The impact of reinforcement contingencies on AD/HD: a review and theoretical appraisal

One of the core deficits in attention deficit/hyperactivity disorder (AD/HD) is thought to be an aberrant sensitivity to reinforcement, such as reward and response cost. Twenty-two studies (N=1181 children) employing AD/HD and reinforcement contingencies are reviewed from vantage points: task performance, motivation, and psychophysiology. Results indicate that reinforcement contingencies have a positive impact on task performance and levels of motivation for both children with AD/HD and normal controls. There is evidence that the effect related to task performance is somewhat more prominent in AD/HD. There is some evidence that a high intensity of reinforcement is highly effective in AD/HD. Children with AD/HD prefer immediate over delayed reward. From a psychophysiological point of view, children with AD/HD seem less sensitive to reinforcement compared to controls. While comorbid disorders are suggested to be confounders of the dependent variables, many studies do not examine the effect of oppositional defiant disorder (ODD) and conduct disorder (CD). We discuss the implications of the findings for five theoretical frameworks, including the model by, the cognitive-energetic model (CEM), the dual-pathway model and the BIS/BAS model. Results show a discrepancy between the theoretical models and the behavioural findings.     

Psychophysiological indices of cerebral maturation.

Maturation (1-21 yr) trajectories for quantitative electroencephalographic (QEEG) frequency spectra are presented for four regions of the human brain. The results show that all four regions exhibited discontinuous maturation rates: five stages were identified. The stages were synchronous across regions during the first 10 1/2 years of life. Thereafter, the four maturation trajectories became independent of one another. Interestingly, a major maturational advance was recorded from the frontal regions, during late adolescence. The relationships between these findings to maturation rates in skull volume, cortical thickness, cortical volume and nerve cell density measurements was discussed. These converging results indicate that the observed QEEG stages can reliably be interpreted as landmarks in cerebral maturation.     

Cortico-limbic circuitry and the airways: Insights from functional neuroimaging of respiratory afferents and efferents

After nearly two decades of active research, functional neuroimaging has demonstrated utility in the identification of cortical, limbic, and paralimbic (cortico-limbic) brain regions involved in respiratory control and respiratory perception. Before the recent boon of human neuroimaging studies, the location of the principal components of respiratory-related cortico-limbic circuitry had been unknown and their function had been poorly understood. Emerging neuroimaging evidence in both healthy and patient populations suggests that cognitive and emotional/affective processing within cortico-limbic circuitry modulates respiratory control and respiratory perception. This paper will review functional neuroimaging studies of respiration with a focus on whole brain investigations of sensorimotor pathways that have identified respiratory-related neural circuitry known to overlap emotional/affective cortico-limbic circuitry. To aid the interpretation of present and future findings, the complexities and challenges underlying neuroimaging methodologies will also be reviewed as applied to the study of respiration physiology.     

Effects of methylphenidate on EEG coherence in attention-deficit/hyperactivity disorder.

This study investigated the effects of methylphenidate on intrahemispheric and interhemispheric EEG coherence in children with Attention-Deficit/Hyperactivity Disorder (AD/HD). Twenty boys with AD/HD Combined type and 20 age- and sex-matched control subjects, aged 8 to 13 years, participated in this study. EEG was recorded from 21 sites during an eyes-closed resting condition. Wave-shape coherence was calculated for eight intrahemispheric electrode pairs (four in each hemisphere), and eight interhemispheric electrode pairs, within each of the delta, theta, alpha and beta bands. AD/HD children were tested both off and, 6 months later, on a therapeutic dose of methylphenidate. In intrahemispheric comparisons, AD/HD children had lower theta coherences at long inter-electrode distances, and reduced lateralisation at both long and short-medium inter-electrode distances than controls. For interhemispheric comparisons, AD/HD children showed increased coherences in the frontal regions for the low frequency bands (delta and theta), and reduced coherences in the alpha bands in all other regions. These EEG coherences suggest reduced cortical differentiation and specialisation in AD/HD, particularly in the frontal regions. Methylphenidate did not produce any changes in coherence values. The lack of sensitivity of coherence measures to methylphenidate in the present study suggests that eyes-closed resting EEG coherence measures are associated with structural connectivity of the underlying regions of the brain rather than the degree of functionality of these regions. These results suggest the existence of structural as well as functional brain dysfunction in AD/HD.     

EEG coherence adjusted for inter-electrode distance in children with attention-deficit/hyperactivity disorder.

Cognition and behaviour depend on the integration of activity in different brain regions, and hence study of the coupling between regions is useful in understanding dysfunctional processes involved in disorders such as attention-deficit/hyperactivity disorder (AD/HD). Such coupling can be estimated by the electroencephalographic (EEG) coherence between scalp electrodes. However, EEG coherence between two points is strongly affected by the distance between them, being inflated by volume conduction effects at short distances and reduced by signal phase differences at larger distances. These distance effects preclude simple comparison of coherence estimates involving different inter-electrode distances. Our group recently introduced a procedure for adjusting coherence measures to remove such distance effects, and explored its potential using normal children. In this study we applied that coherence adjustment procedure to groups of children with AD/HD of the combined (AD/HDcom) and predominantly inattentive (AD/HDin) subtypes, and compared them with a control group. All groups were age- and gender-matched. AD/HD children were found to have a reciprocal pattern of coherence disturbance in the cortico-cortical circuits involved in slow and fast wave activity-elevated slow-wave coherences and reduced fast-wave coherences. This disturbance was larger for inter-hemispheric than intra-hemispheric coherences, and varied markedly with region, suggesting a complex pattern of coherence anomalies with a substantial frontal focus. This complex pattern differed little between subtypes, suggesting that it may constitute the fundamental dysfunction underlying the inattention common to both groups. In contrast, coherence was globally elevated in children with AD/HDcom compared with both AD/HDin and control children. This elevation in coherence may be directly related to the hyperactivity and impulsivity unique to that subtype. Further research using the coherence adjustment procedure appears useful in elucidating the electrophysiological anomalies underlying AD/HD and other disorders.     

Event-related potentials in attention-deficit/hyperactivity disorder of the predominantly inattentive type: an investigation of EEG-defined subtypes.

Research using resting EEG measures suggests that there is a large variability in EEG profiles within the common behaviourally defined DSM-IV subtypes of AD/HD. Within the predominantly inattentive type of AD/HD (AD/HDin), two distinct groups have been identified, based on underlying EEG activity that represents either cortical hypoarousal, or a maturational lag (with EEGs resembling those of younger children). This study investigated whether ERPs from an inter-modal oddball task could differentiate AD/HDin children from controls, and whether the ERPs of the two previously identified subgroups of AD/HDin children with different EEG profiles differ on this task. AD/HDin children (N=54), 27 identified as cortically hypoaroused and 27 as maturationally lagged, and 27 age-matched controls, were presented with an inter-modal oddball task in which the non-target stimulus was a counter-phasing checkerboard and the target was a 2000 Hz auditory tone. Stimuli (20% targets) were presented at a fixed ISI of 1.03 s and participants were required to count all targets. The task successfully differentiated the AD/HDin children from controls, with AD/HDin children having smaller N1, P2 and P3 amplitudes to both the auditory targets and the visual non-targets. These results were interpreted as indicating a generalised stimulus registration, facilitation and processing deficit in AD/HDin. The only difference between the EEG-defined subtypes was a relative increase in left-frontal N1 amplitude in the cortically hypoaroused group. This was interpreted as indicating reduced frontal lateralisation of N1 in the maturational lag group, supporting its labelling, and anomalous lateralisation in the cortical hypoarousal group.     

Topographic distribution and developmental timecourse of auditory event-related potentials in two subtypes of attention-deficit hyperactivity disorder.

The effect of age on the topographic distribution of auditory event-related potentials (ERPs) recorded during a two-tone discrimination, or oddball, task was examined in two subtypes of attention deficit/hyperactivity disorder (AD/HD) as defined by the most recent diagnostic manual, DSM-IV. EEG was recorded at 17 sites from AD/HD predominantly inattentive type (n=50) and AD/HD combined type (n=50) subjects aged from 8 to 17 years 11 months. ERP components were quantified at each site. Results revealed topographic differences from controls (n=50) that were common to both subtypes (e.g. target and standard P2 amplitude, and standard P2 latency) or unique to a particular subtype of AD/HD (Inattentive type: target N1, N2, P3b and standard N2 amplitude, target P2 latency; Combined type: target N1, P2, N2 and P3b amplitude, target N2 and standard N1 latency). These group differences showed different age effects. The across-region results revealed differing patterns of abnormal component development for each subtype, indicating a qualitative difference in information processing stage deficits in each of these AD/HD subtypes.     

Precortical Phase of Alzheimer's Disease (AD)‐Related Tau Cytoskeletal Pathology

Alzheimer's disease (AD) represents the most frequent progressive neuropsychiatric disorder worldwide leading to dementia. We systematically investigated the presence and extent of the AD‐related cytoskeletal pathology in serial thick tissue sections through all subcortical brain nuclei that send efferent projections to the transentorhinal and entorhinal regions in three individuals with Braak and Braak AD stage 0 cortical cytoskeletal pathology and fourteen individuals with Braak and Braak AD stage I cortical cytoskeletal pathology by means of immunostainings with the anti‐tau antibody AT8. These investigations revealed consistent AT8 immunoreactive tau cytoskeletal pathology in a subset of these subcortical nuclei in the Braak and Braak AD stage 0 individuals and in all of these subcortical nuclei in the Braak and Braak AD stage I individuals. The widespread affection of the subcortical nuclei in Braak and Braak AD stage I shows that the extent of the early subcortical tau cytoskeletal pathology has been considerably underestimated previously. In addition, our novel findings support the concept that subcortical nuclei become already affected during an early ‘pre‐cortical’ evolutional phase before the first AD‐related cytoskeletal changes occur in the mediobasal temporal lobe (i.e. allocortical transentorhinal and entorhinal regions). The very early involved subcortical brain regions may represent the origin of the AD‐related tau cytoskeletal pathology, from where the neuronal cytoskeletal pathology takes an ascending course toward the secondarily affected allocortex and spreads transneuronally along anatomical pathways in predictable sequences.     

Shared perturbations in the metallome and metabolome of Alzheimer’s,Parkinson’s,Huntington’s,and dementia with Lewy bodies: A systematic review

Despite differences in presentation, age-related dementing diseases such as Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s diseases (HD), and dementia with Lewy bodies (DLB) may share pathogenic processes. This review aims to systematically assemble and compare findings in various biochemical pathways across these four dementias.PubMed and Google Scholar were screened for articles reporting on brain and biofluid measurements of metals and/or metabolites in AD, PD, HD, or DLB. Articles were assessed using specific a priori-defined inclusion and exclusion criteria. Of 284 papers identified, 198 met criteria for inclusion.Although varying coverage levels of metals and metabolites across diseases and tissues made comparison of many analytes impossible, several common findings were identified: elevated glucose in both brain tissue and biofluids of AD, PD, and HD cases; increased iron and decreased copper in AD, PD and HD brain tissue; and decreased uric acid in biofluids of AD and PD cases. Other analytes were found to differ between diseases or were otherwise not covered across all conditions.These findings indicate that disturbances in glucose and purine pathways may be common to AD, PD, and HD. However, standardisation of methodologies and better coverage in some areas – notably of DLB – are necessary to validate and extend these findings.     

The role of the amygdala in bipolar disorder development

The amygdala has received great interest as a possible neurophysiological substrate of bipolar disorder (BD). This review summarizes information about the structure and function of the amygdala with attention to its role in experienced emotion and mood. We review the evidence for amygdala pathology in psychiatric conditions and discuss the role of the amygdala in BD during development. There appear to be consistent findings in the neuroimaging literature that suggest an etiological model for BD that involves abnormalities in the structure and function of the amygdala, but also depends on the failure of prefrontal cortical regions to modulate amygdala activity. In addition, evidence is accumulating to suggest that this model has flexible outcomes, depending on factors intrinsic and extrinsic to BD, and may follow several possible paths across the course of maturational development.     

Effect of neurofeedback training on the neural substrates of selective attention in children with attention-deficit/hyperactivity disorder: a functional magnetic resonance imaging study

Attention Deficit Hyperactivity Disorder (AD/HD) is a neurodevelopmental disorder mainly characterized by impairments in cognitive functions. Functional neuroimaging studies carried out in individuals with AD/HD have shown abnormal functioning of the anterior cingulate cortex (ACC) during tasks involving selective attention. In other respects, there is mounting evidence that neurofeedback training (NFT) can significantly improve cognitive functioning in AD/HD children. In this context, the present functional magnetic resonance imaging (fMRI) study was conducted to measure the effect of NFT on the neural substrates of selective attention in children with AD/HD. Twenty AD/HD children--not taking any psychostimulant and without co-morbidity-participated to the study. Fifteen children were randomly assigned to the Experimental (EXP) group (NFT), whereas the other five children were assigned to the Control (CON) group (no NFT). Subjects from both groups were scanned 1 week before the beginning of the NFT (Time 1) and 1 week after the end of this training (Time 2), while they performed a Counting Stroop task. At Time 1, for both groups, the Counting Stroop task was associated with significant loci of activation in the left superior parietal lobule. No activation was noted in the ACC. At Time 2, for both groups, the Counting Stroop task was still associated with significant activation of the left superior parietal lobule. This time, however, for the EXP group only there was a significant activation of the right ACC. These results suggest that in AD/HD children, NFT has the capacity to normalize the functioning of the ACC, the key neural substrate of selective attention.     

EEG coherence in adults with attention-deficit/hyperactivity disorder.

Attention-Deficit/Hyperactivity Disorder (AD/HD) is the most common psychiatric disorder of childhood, but it is becoming increasingly more apparent that more than half the childhood sufferers will continue to manifest symptoms of the disorder as adults. While EEG coherence in children with AD/HD has been examined extensively, no studies have investigated coherence in adults with the disorder. This study investigated EEG coherence in adults with AD/HD. EEG was recorded from 18 adult males with AD/HD, and an age- and gender-matched control group, during an eyes-closed resting condition. Waveshape coherence was calculated for 8 intrahemispheric electrode pairs (4 in each hemisphere), and 8 interhemispheric electrode pairs, within each of the delta, theta, alpha and beta bands. A laterality effect was found for intrahemispheric coherence at long inter-electrode distances, with the AD/HD group showing reduced hemispheric differences in the delta band compared to the control group. In the alpha band, at short-medium inter-electrode distances, the AD/HD group also had lower coherences than the control group. The results suggest that theta coherence differences reported in children with AD/HD may be associated with hyperactivity, which is reduced in adults with AD/HD, while reduced alpha coherence could be associated with inattention, which remains in adult with AD/HD. Reduced delta coherence also appears to be an aspect of the disorder which may develop from later childhood into adolescence and adulthood.     

Magnetic resonance imaging of Huntington's disease: preparing for clinical trials

The known genetic mutation causing Huntington's disease (HD) makes this disease an important model to study links between gene and brain function. An autosomal dominant family history and the availability of a sensitive and specific genetic test allow pre-clinical diagnosis many years before the onset of any typical clinical signs. This review summarizes recent magnetic resonance imaging (MRI)–based findings in HD with a focus on the requirements if imaging is to be used in treatment trials. Despite its monogenetic cause, HD presents with a range of clinical manifestations, not explained by variation in the number of CAG repeats in the affected population. Neuroimaging studies have revealed a complex pattern of structural and functional changes affecting widespread cortical and subcortical regions far beyond the confines of the striatal degeneration that characterizes this disorder. Besides striatal dysfunction, functional imaging studies have reported a variable pattern of increased and decreased activation in cortical regions in both pre-clinical and clinically manifest HD-gene mutation carriers. Beyond regional brain activation changes, evidence from functional and diffusion-weighted MRI further suggests disrupted connectivity between corticocortical and corticostriatal areas. However, substantial inconsistencies with respect to structural and functional changes have been reported in a number of studies. Possible explanations include methodological factors and differences in study samples. There may also be biological explanations but these are poorly characterized and understood at present. Additional insights into this phenotypic variability derived from study of mouse models are presented to explore this phenomenon.     

Structural neuroimaging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer’s disease (AD), where both widespread atrophy and ‘signature’ brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.     

Expression of somatostatin receptor subtypes (SSTR1-5) in Alzheimer's disease brain: an immunohistochemical analysis

Somatostatin, widely distributed in human cortical brain regions, acts through specific high affinity somatostatin receptors (SSTR1-5) to exert profound effects on motor, sensory, behavioral, cognitive and autonomic functions. Somatostatin levels are consistently decreased in the cortex of Alzheimer's disease (AD) brain and in cerebrospinal fluid, and have become reproducible markers of this disease. In the present study, the distributional pattern of SSTR1-5 antigens in the frontal cortex of AD and age-matched control brains was studied using antipeptide polyclonal rabbit antibodies directed against the five human somatostatin receptor subtypes. All five SSTRs were differentially expressed as membrane and cytoplasmic proteins in cortical neurons with significant variations in control vs. AD brain. In AD cortical brain region, somatostatin and neuropeptide-Y-positive neurons decreased (>70%), and glial fibrillary acidic protein-positive astrocytes significantly increased (>130%) in comparison to control brain. SSTR2 and 4 were the predominant subtypes followed by SSTR1, 3 and 5. AD cortex showed a marked reduction in neuronal expression of SSTR4 and 5 and a modest decrease in SSTR2-like immunoreactivity without any changes in SSTR1 immunoreactive neurons. In contrast, SSTR3 was the only receptor subtype that increased in AD cortex. In AD cortex, SSTR1-, 3- and 4-like immunoreactivities were strongly expressed in glial cells but not SSTR2 and 5. These findings suggest the differential loss of immunoreactivity of SSTR2, 4 and 5 but not SSTR1, and increased SSTR3 in frontal cortex of AD brain as well as subtype-selective glial expression in AD brain. In summary, subtype-selective changes in the expression of SSTRs at protein levels in AD cortical regions suggest that somatostatin and SSTR-containing neurons are pathologically involved in AD and could possibly be used as markers of this disease.     

Accumulation of neurofibrillary tangles and activated microglia is associated with lower neuron densities in the aphasic variant of Alzheimer’s disease

The neurofibrillary tangles (NFT) and amyloid‐ß plaques (AP) that comprise Alzheimer’s disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical AD variants, including primary progressive aphasia (PPA‐AD). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA‐AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD.     

Connectivity Analysis and Feature Classification in Attention Deficit Hyperactivity Disorder Sub-Types: A Task Functional Magnetic Resonance Imaging Study

Attention deficit hyperactivity disorder (ADHD) is a pervasive neuropsychiatric disorder. Patients with different ADHD subtypes show different behaviors under different stimuli and thus might require differential approaches to treatment. This study explores connectivity differences between ADHD subtypes and attempts to classify these subtypes based on neuroimaging features. A total of 34 patients (13 ADHD-IA and 21 ADHD-C subtypes) underwent functional magnetic resonance imaging (fMRI) with six task paradigms. Connectivity differences between ADHD subtypes were assessed for the whole brain in each task paradigm. Connectivity measures of the identified regions were used as features for the support vector machine classifier to distinguish between ADHD subtypes. The effectiveness of connectivity measures of the regions were tested by predicting ADHD-related Diagnostic and Statistical Manual of Mental Disorders (DSM) scores. Significant connectivity differences between ADHD subtypes were identified mainly in the frontal, cingulate, and parietal cortices and partially in the temporal, occipital cortices and cerebellum. Classifier accuracy for distinguishing between ADHD subtypes was 91.18 % for both gambling punishment and emotion task paradigms. Linear prediction under the two task paradigms showed significant correlation with DSM hyperactive/impulsive score. Our study identified important brain regions from connectivity analysis based on an fMRI paradigm using gambling punishment and emotion task paradigms. The regions and associated connectivity measures could serve as features to distinguish between ADHD subtypes.     

Staging Alzheimer's disease progression with multimodality neuroimaging

Rapid developments in medical neuroimaging have made it possible to reconstruct the trajectory of Alzheimer's disease (AD) as it spreads through the living brain. The current review focuses on the progressive signature of brain changes throughout the different stages of AD. We integrate recent findings on changes in cortical gray matter volume, white matter fiber tracts, neuropathological alterations, and brain metabolism assessed with molecular positron emission tomography (PET). Neurofibrillary tangles accumulate first in transentorhinal and cholinergic brain areas, and 4-D maps of cortical volume changes show early progressive temporo-parietal cortical thinning. Findings from diffusion tensor imaging (DTI) for assessment fiber tract integrity show cortical disconnection in corresponding brain networks. Importantly, the developmental trajectory of brain changes is not uniform and may be modulated by several factors such as onset of disease mechanisms, risk-associated and protective genes, converging comorbidity, and individual brain reserve. There is a general agreement between in vivo brain maps of cortical atrophy and amyloid pathology assessed through PET, reminiscent of post mortem histopathology studies that paved the way in the staging of AD. The association between in vivo and post mortem findings will clarify the temporal dynamics of pathophysiological alterations in the development of preclinical AD. This will be important in designing effective treatments that target specific underlying disease AD mechanisms.     

Neuroimaging findings in primary insomnia

State-of-the-art neuroimaging techniques have accelerated progress in the study and understanding of sleep in humans. Neuroimaging studies in primary insomnia remain relatively few, considering the important prevalence of this disorder in the general population. This review examines the contribution of functional and structural neuroimaging to our current understanding of primary insomnia. Functional studies during sleep provided support for the hyperarousal theory of insomnia. Functional neuroimaging also revealed abnormalities in cognitive and emotional processing in primary insomnia. Results from structural studies suggest neuroanatomical alterations in primary insomnia, mostly in the hippocampus, anterior cingulate cortex and orbitofrontal cortex. However, these results are not well replicated across studies. A few magnetic resonance spectroscopy studies revealed abnormalities in neurotransmitter concentrations and bioenergetics in primary insomnia. The inconsistencies among neuroimaging findings on insomnia are likely due to clinical heterogeneity, differences in imaging and overall diversity of techniques and designs employed. Larger samples, replication, as well as innovative methodologies are necessary for the progression of this perplexing, yet promising area of research.