Can we really ‘read’ art to see the changing brain? A review and empirical assessment of clinical case reports and published artworks for systematic evidence of quality and style changes linked to damage or neurodegenerative disease

The past three decades have seen multiple reports of people with neurodegenerative disorders, or other forms of changes in their brains, who also show putative changes in how they approach and produce visual art. Authors argue that these cases may provide a unique body of evidence, so-called ‘artistic signatures’ of neurodegenerative diseases, that might be used to understand disorders, provide diagnoses, be employed in treatment, create patterns of testable hypotheses for causative study, and also provide unique insight into the neurobiological linkages between the mind, brain, body, and the human penchant for art-making itself. However—before we can begin to meaningfully build from such emerging findings, much less formulate applications—not only is such evidence currently quite disparate and in need of systematic review, almost all case reports and artwork ratings are entirely subjective, based on authors' personal observations or a sparse collection of methods that may not best fit underlying research aims. This leads to the very real question of whether we might actually find patterns of systematic change if fit to a rigorous review—Can we really ‘read’ art to illuminate possible changes in the brain? How might we best approach this topic in future neuroscientific, clinical, and art-related research? This paper presents a review of this field and answer to these questions. We consider the current case reports for seven main disorders—Alzheimer's and Parkinson's disease, frontotemporal and Lewy body dementia, corticobasal degeneration, aphasia, as well as stroke—consolidating arguments for factors and changes related to art-making and critiquing past methods. Taking the published artworks from these papers, we then conduct our own assessment, employing computerized and human-rater-based approaches, which we argue represent best practice to identify stylistic or creativity/quality changes. We suggest, indeed, some evidence for systematic patterns in art-making for specific disorders and also find that case authors showed rather high agreement with our own assessments. More important, through opening this topic and past evidence to a systematic review, we hope to open a discussion and provide a theoretical and empirical foundation for future application and research on the intersection of art-making and the neurotypical, the changed, and the artistic brain.     

Imaging treatment effects in Alzheimer's disease

Alzheimer's disease (AD) is the commonest form of degenerative dementia and is characterised by progressive cognitive decline. Despite extensive research, the cause of AD is unknown and there is no cure at present. Of the deficits found in AD, that affecting the cholinergic neurotransmitter system is the best established and the only one translated into symptomatic treatment. Cholinergic enhancement with cholinesterase inhibitor (ChEI) drugs has been achieved and their efficacy and safety ascertained by conventional clinical trials. The mechanism of action of these drugs, however, is not well understood. Imaging with SPECT, PET, MRI and fMRI after treatment has clarified what happens in the brains of those AD patients treated with ChEI drugs. Studies with these techniques have identified increases in brain blood flow and glucose metabolism, restoration of nicotinic receptor function and re-establishment of task-related regional brain activation in response to cognitive stimulation after treatment. Structural MRI studies have explained, to some degree, why only a proportion of patients benefits from ChEI treatment and there is some evidence that some ChEI drugs might be neuroprotective. There are, however, many unsolved problems. Timing of treatment intervention to obtain maximum response and the determinants of treatment response are mostly unknown. It is also unclear whether administration of treatment in those patients who have no potential for response accelerates disease progression. These issues cannot be solved by conventional clinical trials. Pharmacoimaging studies could assist the development and refinement of drugs to treat those diseases, such as AD, which affect the central nervous system.     

In vivo MRI reveals the dynamics of pathological changes in the brains of cathepsin D-deficient mice and correlates changes in manganese-enhanced MRI with microglial activation

Cathepsin D (CTSD; EC 3.4.23.5) is essential for normal development and/or maintenance of neurons in the central nervous system: its deficiency causes a devastating neurological disorder with severely shortened life span in man, sheep and mouse. Neuropathologically, the CTSD deficiencies are characterized by selective neuronal degeneration, gliosis and accumulation of autofluorescent proteinaceous storage material in neurons. Our aim was to study the dynamics behind the pathological alterations occurring in the brains of CTSD-deficient (CTSD-/-) mice by using in vivo magnetic resonance imaging (MRI) and histology. In order to do this, we measured T(2) signal intensity (SI), apparent diffusion coefficient, area and volume of multiple brain structures from MR images acquired using T(2)-, T(1)- and diffusion-weighted sequences at three time points during disease progression. MRI revealed no differences in the brains between CTSD-/- and control mice at postnatal day 15+/-1 (P15+/-1), representing an initial stage of the disease. In the intermediate stage of the disease, P19(+/-1), SI alterations in the thalami of the affected mice became evident in both T(1)- and T(2)-weighted images. The terminal stage of the disease, P25, was characterized by marked alterations in the T(2) SI, apparent diffusion coefficient and volume of multiple brain structures in CTSD-/- mice. In addition, manganese enhanced high-resolution T(1)-weighted 3D sequences (MEMRI) and histological stainings revealed that the hyperintense signal areas in MEMRI matched perfectly with areas of microglial activation in the brains of CTSD-/- mice at the terminal disease stage. In conclusion, the SI alterations in the thalami of CTSD-/- mice preceded other changes, and the degenerative process was greatly enhanced at the age P19(+/-1), leading to severely reduced brain volume in just 6 days.     

Quantitative estimation of brain white matter abnormalities in elderly subjects using magnetic resonance imaging

Twenty-five elderly subjects were examined with brain magnetic resonance imaging (MRI). The subjects were divided into two groups: those with Mini-Mental State Examination (MMSE) scores above 25, and those subjects with MMSE scores between 18 and 24. The degree of white matter abnormalities (WMA) (expressed as relative volumes) as well as the presence of cerebrovascular risk factors were evaluated in the two groups. We found that a) subjects with low MMSE scores had significantly larger relative volumes of WMA than the subjects with higher scores, b) a significant correlation (r_s = 0.53, p < 0.009) between MMSE scores and the relative volume of WMA was also established, and c) a weak significant correlation (r_s = −0.51, p < 0.05) between arterial blood pressure and WMA was found in the subjects with high MMSE scores. Besides these findings no other correlations between the presence of cerebrovascular risk factors and WMA were found in any of the groups.     

Fetal and Fetal Brain Volume Estimation in the Third Trimester of Human Pregnancy Using Gradient Echo MR Imaging

The Cavalieri method has been applied in combination with gradient echo magnetic resonance imaging (MRI) to investigate the increase in the volume of the fetus and fetal brain in the third trimester of pregnancy. Eighteen women with singleton pregnancies were recruited. Birthweights for the fetuses all lay within the 10–90^th centile based on Liverpool data. A regression analysis, weighted using values derived from the coefficient of error predicted for each volume estimate, revealed a linear relationship between total fetal volume and gestational age (R² = 0.88) and between fetal brain volume and gestational age (R² = 0.71) during the third trimester. Fetal volume increased by an average of 25.2 ml per day and fetal brain volume increased by an average of 2.3 mL per day. Fetal brain volume is on average a constant proportion (10%, SD = 2%) of total fetal volume throughout the third trimester.Volume data were also obtained for eight fetuses diagnosed as abnormal. The volume of seven of the eight abnormal fetuses fell outside the 95% confidence interval established from the data obtained for the normal fetuses. However, for only three of the eight abnormal fetuses did brain volume fall outside the 95% confidence interval established for normals, possibly due to brain sparing occurring in asymmetrical growth retardation. The volume of the fetus and fetal brain may be readily estimated directly using the Cavalieri method and magnetic resonance imaging. These parameters represent potentially useful information for assessing fetal growth.     

A novel approach to segmentation and measurement of medical image using level set methods

The study proposes a novel approach for segmentation and visualization plus value-added surface area and volume measurements for brain medical image analysis. The proposed method contains edge detection and Bayesian based level set segmentation, surface and volume rendering, and surface area and volume measurements for 3D objects of interest (i.e., brain tumor, brain tissue, or whole brain).Two extensions based on edge detection and Bayesian level set are first used to segment 3D objects. Ray casting and a modified marching cubes algorithm are then adopted to facilitate volume and surface visualization of medical-image dataset. To provide physicians with more useful information for diagnosis, the surface area and volume of an examined 3D object are calculated by the techniques of linear algebra and surface integration. Experiment results are finally reported in terms of 3D object extraction, surface and volume rendering, and surface area and volume measurements for medical image analysis.     

Generalised cerebral atrophy following temporal lobectomy for intractable epilepsy associated with mesial temporal sclerosis

Studies of post-operative imaging data have mainly concentrated on brain atrophy following radiotherapy and/or chemotherapy. We have investigated the effect of conventional surgery on the unresected brain tissue based on the comparison of magnetic resonance images acquired pre- and post-operatively in 13 subjects with a history of mesio-temporal epilepsy. The pre- and post-operative scans were co-registered prior to volumetric analysis. The total brain volume (TBV) was calculated by semi-automated segmentation, and the total volume loss was the difference between the post-operative and pre-operative TBV. The total volume of resection was determined by manual delineation in the post-operative scan. The atrophy volume in the post-operative scan was calculated as the difference between the total volume loss and the resection volume. In 6 cases, there was generalised cerebral atrophy of the order 4-5% of the total brain volume. In addition to the automated volumetric technique, the images were assessed by two expert neuroradiologists. There was complete correspondence between their assessment and the automated technique. The causes and significance of this phenomenon are unknown but it requires further investigation as it may be related to seizure control and neuropsychological changes following epilepsy surgery.     

Anatomical Increased/Decreased Changes in the Brain Area Following Individuals with Chronic Traumatic Complete Thoracic Spinal Cord Injury

Objectives: This study aimed to investigate anatomical changes in the brain following chronic complete traumatic thoracic spinal cord injury (ThSCI) using voxel-based morphometry (VBM). That is, it attempted to examine dynamic physical change following thoracic injury and the presence or absence of regions with decreased and increased changes in whole brain volume associated with change in the manner of how activities of daily living are performed. Methods: Twelve individuals with chronic traumatic complete ThSCI (age; 21-63 years, American Spinal Injury Association Impairment Scale; grade C-D) participated in this study. VBM was used to investigate the regions with increased volume and decreased volume in the brain in comparison with healthy control individuals. Results: Decreases in volume were noted in areas associated with motor and somatosensory functions, including the right paracentral lobule (PCL)―the primary motor sensory area for lower limbs, left dorsal premotor cortex, and left superior parietal lobule (SPL). Furthermore, increased gray matter volume was noted in the primary sensorimotor area for fingers and arms, as well as in higher sensory areas. Conclusions: Following SCI both regions with increased volume and regions with decreased volume were present in the brain in accordance with changes in physical function. Using longitudinal observation, anatomical changes in the brain may be used to determine the rehabilitation effect by comparing present cases with cases with cervical SCI or cases with incomplete palsy.     

Diffusion tensor MRI to investigate dementias: a brief review

Diffusion tensor magnetic resonance imaging (DT-MRI) is a powerful quantitative technique with the ability to detect in vivo microscopic characteristics and abnormalities of brain tissue. It has been successfully applied to a number of neurological conditions, such as stroke, multiple sclerosis and brain tumors, providing information otherwise inaccessible on the pathological substrates. DT-MRI has also been used to study patients with cognitive decline, mainly those with Alzheimer's disease. Several image-analysis approaches have been employed, including region of interest, histogram, voxel-based analyses and DT-MRI-based tractography. Specific patterns of spatial distribution of tissue damage and correlations with neuropsychological measures have been reported. This review focuses on the use of DT-MRI to investigate dementias. The main clinical results and the different methods of image analysis will be overviewed and discussed.     

MR image-based measurement of rates of change in volumes of brain structures. Part I: method and validation

A detailed analysis procedure is described for evaluating rates of volumetric change in brain structures based on structural magnetic resonance (MR) images. In this procedure, a series of image processing tools have been employed to address the problems encountered in measuring rates of change based on structural MR images. These tools include an algorithm for intensity non-uniformity correction, a robust algorithm for three-dimensional image registration with sub-voxel precision and an algorithm for brain tissue segmentation. However, a unique feature in the procedure is the use of a fractional volume model that has been developed to provide a quantitative measure for the partial volume effect. With this model, the fractional constituent tissue volumes are evaluated for voxels at the tissue boundary that manifest partial volume effect, thus allowing tissue boundaries be defined at a sub-voxel level and in an automated fashion. Validation studies are presented on key algorithms including segmentation and registration. An overall assessment of the method is provided through the evaluation of the rates of brain atrophy in a group of normal elderly subjects for which the rate of brain atrophy due to normal aging is predictably small. An application of the method is given in Part II where the rates of brain atrophy in various brain regions are studied in relation to normal aging and Alzheimer's disease.     

3D phase encoding 1H spectroscopic imaging of human brain.

A three-dimensional (3D) phase-encoding proton spectroscopic imaging method is presented for a whole body MRI/MRS system. Metabolite images at 2 T of choline, creatine, and N-acetyl aspartate (NAA) of normal brain were obtained with a spatial resolution of 1.5 cc. With PRESS volume preselection and outer volume suppression pulses, brain regions close to the skull could be studied without significant contamination by lipid and water signals.     

A technique for single-channel MR brain tissue segmentation: Application to a pediatric sample

A segmentation method is presented for gray matter, white matter, and cerebrospinal fluid (CSF) in thinsliced single-channel brain magnetic resonance (MR) scans. The method is based on probabilistic modeling of intensity distributions and on a region growing technique. Interrater and intrarater reliabilities for the method were high, and comparison with phantom studies and hand-traced results from an experienced rater indicated good validity. The method was designed to account for spatially dependent image intensity inhomogeneities. Segmentation of MR brain scans of 105 (56 male and 49 female) healthy children and adolescents showed that although the total brain volume was stable over age 4–18, white matter increased and gray matter decreased significantly. There were no sex differences in total gray and white matter growth after correction for total brain volume. White matter volume increased the most in superior and posterior regions and laterality effects were seen in hemisphere tissue volumes. These findings are consistent with other reports, and further validate the segmentation technique.     

4 T Actively detuneable double-tuned 1H/31P head volume coil and four-channel 31P phased array for human brain spectroscopy

Typically 31P in vivo magnetic resonance spectroscopic studies are limited by SNR considerations. Although phased arrays can improve the SNR; to date 31P phased arrays for high-field systems have not been combined with 31P volume transmit coils. Additionally, to provide anatomical reference for the 31P studies, without removal of the coil or patient from the magnet, double-tuning (31P/1H) of the volume coil is required. In this work we describe a series of methods for active detuning and decoupling enabling use of phased arrays with double-tuned volume coils. To demonstrate these principles we have built and characterized an actively detuneable 31P/1H TEM volume transmit/four-channel 31P phased array for 4 T magnetic resonance spectroscopic imaging (MRSI) of the human brain. The coil can be used either in volume-transmit/array-receive mode or in TEM transmit/receive mode with the array detuned. Threefold SNR improvement was obtained at the periphery of the brain using the phased array as compared to the volume coil.     

Tissue similarity maps (TSMs): A new means of mapping vascular behavior and calculating relative blood volume in perfusion weighted imaging

This study introduces a new processing means that uses the original signal (rather than contrast agent concentration) from dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) to calculate a relative cerebral blood volume map and a tissue similarity map (TSM). Ten healthy volunteers and eight multiple sclerosis (MS) patients were studied using high resolution PWI. The TSM is found by choosing a reference region in one slice and comparing its signal in a mean squared error sense to the signal from every pixel in all images throughout the brain. The TSMs provide a means to determine which tissues have similar flow characteristics with high contrast and signal-to-noise ratios. The effective blood volume measured from this approach is nearly identical to that from conventional relative cerebral blood volume (rCBV) maps but with better signal-to-noise. Of interest is the fact that choosing one MS lesion as the reference tissue appears to be enough to find nearly all lesions throughout the brain. That is, these lesions all behave the same from a vascular point of view. The TSM results are robust within and across slices properly nulling the same type of tissue throughout the brain for a given reference region. TSM derived rCBV agrees well with the conventional derived rCBV using contrast agent concentration. TSM may provide a new means to study similarities between blood flow patterns in tissue in the brain and in better diagnosing vascular differences between tissues and lesions.     

Imaging iron stores in the brain using magnetic resonance imaging

For the last century, there has been great physiological interest in brain iron and its role in brain function and disease. It is well known that iron accumulates in the brain for people with Huntington's disease, Parkinson's disease, Alzheimer's disease, multiple sclerosis, chronic hemorrhage, cerebral infarction, anemia, thalassemia, hemochromatosis, Hallervorden-Spatz, Down syndrome, AIDS and in the eye for people with macular degeneration. Measuring the amount of nonheme iron in the body may well lead to not only a better understanding of the disease progression but an ability to predict outcome. As there are many forms of iron in the brain, separating them and quantifying each type have been a major challenge. In this review, we present our understanding of attempts to measure brain iron and the potential of doing so with magnetic resonance imaging. Specifically, we examine the response of the magnetic resonance visible iron in tissue that produces signal changes in both magnitude and phase images. These images seem to correlate with brain iron content, perhaps ferritin specifically, but still have not been successfully exploited to accurately and precisely quantify brain iron. For future quantitative studies of iron content we propose four methods: correlating R2' and phase to iron content; applying a special filter to the phase to obtain a susceptibility map; using complex analysis to extract the product of susceptibility and volume content of the susceptibility source; and using early and late echo information to separately predict susceptibility and volume content.     

Quantitative morphologic evaluation of white matter in survivors of childhood medulloblastoma

In survivors of pediatric brain tumors, cranial radiation therapy can cause a debilitating cognitive decline associated with decreased volume in normal-appearing white matter (NAWM). We applied fractal geometry to quantify white matter (WM) integrity in the brain of medulloblastoma survivors. Fractal features of WM were evaluated by indices of fractal dimensions (FDs) of WM intensity and boundary on T1-weighted magnetic resonance images. The FD index of WM intensity was calculated by using a fractional Brownian motion model, and the FD index of WM boundary was calculated by using a box-counting method. Fractal features of WM on 116 magnetic resonance images of 58 patients with medulloblastoma were investigated at the start of therapy (Start TX) and approximately 2 years later (After TX). Patients were assigned to one of two groups based on change in NAWM volumes. Fractal features in patients with decreased NAWM volume were significantly greater After TX, whereas those in patients with increased NAWM volumes were not. Multiple linear regression analysis showed that fractal features were strongly correlated with NAWM volumes After TX in patients with decreased NAWM volume. These results demonstrated significant deficit in NAWM integrity and WM density changes in children treated for medulloblastoma. Multiple regression analysis illustrated that deficits in NAWM integrity in these children may partly explain the decrease in NAWM volume. We conclude that fractal geometry can be used to monitor the morphologic effects of neurotoxicity in brain tumor survivors.     

Three-dimensional H spectroscopic imaging of cerebral metabolites in the rat using surface coils

Three dimensional metabolite maps of protonated metabolites were obtained using ¹H magnetic resonance spectroscopic imaging at 7 T. Surface coils were used to increase sensitivity and spatial resolution significantly over a volume coil two-dimensional acquisition. Adiabatic pulses were employed to provide homogeneous B₁ excitation and frequency selective refocusing over the volume of the rat brain. These techniques were employed to obtain three-dimensional spectroscopic imaging spectra from nominal voxel volumes of 9–30 μl from rat brain. The improved spatial resolution and sensitivity are also demonstrated with studies of focal ischemia in the rat.     

DTI-based segmentation and quantification of human brain lateral ventricular CSF volumetry and mean diffusivity: Validation,age, gender effects and biophysical implications

The human brain lateral ventricular (LV) cerebrospinal fluid (CSF) volume has been used as a neuroimaging marker of brain changes in health and disease. The LV CSF diffusivity may offer a useful quality assurance measure and become a potential noninvasive marker of deep brain temperature. In this work we sought to validate a method for human brain lateral ventricular (LV) cerebrospinal fluid (CSF) using diffusion tensor imaging (DTI) contrast to provide LV volume and corresponding DTI metrics. We compared LV volume obtained using DTI with that obtained using validated segmentations of the LV on T1-weighted data. DTI and T1-weighted data were acquired at 3 T on 49 healthy males and 56 age-matched females aged 18–59 years. We showed histogram distributions of LV DTI metrics to establish quality assurance measures. We also analyzed the age and gender effects of LV volume and diffusivity. LV volumes estimated using both T1-weighted and DTI correlated strongly in males and females (ICC = 0.99; median Dice index ~ 80%). The LV-to-intracranial volume percentage increased significantly with age only in males, using the DTI-based approach (r = 0.39; p = 0.005). LV CSF Mean diffusivity was greater in males than females ((~ 1.2%; p = 0.03). Mean diffusivity of lateral ventricular CSF decreased significantly with age in healthy adults (r = − 0.30; p = 0.02). Our results highlight the importance of age and gender-based analyses and the potential of LV diffusivity measures as a quantitative marker.     

Proton magnetic resonance spectroscopy in deep human brain structures at 7 T

The increased magnetization and frequency separation at high magnetic field strength, such as 7 T, can provide spectra of high signal-to-noise ratio and spectral resolution. However, most human brain magnetic resonance spectroscopy (MRS) studies at 7 T have employed surface coils and thus limited to superficial brain structures. In this study, volume coil excitation together with volume array reception has been utilized to access deeper brain areas. RF power limitations have been addressed by the use of VERSE-modified pulses, and spectra in parietal and pregenual anterior cingulate cortex (pgACC) have been acquired in eight subjects using STEAM with a short echo time of 20 ms. Spectra were analyzed using LC-model. Therefore, an experimental basis set of in vitro spectra was established from 20 human brain metabolite solutions. An exemplary comparison with an optimized PRESS-based single voxel MRS method at 3 T has been performed. Despite the intrinsically lower signal in STEAM, the 7 T spectra show 1.87 times higher signal-to-noise ratio than at 3 T (using PRESS) and more metabolites could be quantified reliably. The results show that the proposed method can be employed at 7 T in deep brain structures and allows the absolute and relative concentrations of human brain metabolites to be determined with low error levels.     

Comparison of dual-echo DSC-MRI- and DCE-MRI-derived contrast agent kinetic parameters

The application of dynamic susceptibility contrast (DSC) MRI methods to assess brain tumors is often confounded by the extravasation of contrast agent (CA). Disruption of the blood-brain barrier allows CA to leak out of the vasculature leading to additional T(1), T(2) and T(2) relaxation effects in the extravascular space, thereby affecting the signal intensity time course in a complex manner. The goal of this study was to validate a dual-echo DSC-MRI approach that separates and quantifies the T(1) and T(2) contributions to the acquired signal and enables the estimation of the volume transfer constant, K(trans), and the volume fraction of the extravascular extracellular space, v(e). To test the validity of this approach, DSC-MRI- and dynamic contrast enhanced (DCE) MRI-derived K(trans) and v(e) estimates were spatially compared in both 9L and C6 rat brain tumor models. A high degree of correlation (concordance correlation coefficients >0.83, Pearson's r>0.84) and agreement was found between the DSC-MRI- and DCE-MRI-derived measurements. These results indicate that dual-echo DSC-MRI can be used to simultaneously extract reliable DCE-MRI kinetic parameters in brain tumors in addition to conventional blood volume and blood flow metrics.