George Savulich

Today, there is continued, and in some cases growing, availability of not only psychoactive substances, including treatments for mental health disorders such as cognitive enhancers, which can enhance or restore brain function, but also ‘recreational’ drugs such as novel psychoactive substances (NPS). The use of psychoactive drugs has both benefits...

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependenc...

The cognitive biases associated with affective disorders have been well documented and provide extensive evidence of selective abnormalities in information processing of pathology congruent information. However in psychosis, research to date has been narrower. There is ample evidence of a ‘jumping to conclusions’ reasoning bias but relatively littl...

Convergent results from animal and human studies suggest that reducing serotonin neurotransmission promotes impulsive behaviour. Here, serotonin depletion was induced by the dietary tryptophan depletion procedure (TD) in healthy volunteers to examine the role of serotonin in impulsive action and impulsive choice. We used a novel translational analo...

Cognitive enhancement can benefit the individual and society, but also has associated risks and ethical concerns. Cognitive-enhancing drugs are used in the treatment of neuropsychiatric disorders. Nonpharmacological strategies are also emerging, which have the potential to improve motivational deficits associated with neuropsychiatric symptoms and...

The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g., microglia), peripheral innate immune cells (e.g., blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate...

Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportionate to symptom severity and rate of progression. However, evidence for corresponding...

Background/objective: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a patho...

Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). There is a pressing need for scalable and mechanistically relevant blood markers of inflammation to facilitate drug development and experimental medicine. We assessed inflammatory profiles of...

Background Neuroinflammation is an important pathogenic mechanism in frontotemporal dementia (FTD) and related disorders. Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, and as proportionate to symptom severity and rate of progression. However, data on inflammation blood markers of inflammation and th...

Background There is growing evidence for early and extensive synaptic loss in frontotemporal lobar degeneration syndromes from in vivo and post‐mortem studies. We proposed that synaptic loss would affect behaviour, in relation to changes in functional connectivity. Method We recruited 29 participants with progressive supranuclear palsy, 16 partici...

Background The epigenetic mechanism of DNA methylation has been implicated in the pathophysiology of neurodegenerative disorders such as Lewy body dementia (LBD). DNA methylation profiling may help to identify novel treatment targets and early disease markers. We hypothesized that DNA methylation alterations are detectable in blood due the influenc...

Background Novel, validated imaging biomarkers for assessing disease severity and progression in dementia with Lewy Bodies (DLB) are needed as standard neuroimaging changes such as atrophy are not pronounced. Both multi‐modal MR and PET offer opportunities, for example cortical microstructure and dendritic imaging can be assessed using advanced MR...

Background Brain inflammation is an important pathogenic mechanism in many dementias, occurring early in the disease and being predictive of clinical decline. However, data on blood markers of inflammation across different dementia subtypes are limited. Here we assess inflammatory patterns of serum cytokines from patients with Alzheimer’s disease (...

Background Neuroinflammation is an important pathogenic mechanism in frontotemporal dementia (FTD) and related disorders. Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, and as proportionate to symptom severity and rate of progression. However, data on inflammation blood markers of inflammation and th...

There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participant...

Background: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. Objective: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degener...

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteer...

Post‐mortem clinical studies and animal models described severe synaptic loss as an early feature of neurodegenerative disease, including frontotemporal dementia. Recently, PET radiotracers that bind to synaptic vesicle glycoprotein 2A have been developed and proven to enable in vivo quantification of synaptic loss in people with neurodegenerative...

Objective: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in...

The role of the adenosine neurochemical system in human cognition is under-studied, despite such receptors being distributed throughout the brain. The aim of this study was to shed light on the role of the adenosine A2A receptors in human cognition using single-dose istradefylline. Twenty healthy male participants, aged 19-49, received 20 mg istrad...

Synaptic loss is prominent in several human neurodegenerative diseases. We tested the hypothesis that synaptic density is reduced by the primary tauopathies of progressive supranuclear palsy (PSP) and cor- ticobasal syndrome (CBS). Thirty-three participants (10 CBS, 10 PSP, and thirteen age-/sex-/education- matched controls) underwent clinical and...

Chronic drug use negatively impacts ageing, resulting in diminished health and quality of life. However, little is known about biomarkers of abnormal ageing in stimulant drug users. Using morphometric similarity network mapping, a novel approach to structural connectomics, we first mapped cross-sectional morphometric similarity trajectories of agei...

Synaptic loss is an early feature of neurodegenerative disease models, and is often severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) imaging with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synapses in vivo. This study used [11C]UCB-J PET in people...

Objectives This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Methods Plasma phosphorylated tau at threonine-181 (p-tau181), amyloid beta (Αβ)42, Aβ40, ne...

Background Neuroinflammation is implicated in the pathogenesis of neurodegenerative disorders including dementia with Lewy bodies (DLB), but its relationship with disease progression, including cognitive decline, is less well understood. We investigated the predictive value of microglial activation, assessed in vivo using positron emission tomograp...

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods:...

While [18F]-AV-1451 was developed as a positron emission tomography (PET) radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of “off-target” [18F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [18F]-AV-1451 binding was measured in the substantia nig...

The relationship between in vivo synaptic density and molecular pathology in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology...

Objective Adolescence into young adulthood represents a sensitive period in which brain development significantly diverges by sex. Regular cannabis use by young people is associated with neuropsychological vulnerabilities, but the potential impact of sex on these relationships is unclear. Method In a cross-sectional study, we examined sex differen...

Synaptic loss is an early and clinically relevant feature of many neurodegenera-tive diseases. Here we assess three adults at risk of frontotemporal dementia from C9orf72 mutation, using [ 11 C]UCB-J PET to quantify synaptic density in comparison with 19 healthy controls and one symptomatic patient with beha-vioural variant frontotemporal dementia....

Novel psychoactive substances (NPS) are popular “club/party” drugs that first attracted attention in the UK in 2009 and remained legal until the 2016 Psychoactive Substances Act criminalized their distribution. Unlike “traditional” illicit drugs, very little is known about the influence of their analogs on neuropsychological functioning. We charact...

The relationship between in vivo synaptic density and tau burden in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology, in the p...

Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborisation are characteristic and can be quantified in vivo, with [¹¹C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of progressive s...

Introduction: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission t...

Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborisation are characteristic and can be quantified i n vivo , with [ ¹¹ C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of Progressi...

Objective Dementia with Lewy bodies (DLB) is a common cause of dementia, but atrophy is mild compared to Alzheimer’s disease. We propose that DLB is associated instead with severe synaptic loss, and we test this hypothesis in vivo using positron emission tomography (PET) imaging of ¹¹C-UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a ve...

Objectives: Dementia with Lewy bodies (DLB) is a major cause of degenerative dementia, yet the diagnosis is often missed or mistaken for Alzheimer's disease (AD). We assessed whether the revised Addenbrooke's Cognitive Examination (ACE-R), a brief test for dementia, differentiates DLB from AD. Methods: We first compared baseline ACE-R performance...

Alzheimer’s disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, we evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB. Tau deposition was quantified using [¹⁸F]-AV1451 positron emission tomography in people with DLB (n = 11) and AD (n =...

Background Synaptic loss is a prominent and early feature of many neurodegenerative diseases. Objectives We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson’s syndrome) and amyloid‐negative corticobasal syndrome (CBS). Methods Forty‐four participants (15 CBS, 14...

The sixth edition of the foundational reference on cognitive neuroscience, with entirely new material that covers the latest research, experimental approaches, and measurement methodologies. Each edition of this classic reference has proved to be a benchmark in the developing field of cognitive neuroscience. The sixth edition of The Cognitive Neuro...

Background and objectives Cognitive models of psychosis implicate interpretation biases as one of the mechanisms involved in the formation and maintenance of symptoms. First we measured the strength of association between interpretation biases and psychosis-relevant traits. Next we manipulated these biases and quantified the effects of doing so on...

Background The peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). We assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition. Methods 145 participants underwent 3T brain MRI and cognitive ass...

Background Goal-directed control guides optimal decision-making and it is an important cognitive faculty that protects against developing habits. Previous studies have found some evidence of goal-directed deficits when healthy individuals are stressed, and in psychiatric conditions characterised by compulsive behaviours and anxiety. Here, we tested...

Background Synaptic loss is a prominent and early feature of many neurodegenerative diseases. Objectives We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP-Richardson’s syndrome) and amyloid-negative corticobasal syndrome (CBS). Methods Forty four participants (15 CBS, 14 PS...

Acute anxiety impacts cognitive performance. Inhalation of air enriched with carbon dioxide (CO2) in healthy humans provides a novel experimental model of generalised anxiety, but has not previously been used to assess cognition. We used inhalation of 7.5% CO2 to induce acute anxiety and autonomic arousal in healthy volunteers during neuropsycholog...

Rationale Drug addiction has been suggested to develop through drug-induced changes in learning and memory processes. Whilst the initiation of drug use is typically goal-directed and hedonically motivated, over time, drug-taking may develop into a stimulus-driven habit, characterised by persistent use of the drug irrespective of the consequences. C...

Alzheimer's disease and vascular dementia are associated with overlapping symptoms of anxiety and depression. More accurate discrimination between emerging neuropsychiatric and cognitive symptoms would better assist illness detection. The potential for protection against cognitive decline and dementia following early identification and intervention...

Compulsivity is associated with failures in goal-directed control, an important cognitive faculty that protects against developing habits. But might this effect be explained by co-occurring anxiety? Previous studies have found goal-directed deficits in other anxiety disorders, and to some extent when healthy individuals are stressed, suggesting thi...

Work and study increasingly rely on the use of technologies requiring individuals to switch attention rapidly between emails, texts and tasks. This has led to healthy people having problems of attention and concentration and difficulties getting into the “flow,” which impedes goal attainment and task completion. Possibly related to this, there is a...

Impaired social cognitive processes are putative psychological mechanisms implicated in the formation and maintenance of paranoid beliefs. Paranoia denotes unfounded fears about the hostile intentions of others and is prevalent in a significant proportion of the general population. We investigated social cognition in healthy participants selectivel...

Objectives The pathological bases for the cognitive and neuropsychiatric symptoms in normal pressure hydrocephalus (NPH) have not been elucidated. However, the symptoms may indicate dysfunction of subcortical regions. Previously, volume reductions of subcortical deep grey matter (SDGM) structures have been observed in NPH patients. The present stud...

Schizophrenia is a complex mental disorder with genetic and environmental components. Obstetric complications (OCs) are one of the most common environmental risk factors described. However, despite being different in timing and outcome, OCs are usually described as a homogeneous entity. In the present study, we evaluate the presence of different pa...

There is nothing more important than good brain health and wellbeing throughout our lives. Yet, while many people are concerned with their physical health and utilise wearable technology and mobile devices to monitor their exercise, steps, heart rate, and so forth, we are not yet using technology to enhance our brain health and wellbeing. In this c...

Traumatic brain injury (TBI) occurs when an external force to the head alters brain function. TBI is one of the leading causes of death and disability worldwide, with motor vehicle accidents and falls accounting for most hospital admissions. Each year, there are 50-60 million new cases of TBI, which disproportionately affect young men in low- to mi...

Personalised treatments for traumatic brain injury: cognitive, emotional and motivational targets - George Savulich, David K. Menon, Emmanuel A. Stamatakis, John D. Pickard, Barbara J. Sahakian

Background Cognitive dysfunction is as a hallmark feature of schizophrenia. Antipsychotic medication is effective for treating the positive symptoms of psychosis, but their potential for therapeutic effects on cognition continues to divide researchers. Improvements in clinical symptoms can occur independently of cognitive functioning, whereby typic...

Interpretation biases matching the concerns of a psychopathology have been implicated in the etiology of psychological disorders, but little research has investigated their presence in psychosis. Here we investigated negative, and specifically paranoia-relevant, interpretation biases in patients with schizophrenia, with (n = 32) and without (n = 29...

BACKGROUND: Cognitive training is effective in patients with mild cognitive impairment but does not typically address the motivational deficits associated with older populations with memory difficulties. METHODS: We conducted a randomized controlled trial of cognitive training using a novel memory game on an iPad in 42 patients with a diagnosis of...

Background: Cognitive training is effective in patients with mild cognitive impairment but does not typically address the motivational deficits associated with older populations with memory difficulties. Methods: We conducted a randomized controlled trial of cognitive training using a novel memory game on an iPad in 42 patients with a diagnosis of...

Background: We investigated whether negative symptoms, such as poor motivation or anhedonia, were associated with higher body mass index (BMI) in stable patients with schizophrenia chronically treated with antipsychotic medication. Methods: 62 olanzapine- or clozapine-treated patients with illness duration of at least four years were selected fr...

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependenc...

Objective: We conducted a systematic review of the literature and used meta-analytic techniques to evaluate the impact of shunt surgery on neuropsychological performance in patients with normal pressure hydrocephalus (NPH). Methods: Twenty-three studies with 1,059 patients were identified for review using PubMed, Web of Science, Google scholar and...

Objective A functional polymorphism of the brain-derived neurotrophic factor gene (BDNF) Val66Met has been associated with cognitive function and symptom severity in patients with schizophrenia. It has been suggested that the Val66Met polymorphism has a role as a modulator in a range of clinical features of the illness, including symptoms severity,...

Background: The impact of psychotropic drug choice upon admissions for schizophrenia is not well understood. Aims: To examine the association between antipsychotic/antidepressant use and time in hospital for patients with schizophrenia. Methods: We conducted an observational study, using 8 years' admission records and electronically generated...