-PET scans, and neuropsychological evaluation. PET data were analyzed using complementary statistical parametric mapping and region-of-interest methods. Differential patterns of hypometabolism were found in patients relative to healthy controls. Factor analysis of the neuropsychological data revealed that memory performance was associated with retrosplenial and medial temporal metabolism, and executive function was associated with dorsolateral frontal metabolism. The association between memory performance and retrosplenial metabolism remained statistically significant after accounting for measures of cerebral atrophy using MRI. The significance of the retrosplenium as a major relay station between the thalamus and the medial temporal and frontal lobes--sensitive to changes in either--is discussed in the light of the findings.

The rise of buprenorphine prescribing in England: analysis of NHS regional data, 2001-03.

AIMS: Since its launch in the prescribing market in 1999 for the treatment of opiate dependence, buprenorphine has rapidly become established as an alternative to methadone treatment in the United Kingdom. In the absence of evidence of its clinical superiority over methadone, and given its high relative cost, we sought to examine the impact of buprenorphine availability on opiate treatment services in England. METHODS: Quarterly buprenorphine and methadone community prescription figures were obtained for 28 Strategic Health Authorities (SHAs) in England, for the 2-year period September 2001 to September 2003. Rates of buprenorphine prescribing (as proportion of all opiate prescriptions) were examined over time by number of prescriptions and net ingredient cost. RESULTS: Buprenorphine prescription rates increased disproportionately to methadone in all 28 SHAs. By the end of 2003 the number of buprenorphine prescriptions had increased to 23% of all opiate prescriptions, but accounted for 45% of opiate prescription costs in England. Buprenorphine prescribing rates varied substantially across different regions. CONCLUSIONS: Buprenorphine prescribing has increased dramatically and represents a disproportionately large fraction of community opiate prescribing costs. The marked regional variation suggests the need for further research and the development of national guidelines to support rational prescribing and equitable access to treatment.

Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.

BACKGROUND: Depression is associated with interpersonal difficulties related to abnormalities in affective facial processing. OBJECTIVES: To map brain systems activated by sad facial affect processing in patients with depression and to identify brain functional correlates of antidepressant treatment and symptomatic response. DESIGN: Two groups underwent scanning twice using functional magnetic resonance imaging (fMRI) during an 8-week period. The event-related fMRI paradigm entailed incidental affect recognition of facial stimuli morphed to express discriminable intensities of sadness. SETTING: Participants were recruited by advertisement from the local population; depressed subjects were treated as outpatients. PATIENTS AND OTHER PARTICIPANTS: We matched 19 medication-free, acutely symptomatic patients satisfying DSM-IV criteria for unipolar major depressive disorder by age, sex, and IQ with 19 healthy volunteers. Intervention After the baseline assessment, patients received fluoxetine hydrochloride, 20 mg/d, for 8 weeks. MAIN OUTCOME MEASURES: Average activation (capacity) and differential response to variable affective intensity (dynamic range) were estimated in each fMRI time series. We used analysis of variance to identify brain regions that demonstrated a main effect of group (depressed vs healthy subjects) and a group x time interaction (attributable to antidepressant treatment). Change in brain activation associated with reduction of depressive symptoms in the patient group was identified by means of regression analysis. Permutation tests were used for inference. RESULTS: Over time, depressed subjects showed reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex. Symptomatic improvement was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum. CONCLUSIONS: Antidepressant treatment reduces left limbic, subcortical, and neocortical capacity for activation in depressed subjects and increases the dynamic range of the left prefrontal cortex. Changes in anterior cingulate function associated with symptomatic improvement indicate that fMRI may be a useful surrogate marker of antidepressant treatment response.

FDG-PET findings in the Wernicke-Korsakoff syndrome.

This study reports FDG-PET findings in Wernicke-Korsakoff patients. Twelve patients suffering amnesia arising from the Korsakoff syndrome were compared with 10 control subjects without alcohol-related disability. Subjects received [18F]-fluorodeoxyglucose (FDG-PET) imaging as well as neuropsychological assessment and high-resolution MR imaging with volumetric analysis. Volumetric MRI analysis had revealed thalamic and mamillary body atrophy in the patient group as well as frontal lobe atrophy with relative sparing of medial temporal lobe structures. Differences in regional metabolism were identified using complementary region of interest (ROI) and statistical parametric mapping (SPM) approaches employing either absolute methods or a reference region approach to increase statistical power. In general, we found relative hypermetabolism in white matter and hypometabolism in subcortical grey matter in Korsakoff patients. When FDG uptake ratios were examined with occipital lobe metabolism as covariate reference region, Korsakoff patients showed widespread bilateral white matter hypermetabolism on both SPM and ROI analysis. When white matter metabolism was the reference covariate; Korsakoff patients showed relative hypometabolism in the diencephalic grey matter, consistent with their known underlying neuropathology, and medial temporal and retrosplenial hypometabolism, interpreted as secondary metabolic effects within the diencephalic-limbic memory circuits. There was also evidence of a variable degree of more general frontotemporal neocortical hypometabolism on some, but not all, analyses.