The treatment of schizophrenia represents one of the most difficult areas of medicine for carrying out reliable

and informative clinical trials of new medicinal products. The methodological issues that affect studies of neuroleptic agents are not unique. The evaluation of treatments for negative symptoms probably represents the most, unusual methodological problem (not covered in this paper), but from a statistical perspective this problem has parallels elsewhere in medicine. The real reason why clinical trials in schizophrenia are so difficult, is the fact that a number of methodological issues Inhibitors,research,lifescience,medical are present, together and in a severe form. This paper is concerned largely with trials that provide the confirmatory evidence of the efficacy of new medicinal agents, that, is those carried out during their phase 3 development, or perhaps during the development of a new indication in Inhibitors,research,lifescience,medical phase 4. Hence, it is concerned only with controlled trials that provide the most reliable and informative

evidence of efficacy Inhibitors,research,lifescience,medical for licensing decisions. General guidance on the statistical issues that arise in confirmatory trials and that relate to regulatory decisions can be found in ICH E9 (ICH, International Conference on Harmonization of Technical Requirements for Registration Inhibitors,research,lifescience,medical of Pharmaceuticals for Human Use).1 Guidance on the design, conduct, analysis, and interpretation of these trials in the field of schizophrenia can be found in the Committee for Proprietary Medicinal Products (CPMP) Note for guidance.2 Two issues require a broader introduction before discussing their impact, on trials in schizophrenia. The

Inhibitors,research,lifescience,medical first is the use of placebo. TTic most recent revision of the Declaration of Helsinki3 in October 2000 Dipeptidyl peptidase caused alarm among those conducting and carrying out controlled clinical trials by appearing to limit the future role of placebo to a serious extent. The use of placebo in schizophrenia trials was already a problematic matter. Hence in the context of this paper, it is important to check details clarify the basis of the concerns surrounding its use and to explain the current resolution. The second issue is the design of studies to evaluate the long-term maintenance treatment of an episodic, or partly episodic, condition. The use of medicinal products for this purpose arises in a number of psychiatric and other indications, and a terminology has been developed to communicate thoughts and conclusions.

20 It is also interesting in that this and several of the other cohort studies point to receptive language deficits as being particularly noticeable in preschizophrenic individuals.14,15,18,21 Much research indicates that auditory hallucinations are Tivantinib in vivo disorders of inner language.22,23 Perhaps it is not surprising that children who have impaired language perception are more prone to misperceive their own inner speech as voices in adult life. Isohanni et al24 studied Inhibitors,research,lifescience,medical over 12 000 subjects from the 1966 Finnish birth cohort at the time of their 31st birthday. Using a national hospital register, they identified 100 cases

of schizophrenia, 55 other psychoses, and 315 nonpsychotic disorders. Data on the ages at which subjects learned to stand, walk, and control bowel and bladder functions were compared across the groups. Delayed milestones increased the risk for later psychosis Inhibitors,research,lifescience,medical in a linear fashion (so early milestones implied protection). There was no such association between milestones and nonpsychotic disorders. Apart from the interesting “dose-response effect” described, this study suggests that the childhood precursors may be specific to psychotic disorders as opposed to conveying risk for general psychopathology. Neuropsychological characteristics Inhibitors,research,lifescience,medical in late adolescent/early adult life David et al25

Inhibitors,research,lifescience,medical investigated the association between 10 and the later development of psychosis in a cohort study of nearly 50 000 18-year-old males who were conscripted into theSwedish army in 1969 to 1970. By 1983, 195 subjects in the cohort had been admitted to hospital with schizophrenia and another 192 with nonschizophrenic psychosis. There was a highly significant association between low IQ scores and the subsequent development of schizophrenia. Indeed, the relationship between schizophrenia and IQ was linear, with risk gradually Inhibitors,research,lifescience,medical increasing as IQ fell at all levels of intellectual ability. The risk for nonschizophrenic

psychoses was also higher in those with lower IQ, but the effect was less marked and nonlinear. The effect size of the low IQ risk factor exceeded that of any other known environmental risk factors. The association between low IQ and schizophrenia could be directly causal with cognitive Cell press impairment leading to false beliefs and perceptions. Alternatively, the association could be indirect with factors such as abnormal brain development increasing the risk for schizophrenia, and incidentally causing the lower IQ. Davidson et al26 examined assessment scores for nearly 10 000 16- and 17-year-old boys entering the Israeli army Deficits in social functioning, organizational ability, and intellectual functioning predicted later hospitalization with schizophrenia.

Even short periods of caffeine deprivation, equivalent to skipping a regular morning coffee, can produce deficit In sustained attention.82 Withdrawal symptoms are rapidly relieved by caffeine Intake. Signs and symptoms of withdrawal, In decreasing order of frequency, Include headache, drowsiness, Impaired concentration, work difficulty, depression, anxiety, irritability, nausea or vomiting, and muscle aches and stiffness.83 The withdrawal syndrome usually shows an onset 18 to Inhibitors,research,lifescience,medical 24 h after cessation; Its Intensity peaks between 20 to 48 h after abstinence; its duration ranges from 2 days to a week. Tolerance to the sleep-disturbing effects of caffeine has been demonstrated. However, there Is little

evidence for upward dose adjustment, possibly because of the unpleasant

Inhibitors,research,lifescience,medical effects of higher doses. Since caffeine is not associated with significant health hazards or Incapacitation, Its potential to Induce dependence does not pose a serious problem for the Individual or society. Overlapping addictions No psychoactive drug has been studied In so many individuals as have alcohol, nicotine, and caffeine. The experience that we have with these Inhibitors,research,lifescience,medical compounds Is tantamount to an open trial conducted over a couple of millennia In billions of subjects! This review of mankind’s most consumed drugs could also have encompassed betel and khat, which are both widely consumed In Africa and Asia for their mild stimulant properties. In the near future, we are likely to gain more experience with cannabis, the use of which Inhibitors,research,lifescience,medical Is

tending to be signaling pathway decriminalized. Since these drugs are so much appreciated, It may be assumed that they procure beneficial and pleasant effects. The benefits obtained in terms of creativity, anxiety reduction, social disinhibition, and pleasure have been extensively described In poetry and literature, rather that In medical treatises. There exists a tendency for some normally functioning adults to have multiple addictions. This led many authors to discuss theories of addictive personality. A study84 of overlapping addictions to common substances (alcohol, caffeine, chocolate, or cigarettes) and activities (exercise, gambling, Internet use, Inhibitors,research,lifescience,medical television, or video games) In college men and women found moderate to large correlations, Bumetanide both within and between substances and activities. Several gender differences In addictive tendencies were also revealed: men scored higher than women on addiction to alcohol, cigarettes, gambling, television, and Internet use, but women scored higher on caffeine and chocolate. Animal studies have shown that rewards obtained from various drugs, as well as food, playing, and sex, stimulate a midbrain reward circuit, involving dopamine and structures such as the nucleus accumbens. The Issue of addiction Is more complex In humans, who have the conscious capacity to evaluate, In the prefrontal cortex, whether pleasurable activities are appropriate and acted upon, or should be deferred or resisted.

Further advances have been limited by the observation that any additional increase in tumour control appears often to be balanced by an increase in acute and late normal tissue toxicity. The current national trial in the UK (ARISTOTLE) is examining the selleck kinase inhibitor utility of the incorporation of irinotecan into pre-operative CRT in MRI defined unresectable/borderline resectable rectal cancer (www.controlled-trials.com/ISRCTN09351447). Similar phase II trials with oxaliplatin appeared encouraging (36,37). However, preliminary results from

randomized phase III trials, evaluating the addition of oxaliplatin to preoperative fluoropyrimidines-based CRT, have not shown a significant impact on Inhibitors,research,lifescience,medical early pathological response (STAR-01, ACCORD 12/0405-Prodige 2, NSABP R-04) with the exception of the German CAO/ARO/AIO-04 study. In addition, the PETACC-6 trial randomized patients between preoperative RT (50.4 Gray in 25 fractions) with capecitabine Inhibitors,research,lifescience,medical alone the same radiation schedule with capecitabine + oxaliplatin (50 mg/m2). Results have not yet been reported (Table 2). Table 2 Short

Inhibitors,research,lifescience,medical term outcomes from randomised phase III studies integrating oxaliplatin as radiosensitizer Efforts to improve the outcome from chemoradiotherapy further have focussed on adding biological agents to avoid overlapping toxicities. A landmark randomised phase III study in patients with locally advanced head and neck cancer showed that cetuximab in combination with radical Inhibitors,research,lifescience,medical radiotherapy significantly improved overall survival (41) compared to radiation alone. Many mechanisms have been postulated (42), including inhibition of repopulation during the latter phase of radiotherapy. Accelerated treatments improve outcome only in head and neck cancers, which have high EGFR expression (43). Yet, this benefit from cetuximab has not been extended to chemoradiation. In the Radiation Therapy Oncology Group (RTOG) 0522 trial patients

with locally advanced head and neck showed a 2-year progression-free survival (PFS) of 63.4% with cetuximab versus 64.3% with cisplatin-based Inhibitors,research,lifescience,medical chemoradiation alone, and overall survival improved slightly but not significantly with cetuximab (44). Hence, with our next increasing knowledge of molecular pathways in cancer, can we identify sufficient potential targets that may be manipulated to enhance the radiation response selectively in rectal cancers compared to normal tissues such as small bowel and the sphincter complex? We found 13 papers documenting combinations of chemoradiotherapy with cetuximab, 2 with panitumumab and 15 with bevacizumab. Cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response/ pathologic complete responses in locally advanced rectal cancer patients in recent phase I/II trials (Tables 3,​,4).4). The data with panitumumab and small molecules is even sparser (Table 5).

All patients achieved immediate/rapid or slow complete regression as demonstrated by normalization of previously elevated LDH and B-HCG levels and by CT scans. In five (19%) patients, in whom the tumoral mass shrinkage was very slow, follow-up consisted of CT scans, and six patients also had PET scans (Table 2). In two patients, para-aortic lymph node

packets could be followed Inhibitors,research,lifescience,medical on CT scans during 1 year of follow-up until disappearance. No evidence of persistent or regrowing masses was demonstrated. The three patients with pathologically and radiologically confirmed IIIA disease also responded completely to BEP. After a median follow-up of 120 months (range 24–268 months) all patients are alive with no evidence of disease. Table 2. Treatment Modalities, Side Effects, and Results. One patient (Table 3, #22) developed lung metastases 4 years after his first CR. He responded to vinblastine/ifosfamide/cisplatinum (VeIP) salvage chemotherapy for 4 years, but eventually

his disease recurred in the Inhibitors,research,lifescience,medical lungs and pelvis. This patient entered Inhibitors,research,lifescience,medical a third CR following high-dose chemotherapy (HDCT) with autologous peripheral stem cell transplantation (APSCT) and local radiation therapy, resulting in long-term (third) CR. Currently, 16 years following his last treatment, he is alive with no evidence of testicular tumor. Another patient (#19) preferred surveillance initially, but relapsed after 9 months with a IIC Fostamatinib chemical structure abdominal mass and achieved prompt and durable complete remission with three BEP cycles. Table 3. Staging, Chemotherapy Regimens, Response, and Latest Status. Side effects were manageable (Table 2). In three patients, cisplatinum was replaced by carboplatin due to the development Inhibitors,research,lifescience,medical of tinnitus and mild hearing loss, respectively. In seven patients, bleomycin was omitted for the fourth

cycle, and the fourth cycle was modified in two patients due to neutropenic fever. Within a range of 2–4 months, three patients Inhibitors,research,lifescience,medical developed clinical and radiological signs of bleomycin lung toxicity Histone demethylase after reaching a cumulative dose in the range of 180–240 units of bleomycin. Clinically, they presented with non-productive cough, exertional dyspnea, and low-grade fever. The chest X-ray showed bilateral, bibasilar infiltrates, with later consolidation (Figure 1, panels A and B) which was totally reabsorbed with no progression (Figure 1, Panel C) into irreversible diffuse fibrosis. The three patients responded well to high-dose steroids and broad-spectrum antibiotics. Figure 1. A CT Scan Following Completion of BEP Regimen (cumulative bleomycin dose 240 units) at 2 Months (A), 5 Months (B), 10 Months (C). Following a thorough search on the website of the Ministry of Interior Affairs, we found that all the treated patients are alive and well with no evidence of their previous testicular tumor.

61,62 When compared with the BZs and GABA A selective medications, ramelteon has the major advantage of an apparent lack of abuse potential. In fact, it is the only currently available FDA-approved hypnotic that is not classified as a controlled substance. Experience with treating insomnia associated with depression and other mood disorders is, to

date, quite limited and it would be premature to consider this promising medication a proven treatment for the sleep disturbances of patients taking antidepressants. Inhibitors,research,lifescience,medical Patients with insomnia often self -medicate with over-thecounter medications and remedies, with range from various antihistaminergic compounds (such as diphenhydramine) to “natural” agents such as melatonin and valerian root. The utility (or, Inhibitors,research,lifescience,medical more accurately, the lack of efficacy) of these nonprescription medications has been reviewed elsewhere in more detail63-65

Suffice it to say that if a patient warrants treatment for relief of a significant persistent sleep disturbance, there are a number of more promising interventions that can be utilized. Cognitive-behavioral management of insomnia The past decade has witnessed increased interest in non-pharmacologic approaches to management Inhibitors,research,lifescience,medical of insomnia, particularly those emphasizing cognitive and behavioral methods.65,66 Beyond explicit attention to sleep hygiene, cognitive behavior therapy (CBT) for insomnia utilizes stimulus control and arousal reduction techniques. There is evidence from studies of primary insomnia that comprehensive CBT results in short-term improvements that are – at the least – as effective as pharmacotherapy with sedative-hypnotics.67 The potentially greatest advantage

of CBT is evident over time, however, as effectiveness is more durable Inhibitors,research,lifescience,medical than pharmacotherapy and benefits persist after therapy is terminated.68 Thus, although CBT may be a more costly approach than Inhibitors,research,lifescience,medical pharmacotherapy in the short run, it becomes a cost-effective approach across 6 months or longer. Given the positive experience as a treatment of primary insomnia, there is a clear need for studies on the utility of CBT – in combination with antidepressant therapy- for patients with major depressive disorder.69 It is noteworthy that other models of CBT GSK1120212 ic50 directed more broadly at the overall depressive syndrome often fail to vigorously address insomnia. For example, in one large comparative study of patients with chronic forms of major depressive disorder, the antidepressant nefazodone had a substantial advantage Carnitine palmitoyltransferase II over the cognitive behavior analysis system of psychotherapy for relief of both objective and subjectively assessed depressive insomnia, even though the two therapies had comparable overall effects.70,71 Given the relatively inconsistent performance of various models of psychotherapy for treatment of more severe depressive states72 it would be prudent for therapists to consider adding a more specific CBT module to address insomnia.

” Watson, the father of behaviorism, was also very critical of what he called the “introverted viewpoint” of James’ theory. He considered that there were only three types of unlearned emotional responses, which he called “fear,” “rage,” and “love” for convenience, although he wanted to “[...] strip them out of all their old connotations.”10 These three emotional responses can be elicited by three sets of specific stimuli. Thus, a sudden noise or loss of Inhibitors,research,lifescience,medical physical support can induce an innate fear reaction, and restraint of bodily

movements triggers rage. He also mentioned the fact that these emotional responses can be conditioned and that, although these reactions are usually accompanied by specific behaviors, “[...] visceral and glandular factors predominate.” Papez’s (1937) theory of emotions also had a physiological basis. For him, connections between the Inhibitors,research,lifescience,medical cerebral hemispheres and the hypothalamus, and between the cerebral

hemispheres and the dorsal thalamus mediate emotions. He held the view that emotion implies behavior (expression) and feeling (experience, subjective aspects). Expression Inhibitors,research,lifescience,medical depends on the hypothalamus, and GDC-0068 supplier experience on the cortex. Although the “circuit of Papez” is still presented as “the emotional brain” in some handbooks, it is clear that many details of his original theory are now outdated. More recently, Schachter Inhibitors,research,lifescience,medical (1975) emphasized the importance of cognitive processes: bodily states are interpreted in a cognitive context and are modulated by experience. He also showed that the visceral response appears to be a necessary, although not sufficient, condition for the occurrence of emotion. The view that there is a limited set of emotions (eg, fear, anger, etc) with specific neurophysiological Inhibitors,research,lifescience,medical and neuroanatomical substrates that can be considered as “basic” and serve as the primitive building blocks from which the other, more complex emotions are built, was challenged as late as 1990.11 However, Ekman has convincingly argued that there is now enough evidence of universals in expression and in physiology to suggest a biological

basis for these elementary emotions.12 Panksepp added to these arguments by stating that “genetically dictated brain systems that mediate affective-emotional processes do exist, even though there are bound to be semantic ambiguities Isotretinoin in how we speak about these systems.”13 The biology of fear and anxiety Fear versus anxiety: is there a difference? The main function of fear and anxiety is to act as a signal of danger, threat, or motivational conflict, and to trigger appropriate adaptive responses. For some authors, fear and anxiety are undistinguishable, whereas others believe that they are distinct phenomena. Ethologists define fear as a motivational state aroused by specific stimuli that give rise to defensive behavior or escape.

In the longer term, other approaches to brain stimulation may become clinically viable

and eventually replace ECT Such a projection must be made with due caution. The epitaph of ECT has been written repeatedly over the past 50 years. Nevertheless, it remains one of the longest-standing, continuously used treatments in medicine. Research efforts over the next decade in the field of brain stimulation will be crucial in establishing how long ECT will continue to occupy this unique position. Inhibitors,research,lifescience,medical Selected abbreviations and acronyms DBS deep brain stimulation ECT electroconvulsive therapy MST magnetic seizure therapy TMS transcranial magnetic stimulation VNS vagus nerve stimulation
Depression is sometimes described as the “common cold” of psychiatry It is certainly common, and it is also present most commonly in mild forms, which extends the analogy somewhat. However, in its most severe forms it is the major problem that may preoccupy any ill Inhibitors,research,lifescience,medical patient- to the point where he or she may commit suicide. Indeed, a formal major

depressive episode can occur in association with virtually all the other psychiatric and physical diagnoses. This review will address primarily physical illnesses. Physical this website illness increases the risk of developing severe depressive illness. There are two broadly different mechanisms that may explain this, which are not mutually Inhibitors,research,lifescience,medical exclusive. The first is the most obvious, probably the most common, and is usually described as having a psychological or cognitive mechanism. It may be understandable as the threat that any severe and/or chronic illness may pose to an individual’s sense of purpose and meaning in life. Thus, the illness may provide the life event or chronic difficulty that triggers a depressive episode in a vulnerable individual. Physical Inhibitors,research,lifescience,medical illness may thereby be a component of the complex pathway that determines the emergence of depression. The mechanisms may be both genetic and nongenetic, and have been best teased out by twin studies, primarily

in women.1-3 Such an Inhibitors,research,lifescience,medical association between depression and physical illness may be highly nonspecific and unbiological. However, this cannot be assumed axiomatically to be true. Indeed, all severe depression is in some sense biological, and some unexpected associations may be mediated by a biology that is related to both the physical illness and to the systems that support depressive reactions. Examples already of the more specific association will be given below; they may turn out to be of particular etiological interest. In addition, major depression, but especially minor depression, dysthymia, and depressive symptoms merge with other manifestations of human distress, with which patients present to their doctors. Such somatic presentations test the conventional distinction between physical and mental disorder, and are a perennial source of controversy While it will not be possible to do the topic full justice, the key issues will be noticed.

Other activating events include PTEN loss and AKT amplification (59)-(61). Activation of this Ponatinib in vivo pathway was associated with poor prognosis

and contributed to chemoresistance in many cancers (62)-(66). Thus, the PI3k/Akt/mTOR pathway is an attractive pathway to target in pancreas cancer. mTOR inhibitors Everolimus 10mg daily was evaluated in 33 metastatic gemcitabine-refractory pancreas Inhibitors,research,lifescience,medical cancer patients (67). No objective responses (complete and partial) were reported and 21% had stable disease at the time of first surveillance CT scan. Median PFS and OS were 1.8 and 4.5 months respectively. In two smaller clinical trials, 4 gemcitabine-refractory patients received temsirolimus (CCI-779) and 16 received a combination of everolimus (30mg once weekly) and erlotinib (150 mg daily) (68). The former study with temsirolimus was halted due to toxicities and no objective response was observed, and the median PFS was 19 days and survival 44 days. The everolimus and erlotinib combination was better tolerated, but no response was observed and median PFS Inhibitors,research,lifescience,medical and survival Inhibitors,research,lifescience,medical was 49 days and 87 days respectively. These trials demonstrate that mTOR inhibition as a single agent is ineffective and combining inhibitors of multiple steps and the role for these inhibitors may lie in combination regimens. Akt inhibitors Akt inhibitors are another class

of agents that abrogate Akt/mTOR signaling. MK-2206, an allosteric Akt1-3 inhibitor, was evaluated in a phase I trial of 70 patients with advanced cancers (69). Interestingly, tumor shrinkage (23%) Inhibitors,research,lifescience,medical was observed in a patient with PTEN-negative pancreas cancer and was associated with a 60% decrease in CA19-9. MK-2206 is being evaluated as weekly (300mg) and every other day (75mg and 90mg) dosing schedules. MK-2206 is also being evaluated in combination with cytotoxic chemo-agents and inhibitors of c-Met and EGFR (70),(71). RX-0201 is an antisense oligonucleotide against Akt1 mRNA, thereby interrupting the pathway’s activation. Inhibitors,research,lifescience,medical The anti-sense oligonucleotide demonstrated activity against pancreas cancer cell lines in low nanomolar range, reducing the expression of Akt1

mRNA and protein. Vasopressin Receptor In in vivo studies, RX-0201 treatment led to complete response in 2 out of 3 pancreas tumor-bearing mice (72). As such, RX-0201 in combination with gemcitabine is currently being evaluated in a phase II trial for metastatic pancreas cancer patients (73). Given the short half-life typical of anti-sense agents, RX-0201 is being administered by continuous infusion for 14 days of a 21-day cycle and presents a potential obstacle to patient accural. Liposomal formulations are in development (74). PI3K inhibitors XL147 and BKM120 are oral class I PI3k inhibitors that are being evaluated in phase I trials, alone and in combination therapies (75)-(77). These trials have focused on lung, colorectal and breast cancers given the higher frequency of pathway aberrations in these tumor types.

Table V shows magnetic resonance imaging (MRI) neuroimaging techniques. Nevertheless, significant challenges exist, in terms of summarizing existing findings and translating data to improve clinical practice. Studies often involve diverse cohorts (eg, mild TBI, combat, veterans), and employ different paradigms (symptom provocation, cognitive activation) and modalities (eg, diffusion tensor imaging [DTI], functional magnetic resonance imaging [fMRI],

single photon emission computed tomography [SPECT]).50 As such, findings have varied. Peskind and colleagues noted that Inhibitors,research,lifescience,medical fluorodeoxyglucose positron emission tomography (FDG-PET) abnormalities in those with PTSD versus those without this disorder have been “limited and conflicting” (p 5).51 In terms of validation, experiments supporting newer functional imaging techniques often rely on neuropsychological paradigms. For example, in response to findings regarding Inhibitors,research,lifescience,medical the positive relationship between DTI results and neuropsychological test performance among those with mild, moderate, and severe injuries, Kraus ct al3 suggested that white matter load may be a “useful index.“ Much work is being conducted to support, these new imaging techniques, and findings are

increasing our knowledge regarding those with TBI and/or PTSD. Table V. Magnetic resonance imaging (MRI) Inhibitors,research,lifescience,medical neuroimaging techniques. BOLD, blood oxygen level dependent; DTI, diffusion tensor imaging, fMRI, functional MRI; MRS, magnetic resonance spectroscopy; PW-MRI, perfusion weighted MRI; SWI, susceptibility-weighted imaging … TBI Although newer techniques have begun to allow clinicians to explore questions regarding pathogenesis, natural history, neuroplasticity, and treatment, response,52 historically, neuroimaging has been used to identify Inhibitors,research,lifescience,medical and manage acute modcratc-to-sevcre TBI. Less sophisticated structural imaging techniques such as computed tomography (CT) or MRI have been useful in identifying skull fractures or more severe injuries (eg contusion, intraparaenchymal hemorrhage); however, they generally fail to adequately Inhibitors,research,lifescience,medical detect DAI or brain volume loss. Moreover, in combat, or deployment,

settings these generally common diagnostic tools may not be available isothipendyl to the clinician.53 Research among both Veteran and civilian populations suggests that, use of CT and MRI has limited utility in confirming acute or post-acute mild TBI.54-56 In looking at MRI results of veterans long postTBI, Brenner and colleagues55 found that those with Alvespimycin moderate to severe TBI were significantly more likely to have trauma-related findings (physical) than those with mild TBI. In specific, 11 out of 16 veterans with moderate to severe TBI versus 0 out 16 with mild TBI had MRI findings. Research regarding newer functional imaging techniques (eg, FDG-PET, DTI, SPECT) suggests that in the future they may be of significant clinical utility, particularly in the context of mild TBI and/or post-acute injuries.