Ebook Textbook of clinical neuropsychology (2/E): Part 2

Part 2 book “Textbook of clinical neuropsychology” has contents: Toxins in the central nervous system, multiple sclerosis and related disorders, sports-related concussion, the three amnesias, basics of forensic neuropsychology, pediatric forensic neuropsychology, clinical psychopharmacology,… and other contents.

23 Cognitive Functions in Adults With Central Nervous System and Non-Central Nervous System Cancers Denise D Correa and James C Root Introduction Brain Tumors Cognitive dysfunction is common in many cancer patients and can be related to the disease and to treatment with chemotherapy and/or radiotherapy (RT) The neuropsychological domains affected and the severity of the deficits may vary as a result of disease and treatment type, but difficulties in executive functions, motor speed, and learning, and retrieval of information are the most prevalent In a significant number of cancer patients, changes in cognitive functions interfere with their ability to resume work and social activities at prediagnosis levels There has been an increase in the number of studies and clinical trials that incorporate standardized cognitive outcome measures for the assessment of patients with cancer of the central nervous system (CNS; see Correa, 2006; Taphoorn & Klein, 2004) New developments have been described in the study of the cognitive side effects of chemotherapy for non-CNS cancers (Correa & Ahles, 2008) These lines of research have provided valuable information about the incidence of cognitive dysfunction in patients with various cancers, and the contribution of treatments involving different regimens and modalities Studies have also begun to investigate the underlying mechanisms that may contribute to the neurotoxicity of RT and chemotherapy (Dietrich, Han, Yang, Mayer-Proschel, & Noble, 2006; Nordal & Wong, 2005) and interventions to minimize or prevent both structural and functional damage associated with these regimens have been proposed (Gehring, Sitskoorn, Aaronson, & Taphoorn, 2008) The current chapter reviews studies involving patients with brain tumors and breast cancer, considering that most of the research has been conducted in these patient groups Of note, other emerging areas of study include cognitive dysfunction associated with androgen ablation for prostate cancer (Jamadar, Winters, & Maki, 2012; Nelson, Lee, Gamboa, & Roth, 2008), chemotherapy for ovarian cancer (Correa & Hess, 2012; Correa et al., 2012; Correa, Zhou, Thaler, Maziarz, Hurley, & Hensley, 2010), and high-dose chemotherapy and stem cell transplantation for hematological cancers (Correa et al., 2013; Syrjala et al., 2011; Syrjala, Dikmen, Langer, Roth-Roemer, & Abrams, 2004) Primary brain tumors are classified by their predominant histologic appearance and location; they account for less than 2% of all cancers Gliomas are the most common primary tumors accounting for approximately 40% of all CNS neoplasms (Greenberg, Chandler, & Sandler, 1999) High-grade gliomas (WHO Grade III-IV) include glioblastoma multiforme, anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic mixed gliomas Low-grade gliomas (WHO Grade I-II) include astrocytomas, oligodendrogliomas, and mixed gliomas Other less frequent brain tumors are primary CNS lymphoma (PCNSL), ependymomas, meningiomas, and medulloblastomas (Bondy, El-Zein, Wrench, 2005) Brain metastases are also common intracranial tumors in adults (Mehta & Tremont-Lukas, 2004) Figure 23.1 Coronal and axial MRIs showing a brain tumor involving cortical and subcortical regions Cognitive Functions in Adults With Cancers As effective treatment interventions have increased survival, there has been greater awareness that many brain tumor patients experience cognitive dysfunction, despite adequate disease control (Poortmans et al., 2003) This dysfunction can be related to both the disease and its treatment including surgery, RT, and chemotherapy The side effects of medications such as corticosteroids and antiepileptics often contribute to or exacerbate these cognitive difficulties The relevance of including cognitive and quality of life (QoL) evaluations as outcome variables in neuro-oncology research has been increasingly recognized (Johnson & Wefel, 2013; Meyers & Brown, 2006) and the National Cancer Institute (NCI) Brain Tumor Progress Review Group report has recommended that routine cognitive and QoL assessment become the standard care for patients with brain tumors (BTPRG, 2000) Meyers and Brown (2006) published guidelines for the neuropsychological assessment of patients with brain tumors within the context of clinical trials The suggested core neuropsychological test batteries include standardized instruments with demonstrated sensitivity to the neurotoxic effects of cancer treatment and include tests of attention, executive functions, learning, and retrieval of new information, and graphomotor speed (Correa et al., 2004; Wefel, Kayl, & Meyers, 2004) The feasibility of incorporating a relatively brief cognitive test battery in multi-institutional clinical trials within the context of the Radiation Therapy Oncology Group (RTOG) has also been demonstrated (Meyers et al., 2004; Regine et al., 2004) Recent longitudinal studies documented that along with age, histology, and performance status, cognitive functioning is a sensitive and important factor in clinical trials involving patients with high-grade tumors (Reardon et al., 2011; Wefel et al., 2011) Performance on a test of verbal memory was independently and strongly related to survival after accounting for age, performance status, histology, extent of resection, number of recurrences, and time since diagnosis in patients with glioblastoma or anaplastic astrocytoma (Meyers, Hess, Yung, & Levin, 2000) Neuropsychological test performance predicted survival in patients with metastases and leptomeningeal disease (Meyers et al., 2004), and glioblastomas (Johnson, Sawyer, Meyers, O’Neill, & Wefel, 2012; Klein et al., 2003) Cognitive decline preceded radiographic evidence of tumor progression by several weeks in glioma patients (Armstrong, Goldstein, Shera, Ledakis, & Tallent, 2003; Brown et al., 2006; Meyers & Hess, 2003) However, these results are interpreted with caution considering that some studies had missing data, lacked a control group, and did not account for the possible effects of medications (Mauer et al., 2007) Disease and Treatment Effects Seizures, headaches, increased intracranial pressure, focal neurological signs, and cognitive impairment are common presenting symptoms in patients with brain tumors Several studies documented cognitive impairment at diagnosis and prior to RT or chemotherapy in patients with high-grade 561 gliomas (Klein et al., 2001), low-grade gliomas (Klein et al., 2002), and PCNSLs (Correa, DeAngelis, & Shi, 2007) Cognitive difficulties present at the time of diagnosis are often related to the location of the tumor (Klein et al., 2001), but a diffuse pattern of deficits has also been reported (Crossen, Goldman, Dahlborg, & Neuwelt, 1992) Rate of tumor growth is a predictor of cognitive impairment, as slow-growing tumors (e.g., low-grade gliomas) are often associated with less severe cognitive dysfunction than rapidly growing tumors (e.g., high-grade gliomas) (Anderson, Damasio, & Tranel, 1990; Hom & Reitan, 1984) Tumor type or volume has not been found to predict cognitive performance (Kayl & Meyers, 2003) Surgical resection can be associated with transient neurological and cognitive deficits due to damage to tumorsurrounding tissue and edema (Bosma et al., 2007; Duffau, 2005), with impairments often consistent with tumor location (Klein, 2012) Intraoperative stimulation mapping has been used in patients undergoing surgical resection for gliomas, and a recent meta-analysis (De Witt Hamer, Robles, Zwinderman, Duffau, & Berger, 2012) showed that the procedure was associated with fewer neurological deficits and allowed for more extensive resections However, the incidence and extent of cognitive dysfunction related to tumor surgical resection is unknown, given the relatively limited number of studies including pre- and postsurgical neuropsychological evaluations In addition, the specific contribution of the tumor to cognitive performance is difficult to ascertain considering that the majority of patients receive corticosteroids and antiepileptic medications following diagnosis and perioperatively Steroids may improve cognitive deficits due to resolution of edema (Klein et al., 2001), but can also be associated with transient mood disturbance and working memory difficulties (Bosma et al., 2007; Lupien, Gillin, & Hauger, 1999) Antiepileptics can disrupt some aspects of cognitive functions in brain tumor patients, particularly graphomotor speed and executive abilities (van Breemen, Wilms, & Vecht, 2007) Whole-Brain and Conformal Radiotherapy MECHANISMS OF CNS INJURY The pathophysiological mechanisms of radiation injury involve interactions between multiple cell types within the brain including astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes (Greene-Schloesser, Moore, & Robbins, 2013; Greene-Schloesser et al., 2012) Suggested mechanisms include depletion of glial progenitor cells and perpetuation of oxidative stress (Tofilon & Fike, 2000) Radiation may diminish the reproductive capacity of the O-2A progenitors of oligodendrocytes, disrupting the normal turnover of myelin Blood-vessel dilatation and wall thickening with hyalinization, increased blood-brain barrier 562 Denise D Correa and James C Root (BBB) permeability due to endothelial cell loss and apoptosis, and a decrease in vessel density have also been hypothesized to lead to white matter necrosis (Nordal & Wong, 2005; Warrington et al., 2013) The extent to which radiation damage is due to direct toxicity on cells or secondary to deleterious effects on the vasculature remains to be elucidated (Noble & Dietrich, 2002) Progressive demyelination may take months to cause symptoms because of the slow turnover of oligodendrocytes, contributing to the latency in onset of neurotoxicity and its progressive nature In addition, RT achieves therapeutic effects in part through DNA damage by introducing interstrand DNA and DNA-protein crosslinks, single- and double-stranded DNA breaks, methylation, oxidation, and by increasing formation of reactive oxygen species (ROS) Increased numbers of reactive astrocytes and microglia have been shown to produce ROS, proinflammatory cytokines, and growth factors that may cause progressive inflammatory injury (Kim, Brown, Jenrow, & Ryu, 2008) The accumulation of DNA damage in neuronal cells, when unrepaired, can lead to the transcription of defective proteins, apoptosis, and neurodegeneration (Fishel, Vasko, & Kelley, 2007) Recent animal and human studies have documented that RT, chemotherapy, and corticosteroids can disrupt hippocampal neurogenesis (Dietrich et al., 2006; Fike, Rosi, & Limoli, 2009; Monje & Dietrich, 2012; Monje et al., 2007) RT produces elevation of inflammatory cytokines in the brain (Lee, Sonntag, Mitschelen, Yan, & Lee, 2010), and inflammation surrounding neural stem cells may contribute to neurogenesis inhibition (Monje, Toda, & Palmer, 2003) RT-induced apoptosis and a decline in neurogenesis in the subgranular zone of the dentate gyrus were associated with deficits in hippocampal-dependent tasks in some studies (Madsen, Kristjansen, Bolwig, & Wortwein, 2003; Raber et al., 2004) CLINICAL FINDINGS Radiation encephalopathy has been classified into three phases according to the time between the administration of RT and the development of symptoms (DeAngelis & Posner, 2009) These are described as acute, early delayed, and late delayed Acute encephalopathy develops within days of RT and the most common symptoms are nausea, headache, and worsening of neurological signs Disruption of the BBB by endothelial apoptosis, increased cerebral edema, and intracranial pressure have been suggested as underlying mechanisms Early delayed effects occur within a few weeks to six months following RT and are reversible in most cases Lethargy, somnolence, and resurgence of neurological signs, and a transient decline in cognitive functioning may occur, but these factors are not predictive of delayed cognitive deficits Transient white matter hyperintensity suggesting demyelination may be seen on magnetic resonance imaging (MRI), and are thought to be related to BBB disruption or injury to oligodendrocytes The late-delayed effects of RT become apparent a few months to many years after treatment, and often produce irreversible and progressive damage to the CNS (Sheline, Wara, & Smith, 1980) Risk factors for developing delayed RT-induced brain injury include greater volume of radiated tissue, higher total dose of RT (> Gy dose per fraction), concomitant administration of chemotherapy, age greater than 60 years, and presence of comorbid vascular risk factors (Behin, 2003; Constine, Konski, Ekholm, McDonald,  & Rubin, 1988; DeAngelis & Posner, 2009) MRI typically shows hyperintensities in periventricular and subcortical white matter, and these changes are often more pronounced in older patients (see Figure 23.2) Radiationinduced microbleeds were recently described in patients with gliomas treated with external-beam RT (Bian, Hess, Chang, Nelson, & Lupo, 2013) In a diffusion tensor imaging (DTI) study, there was evidence of early dose-dependent progressive demyelination and axonal degeneration after RT, and subsequent diffuse dose-independent demyelination (Chapman et al., 2013; Nagesh et al., 2008) Chapman et al (2013) used DTI to study 14 patients with brain metastases before and after whole-brain RT ± chemotherapy The results showed regional variation in white matter changes post-RT, with a significant decrease in fractional anisotropy in the cingulate and fornix A study using positron emission tomography (PET) in a small cohort of brain tumor patients reported dose-dependent reduction in glucose metabolism in brain regions that received greater than 40 Gy at three- and sixmonth follow-ups; these changes correlated with decreased performance on tests of problem solving and cognitive flexibility (Hahn et al., 2009) A substantial number of brain tumor patients treated with RT experience cognitive dysfunction that varies from mild to severe, and it is currently considered the most frequent complication among long-term survivors (Behin, 2003) The peak of neurocognitive difficulties resulting from RT occurs Figure 23.2 T1-weighted axial MRIs showing periventricular white matter abnormalities in a 50-year-old man six years post treatment with high-dose chemotherapy and whole-brain radiotherapy Cognitive Functions in Adults With Cancers approximately six months to two years after treatment completion, and its incidence is proportional to the percentage of patients with disease-free survival (DeAngelis, Yahalom, Thaler, & Kher, 1992) The variability in the documented frequency of RT-induced cognitive deficits may be partially associated with the insensitivity of the methods of assessment used, duration of follow-up, retrospective nature of many studies, inclusion of patients treated with different regimens, and population discrepancies In addition, the high incidence of tumor recurrence and short-term survival in patients with high-grade malignancies have often been considered confounding variables that hampered the ability to quantify the frequency, onset, and course of the delayed cognitive effects of RT (Crossen, Garwood, Glatstein, & Neuwelt, 1994) A review of the literature suggests that the pattern of neuropsychological impairments associated with the delayed effects of whole-brain RT is diffuse (Duffey, Chari, Cartlidge, & Shaw, 1996), and most consistent with frontal-subcortical dysfunction with deficits in attention, executive functions, learning and retrieval of new information, and graphomotor speed (Archibald et al., 1994; Crossen et al., 1994; Salander, Karlsson, Bergenheim, & Henriksson, 1995; Scheibel, Meyers, & Levin, 1996; Taphoorn & Klein, 2004; Wefel, Kayl, et al., 2004; Weitzner & Meyers, 1997) In recent years, conformal RT that includes the area of the tumor and surrounding margin has supplanted whole-brain RT in the treatment of gliomas due to equivalent efficacy and reduced neurotoxicity (DeGroot, Aldape, & Colman, 2005) Some studies suggest that conformal RT is associated with less severe cognitive dysfunction than whole-brain RT (Torres et al., 2003), but most studies were retrospective and revealed variable outcomes ranging from no morbidity to marked cognitive deficits (Armstrong et al., 2000; Armstrong et al., 2002; Postma et al., 2002; Surma-aho et al., 2001; Taphoorn et al., 1994) Recent research reported that radiation dose to specific regions, such as the right temporal lobes and the hippocampi, may be more predictive of cognitive impairment than total RT dose (Peiffer et al., 2013) Similarly, a prospective study of patients with low-grade or benign tumors treated with fractionated stereotactic RT reported a dose-response relationship, with higher RT doses to the hippocampi showing an association with impairment in word-list delayed recall (Gondi, Hermann, Mehta, & Tome, 2013) Chemotherapy Alone or Combined WithRadiotherapy The pathophysiological mechanisms of chemotherapyinduced CNS damage are not well understood Candidate mechanisms include demyelination, secondary inflammatory response, oxidative stress, and DNA damage; immune dysregulation; and microvascular injury (Ahles & Saykin, 2007) There is increasing evidence that chemotherapy has direct toxic effects on progenitor cells, oligodendrocytes, white matter, gliogenesis, and neurogenesis (Dietrich, 2010) Increased cell death and decreased cell division in the subventricular 563 zone and in the dentate gyrus of the hippocampus have been reported in mice (Dietrich et al., 2006; Dietrich, Monje, Wefel, & Meyers, 2008); neural progenitor cells and oligodendrocytes are particularly vulnerable Neurotoxicity has been reported after high-dose regimens with procarbazine, lomustine, and vincristine (PCV) chemotherapy (Postma et al., 1998), and after high-dose methotrexate (HD-MTX) and high-dose cytarabine, particularly if RT is administered before or during chemotherapy (DeAngelis & Shapiro, 1991; see Figure 23.2) Chemotherapy administered intrathecally is more likely to cause CNS toxicity than when it is applied systemically Combined treatment with RT and chemotherapy may have a synergistic effect (Keime-Guibert, Napolitano, & Delattre, 1998), as chemotherapy agents may interfere with the same cellular structures as radiation and may act as a radiosensitizer Radiation may alter the distribution kinetics of chemotherapeutic agents in the CNS by increasing the permeability of the BBB, affecting the ability of arachnoid granulations or choroid plexus to clear the drug, or interrupting the ependymal barrier to allow drugs in the cerebrospinal fluid to enter the white matter Finally, RTinduced cellular changes may allow greater amounts of the drug to enter nontumor cells or less of it to exit The interactions between RT and HD-MTX are the most clearly demonstrated (Keime-Guibert et al., 1998), and nonenhancing, confluent lesions in the periventricular and subcortical white matter have been documented on MRI studies (Correa et al., 2004; Keime-Guibert et al., 1998) Decrease in white matter density in the corpus callosum, hippocampal cell death, and memory impairments were reported in rats treated with HDMTX (Seigers et al., 2009) Carmustine, cyclophosphamide, cisplatin, cytarabine, thiotepa, and methotrexate were found to be associated with neurotoxicity, with changes in cortical and subcortical brain regions (Rzeski et al., 2004) Deficits in spatial and nonspatial memory have been described after administration of methotrexate and 5-fluorouracil in mice (Winocur, Vardy, Binns, Kerr, & Tannock, 2006) However, the cognitive side-effects of chemotherapy are often difficult to determine in brain tumor patients as most also receive RT in the course of their treatment Variation in genetic polymorphisms may increase the susceptibility to cognitive dysfunction following RT ± chemotherapy In a recent cross-sectional study (Correa, et al., 2013), brain tumor patients with at least one Apolipoprotein E (APOE) є-4 allele had significantly lower scores in verbal learning and delayed recall, and marginally significant lower scores in executive function, in comparison to non-carriers of a є-4 allele Neuropsychological Studies High-Grade Tumors Patients with high-grade gliomas often present with symptoms of increased intracranial pressure, seizures or focal 564 Denise D Correa and James C Root neurological signs (Greenberg et al., 1999) The majority of patients undergo surgical tumor resection and receive a combined modality regimen of RT and chemotherapy; recent trials involving glioblastoma patients have also included antiangiogenic therapy with bevacizumab (Gilbert et al., 2014) The median survival time is less than two years for patients with glioblastomas, and two to three years for anaplastic astrocytomas (Carson, Grossman, Fisher, & Shaw, 2007; Stupp et al., 2005) Cognitive impairment in patients with high-grade gliomas is multifactorial and includes the tumor and the adverse effects of treatment Disease recurrence and short-term survival have been considered confounding variables that limit the ability to quantify the frequency, onset, and course of the delayed cognitive effects of RT and chemotherapy Several studies have suggested that tumor progression contributes significantly to cognitive decline, and that relatively stable performance is seen in patients without recurrent disease (Brown et al., 2006) Klein et al (2001) studied cognitive functioning in 61 patients with high-grade gliomas following surgery or biopsy, and included comparison groups of 50 patients with lung cancer and age-matched healthy controls As compared to healthy controls, cognitive impairment (i.e., attention and executive functions) was evident in all glioma patients and 52% of lung cancer patients The use of antiepileptic medication was associated with working memory deficits Patients with tumors in the right hemisphere had greater difficulties in visuospatial tests, and patients with left hemisphere tumors showed greater susceptibility to interference and slower visual scanning Bosma et al (2007) assessed cognitive functions at eight- and 16-month intervals after RT in 32 and 18 high-grade glioma patients, respectively Patients with tumor progression had a more pronounced cognitive decline (i.e., psychomotor speed, executive functions) than patients who remained stable; however, the decline was also considered to be in part related to the side effects of antiepileptics and corticosteroids However, in a recent study of patients with high-grade tumors (de Groot et al., 2013) treated with levetiracetam (n = 35), valproic acid or phenytoin (n = 38), or no antiepileptics (n = 44), there were no significant differences on cognitive test performance between patients on newer compared to older antiepileptics and patients receiving no medication six weeks postsurgery; there was a beneficial effect of both antiepileptics on verbal memory Hilverda et al (2010) studied 13 patients with glioblastoma multiforme treated with RT and temozolomide with no evidence of disease progression Neurocognitive evaluations were performed after surgery, six weeks post-RT and concomitant temozolomide, and after three cycles of adjuvant temozolomide in progression-free patients The results showed that at baseline, 11 patients had impaired attention, information processing speed, and executive functions in comparison to healthy controls At the first follow-up, four patients improved, four deteriorated, and the others were relatively stable At the last follow-up, cognitive performance remained stable in all domains for 11 patients, with one patient improving and one patient declining in the interim The authors concluded that cognitive functions are likely to be relatively stable in the absence of disease progression Froklage and colleagues (2013) assessed cognitive functions and radiological abnormalities in patients with newly diagnosed high-grade gliomas treated with chemoradiation followed by adjuvant temozolomide Neuropsychological assessments were conducted before treatment and prior to adjuvant temozolomide (n = 33), during and after temozolomide (n = 25 and 17, respectively), and three and seven months post treatment completion (n = and 5, respectively); patient dropout was primarily due to disease progression In comparison to matched healthy controls, 63% of patients had deficits in executive functions, processing speed and working memory at baseline Approximately 70% of the patients remained stable during the follow-up period, and most of the patients who declined had tumor progression Cerebral atrophy and white matter hyperintensities developed or worsened in approximately 45% of patients during follow-up Brown et al (2006) reported the results of prospective Mini-Mental Status Examinations (MMSE) in 1, 244 highgrade tumor patients who participated in the North Central Cancer Treatment Group treatment trials, which used radiation and nitrosurea-based chemotherapy The proportion of patients without tumor progression who had significant cognitive deterioration ranged from 13% to 18%, and remained stable over the 24-month follow-up period; a decline in MMSE scores was a predictor of more rapid time to tumor progression and preceded radiographic changes Corn et al (2009) examined QoL and mental status in 203 patients with glioblastoma multiforme within the context of a Phase I/ II study of the RTOG to assess the impact of dose escalation conformal RT Patients were administered the MMSE at the start and at the end of radiation, and at four-month intervals subsequently The results showed a decline in the MMSE over the follow-up period, and this was considered to be at least in part related to RT However, considering the demonstrated low sensitivity of cognitive screening measures (e.g., MMSE) to detect cognitive dysfunction in brain tumor patients (Meyers & Wefel, 2003), the findings of these two large studies may represent an underestimation A Phase II trial evaluated cognitive functioning in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy (Wefel et al., 2011) Patients with objective response to treatment or progression free survival greater than six months had stable median cognitive test scores across the 24-month follow-up, but patients with evidence of progressive disease exhibited cognitive decline In a prospective study of newly diagnosed glioblastoma patients treated with temozolomide, hypofractionated stereotactic RT and bevacizumab, 37 patients underwent longitudinal neuropsychological evaluations (Correa et al., 2011) Linear mixed model analyses showed a significant decline in Cognitive Functions in Adults With Cancers set-shifting and verbal learning (p < 0.05) from baseline to the four-month follow-up, and performance remained stable or improved slightly at subsequent intervals Visuospatial memory was stable at four months, but showed a trend toward a decline at subsequent follow-ups The decline in executive functions and memory in the early phase of treatment was thought to be related to the acute effects of RT In a recent, large clinical trial for patients with newly diagnosed glioblastoma comparing the efficacy of standard chemo-radiation, maintenance temozolomide, and placebo or bevacizumab, cognitive evaluations were performed longitudinally in patients without disease progression (Gilbert et al., 2014) The initial results suggested that patients randomized to bevacizumab, compared to placebo, experienced greater decline over time in executive functions and information processing speed, suggesting either bevacizumab-related neurotoxicity or unrecognized tumor progression In a recent study of long-term survivors of anaplastic oligodendrogliomas treated with RT versus RT and procarbazine, lomustine and vincristine (Habets et al., 2014), a variable pattern of cognitive impairment was seen in 75% of patients who were progression free, regardless of initial treatment type Low-Grade Tumors Low-grade gliomas are slow-growing infiltrative tumors most common in young and middle-aged adults, and the majority of patients present with seizures and headaches (Greenberg et al., 1999) The median survival ranges from five to ten years, and these tumors invariably progress to more aggressive high-grade gliomas (Shaw et al., 2002) Treatment interventions remain controversial regarding the optimal timing of surgical intervention, RT, and chemotherapy (Cairncross, 2000; Kiebert et al., 1998; Shaw et al., 2002; Soffietti et al., 2010) Several studies that documented cognitive dysfunction in low-grade glioma patients found that the tumor itself, rather than RT, was the primary contributing factor (Laack et al., 2003; Taphoorn et al., 1994; Torres et al., 2003) However, studies including long-term survivors reported that both partial and whole-brain RT was associated with cognitive dysfunction several years after treatment completion (Douw et al., 2009), and a decline in nonverbal memory was evident in some studies Tumor-related epilepsy and the side effects of antiepileptic medications also contribute to cognitive dysfunction in these patients (Klein, 2012) Methodological problems including differences in the sensitivity of the neuropsychological measures administered, retrospective designs, and the inclusion of patients with high- and lowgrade tumors, and patients treated with partial and wholebrain RT (Imperato, Paleologos, & Vick, 1990; Kleinberg, Wallner, & Malkin, 1993; Torres et al., 2003) may account for some of the variability of the findings in the literature A recent report by the Response Assessment in NeuroOncology group (RANO), recommended that standardized assessments of cognitive functions and QoL be incorporated 565 in clinical trials involving low-grade glioma patients (van den Bent et al., 2011) The characterization of tumor- and treatment-related cognitive dysfunction in patients with low-grade tumors is particularly relevant given the relatively prolonged survival and the controversy in the effectiveness of early treatment A cross-sectional study assessed cognitive outcome in 195 low-grade glioma patients (104 treated with RT 1–22 years prior to enrollment) compared to 100 low-grade hematological cancer patients, and 194 healthy controls (Taphoorn et al., 1994) Glioma patients completed the cognitive evaluation at a mean of six years after diagnosis, and obtained lower test scores than the cancer control group on psychomotor speed, visual memory, and executive functions Although the authors concluded that the tumor had the most detrimental effects on cognition, decreased verbal and visual memory was evident in patients who received RT in daily fractions exceeding Gy, and some of the cognitive test scores declined over time only among those treated with RT Antiepileptic treatment was associated with more pronounced cognitive dysfunction A follow-up study (Douw et al., 2009) included 65 of these patients who underwent a neuropsychological re-evaluation at a mean of 12 years (range 6–28 years) after the initial assessment Patients who received RT showed a decline in attention, executive function, and information processing speed, regardless of fraction dose White matter hyperintensities and cortical atrophy correlated with worse cognitive test performance Surma-aho et al.(2001) assessed cognitive functioning in low-grade glioma patients approximately seven years post-RT ± chemotherapy (n = 28) or surgical resection alone (n = 23); 19 patients had whole-brain RT and nine had focal RT The results showed that patients treated with RT had significantly lower scores in percent retention of visual materials and estimated Performance IQ, and more extensive periventricular white matter abnormalities on MRI, in comparison to patients who did not receive RT The authors concluded that RT increased the risk for cognitive impairment and leukoencephalopathy in patients with low-grade tumors Correa et al (2007) studied cognitive functions in 40 patients with low-grade gliomas: 24 patients had surgery only, and 16 had conformal RT ± chemotherapy Patients treated with RT ± chemotherapy had lower scores in attention and executive functions, psychomotor speed, verbal and nonverbal memory, and naming than untreated patients In addition, patients who completed treatment at intervals greater than three years had significantly lower scores in nonverbal memory Antiepileptic polytherapy, treatment history, and disease duration contributed to reduced psychomotor speed; 62% of treated patients had white matter disease on MRI, whereas only 10% of the untreated patients had such changes In a subsequent study (Correa et al., 2008), 25 of these patients completed additional cognitive follow-ups The results showed a mild decline in nonverbal memory 12 months after the initial evaluation regardless of treatment 566 Denise D Correa and James C Root status; scores remained one standard deviation below normative values in other cognitive domains Among the 16 patients who completed a subsequent evaluation (12–27 months later), there was improvement in untreated patients, but a decline in some aspects of executive function in patients treated with RT ± chemotherapy Disease duration and treatment history were thought to contribute to the pattern of findings Armstrong et al (2000) assessed cognitive functions prospectively in 20 patients with low-grade tumors treated with conformal RT A decrement in verbal memory retrieval was evident during the early delayed period following RT with improvement at longer intervals The long-term effects of RT on cognition were examined in a subsequent study involving 26 patients with low-grade tumors (Armstrong, Stern, & Corn, 2001) A selective decline in learning and recall of visual information five years post-RT was detected despite continued improvement up to that point Long-term improvements were noted on tests of attention, executive functions, and verbal recall The authors concluded that partial RT was not associated with significant delayed cognitive impairments in this population In a recent study (Gondi et al., 2013), 18 patients with low-grade or benign tumors treated with fractionated stereotactic RT completed a neuropsychological evaluation at baseline and 18 months following treatment The results suggested that RT dose greater than 7.3 Gy to 40% of the bilateral hippocampi was associated with impairment on a list-learning delayed recall test Alterations in functional connectivity using magnetoencephalography have also been described recently in patients with low-grade gliomas (Bosma et al., 2008) Primary Central Nervous System Lymphoma (PCNSL) PCNSL is a rare infiltrative tumor that develops most frequently in the subcortical periventricular white matter, with single lesions occurring in 60%–70% of patients and multifocal lesions in 30%–40% It is a disease of middle and late adult life with a mean age at diagnosis of 60 years, and it is slightly more common in men Focal neurological signs are the most common presentation followed by psychiatric symptoms, headaches, and seizures (Batchelor et al., 2012; Rubenstein, Ferreri, & Pittaluga, 2008) The standard treatment for PCNSL often includes HD-MTX regimens and whole-brain RT Although this treatment approach is effective, with a median survival of 30 to 60 months (DeAngelis et al., 2002), it is associated with delayed neurotoxicity in most patients (Correa et al., 2012; Poortmans et al., 2003; Thiel et al., 2010) Delayed treatment-related cognitive dysfunction has been recognized as a frequent complication among long-term survivors, and may interfere with QoL (Correa et al., 2007) Recent studies suggest that HD-MTX without RT can be efficacious in the treatment of PCNSL and diminish the risk for delayed neurotoxicity (Juergens et al., 2010; Rubenstein et al., 2013; Thiel et al., 2010) However, since disease relapse is relatively common and some patients require salvage therapy, the optimal induction and consolidative therapy for PCNSL remains controversial The importance of assessing the incidence and extent of cognitive dysfunction associated with HD-MTX regimens with and without WBRT has been recognized by the International Primary CNS Lymphoma Collaborative Group (IPCG; (Abrey et al., 2005; Ferreri, Zucca, Armitage, Cavalli, & Batchelor, 2013) and guidelines for standardized cognitive assessments to be incorporated in clinical trials have been developed (Correa et al., 2007) A literature review indicated that cognitive function was evaluated systematically in a relatively limited number of studies, and methodological problems limited the understanding of the contribution of disease and treatments (Correa et al., 2007) RT AND CHEMOTHERAPY REGIMENS Studies involving patients treated with whole-brain RT and HD-MTX, or with whole-brain RT and chemotherapy with BBB disruption reported significant cognitive impairment The pattern of cognitive deficits was diffuse and the domains disrupted included attention and executive functions, psychomotor speed, and learning and retrieval of new information Harder et al (2004) studied cognitive functions in 19 PCNSL patients at a mean of 23 months after treatment with HD-MTX followed by whole-brain RT In comparison to a non-CNS-cancer control group, PCNSL patients had lower scores on verbal and nonverbal memory, attention, executive function, and motor speed Correa et al (2012) studied 50 PCNSL treated with whole-brain RT and HDMTX (n = 24), or HD-MTX alone (n = 26) between three and 54 months posttreatment Patients treated with whole-brain RT and HD-MTX had impairments in selective attention and executive functions, verbal memory, and graphomotor speed across most cognitive domains; these were of sufficient severity to interfere with QoL as more than 50% were not working due to their illness Patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen Patients with more extensive white matter disease on MRIs had lower scores on tests of set-shifting and memory Thirty-three patients completed an additional follow-up cognitive evaluation at a mean of 14–16 months after the initial visit The results suggested no significant changes on any of the cognitive tests among patients treated with whole-brain RT and HD-MTX, but patients who received HD-MTX alone obtained a significantly higher score on auditory attention Doolittle, Korfel, et al (2013) studied neuropsychological functions and neuroimaging outcomes in 80patients with PCNSL evaluated at a median of 5.5 years (range: to 26 years) after diagnosis Treatment modalities included: HD-MTX (n = 32), HDMTX (intra-arterial) in conjunction with BBB disruption (n = 25), HD-MTX followed by high-dose chemotherapy and Cognitive Functions in Adults With Cancers autologous stem cell transplant (ASCT) (n = 8), and HDMTX followed by whole-brain RT (n = 15); five of these patients also received high-dose chemotherapy and ASCT prior to whole-brain RT Patients treated with HD-MTX and whole-brain RT had significantly lower mean scores in attention, executive function, and motor speed than patients treated with HD-MTX in conjunction with BBB disruption, and all patients treated without WBRT combined Among patients treated with BBB disruption chemotherapy, there was a significant improvement in executive functions and no evidence of decline in other domains (Doolittle, Dosa, et al., 2013) White matter abnormalities were more extensive in the patients treated with RT The findings were consistent with other studies, suggesting increased risk for delayed neurotoxicity following combined modality regimens However, the retrospective nature of these studies limited the ability to examine the specific contributions of the tumor and the delayed effects of treatment In a recent prospective study (Correa et al., 2009; Morris et al., 2013), PCNSL patients treated with induction rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain RT (23.4 Gy) and cytarabine underwent cognitive evaluations prior to treatment and up to four years after treatment completion At baseline, impairments in selective attention, memory, and motor speed were evident After induction chemotherapy, there was a significant improvement in executive function and memory There was no evidence of significant cognitive decline during the follow-up period, except for motor speed The preliminary findings were interpreted as evidence that cognitive dysfunction was primarily related to the disease, and that the new treatment approach with low-dose RT may not be associated with progressive cognitive decline CHEMOTHERAPY REGIMENS The studies that reported cognitive outcome in PCNSL patients treated with HD-MTX alone or with BBB disruption chemotherapy without RT were mostly prospective (Correa et al., 2007) Several studies documented cognitive impairment prior to therapy in attention, executive functions, memory, graphomotor speed, and language Posttreatment follow-up intervals were variable across studies, but several reported either stable or improved cognitive performance Methodological problems in several of these studies, however, limited the ability to discern the specific contributions of the disease and chemotherapy alone regimens to cognitive dysfunction Pels et al (2003) performed cognitive evaluations in 22 patients between four and 82 months after completion of treatment with HD-MTX There was no evidence of decline in attention, verbal memory, visual memory, word fluency, or visual-construction abilities in patients who had either a partial or a complete response to treatment Fliessbach et al (2005) assessed cognitive functions in 23 patients prior 567 to and up to a median of 44 months after treatment with HD-MTX (all patients were in disease remission) At the pretreatment baseline, impairments were evident in attention and executive functions, verbal and nonverbal memory, and word fluency; these were classified as mild (z ≤ −1.5) in three patients, moderate (z ≤ −2 and > −3) in ten, and severe (z ≤ −3) in six patients At the last follow-up, impairment (in at least one domain) was mild in five patients, moderate in five, and severe in one; 12 patients had no deficits Twenty-one patients improved, but scores remained in the low average range on tests of attention, non-verbal memory, and word fluency The authors concluded that the cognitive deficits were associated primarily with tumor and there was no treatment-related cognitive decline The most sensitive domains were attention, executive functions, and memory McAllister et al (2000) studied a cohort of 23 prior to and post BBB disruption chemotherapy (mean =16.5 months, SD = 10.9) The results showed significantly improved cognitive functioning posttreatment (summary z-score) When examining individual tests, there was evidence of improvement in intellectual functioning, learning, memory, attention, and visuospatial skills, with a nonsignificant trend demonstrated for executive functioning; seven patients had cognitive decline, mostly in motor speed Neuwelt et al (1991) studied 15patients before and one year after BBB disruption chemotherapy; nine patients were also seen for long-term follow-up (mean of 3.5 years after diagnosis) Focus of data analysis was on the summary z-score, which ranged at baseline from −2.59 to 0.46 with a mean of −1.1 (SD = 1.1) At the end of treatment, the summary score ranged from −1.45 to 0.26 with a mean of 0.35 (SD = 0.52), suggesting a significant improvement in cognitive functioning from baseline As reported recently by Doolittle, Dosa, et al (2013), longterm follow-up of PCNSL patients at a median of 12years after BBB disruption chemotherapy indicated either stable or improved cognitive functions Metastatic Brain Tumors Brain metastases are common and develop most often in patients with lung cancer (50%), followed by breast cancer (15%–20%) and melanoma (10%), and less frequently in other cancers (e.g., colorectal, kidney) (Lassman & DeAngelis, 2003) Patients may present with headaches, focal weakness, altered mental status, and seizures Standard treatment has involved surgical resection and external beam whole-brain RT; the median survival is four to six months (Lassman & DeAngelis, 2003) Recent randomized trials comparing stereotactic radiosurgery plus whole-brain RT versus whole-brain RT alone reported improvement in survival with the addition of radiosurgery in patients with solitary metastases (Andrews et al., 2004; Ayoma et al., 2006) Temozolomide and radiosensitizers have also been added to the regimen recently (Abrey et al., 2001) Although wholebrain RT has been shown to improve tumor control across 568 Denise D Correa and James C Root several studies (Brown, Asher, & Farace, 2008) and to reduce the development of subsequent metastases (Kocher et al., 2011), the neurotoxicity of whole-brain RT, including cognitive dysfunction, has been a concern A recent report by RANO supports the inclusion of standardized assessments of cognitive functions and QoL in clinical trials involving patients with brain metastases (Lin et al., 2013) Deficits in memory and motor speed have been documented in patients with newly diagnosed or recurrent metastases evaluated either during or after whole-brain RT (Herman et al., 2003; Platta, Khuntia, Mehta, & Suh, 2010) Several studies also documented cognitive dysfunction prior to therapy, and Meyers et al (2004) reported that baseline cognitive performance predicted survival in patients with brain metastases A pilot study including 15 patients treated with stereotactic radiosurgery alone (Chang et al., 2007) documented impaired executive function, manual dexterity, and memory at baseline; 13 patients declined on one or more tests at the one-month follow-up, and the five long-term survivors had stable or improved cognitive performance Welzel et al (2008) studied memory functions prospectively in 44 patients treated with prophylactic RT for small-cell lung cancer and in patients with brain metastases treated with whole-brain RT At baseline, lung cancer patients had lower memory scores than patients with brain metastasis Verbal memory decline was evident during RT in patients with metastases only, but at the eight-week post-RT follow-up both groups had memory impairment Meyers et al (2004) studied cognitive outcome in the context of a Phase II randomized trial involving 400 patients with brain metastases treated with whole-brain RT alone or in combination with motexafin gadolinium At baseline, 91% of patients had impairment in one or more cognitive domains, and 42% had impairment in four of eight tests Optimal tumor control following treatment correlated with preservation of cognitive function, and in a small group of long-term survivors there was stable or improved performance In a Phase III trial involving 554 patients with brain metastasis (Mehta et al., 2009), the interval to neurocognitive decline was prolonged in the group treated with whole-brain RT and motexafin gadolinium Serial neurocognitive assessments were performed in the context of a randomized trial involving patients with one to three brain metastases treated with radiosurgery (n = 30) versus radiosurgery plus wholebrain-RT (n = 28) (Chang et al., 2009) Patients treated with radiosurgery plus whole-brain RT were significantly more likely to show a decline in verbal learning at four months posttreatment than patients treated with radiosurgery alone In a study of 208 brain metastases patients treated with whole-brain RT (30 Gy) (Li, Bentzen, Renschler, & Mehta, 2007), the median time to decline in executive and motor functions was longer in patients with a poor response to treatment (i.e., less tumor shrinkage) In patients surviving more than 15 months, reduced tumor size was correlated with preserved executive and motor functions, but not with memory performance; a significant decline in memory at four months posttreatment was noted In addition, the risk of delayed leukoencephalopathy was found to be significantly higher for patients with brain metastases treated with radiosurgery and whole-brain RT relative to patients who had radiosurgery alone (Monaco et al., 2013) A recent review of randomized controlled studies involving patients treated with prophylactic RT, radiosurgery, and radiosurgery and whole-brain RT suggested that whole-brain RT, particularly high-dose regimens (36 vs 25 Gy), was associated with a deleterious effect in memory, executive functions, and processing speed (McDuff et al., 2013) Preventive or Treatment Interventions There are no established preventive or therapeutic interventions for cancer-treatment-related cognitive dysfunction Ghia et al (2007) developed a hippocampal-sparing intensity-modulated approach to whole-brain RT that limits the radiation dose to the hippocampus with the intent of reducing the neurocognitive sequelae of RT Preliminary results from a clinical trial involving 113 patients with brain metastases (Gondi et al., 2013) showed that sparing the subgranular zone of the hippocampus during whole-brain RT was associated with more preserved memory function at the fourand six-month posttreatment follow-ups, in comparison to historical controls treated with standard whole-brain RT; however, only 28 patients were available for the six-month assessment (Brown et al., 2013) In a randomized study, the potential protective effects of memantine versus placebo on cognitive function were evaluated in 508 patients with brain metastases receiving whole-brain RT (Brown et al., 2013) The results showed that patients treated with memantine had significantly longer time to cognitive decline, and a reduced rate of decline in memory, executive function, and processing speed compared to placebo; however, attrition may have limited statistical power as only 29% of patients completed the 24-week assessment Treatments that target the vascular mechanism of RT damage including hyperbaric oxygenation, anticoagulation, and aspirin have been attempted, but without clear benefits (DeAngelis & Posner, 2009) There is preliminary evidence suggesting that bevacizumab may reduce abnormal enhancement associated with necrosis, possibly through the removal of VEGF-induced reactive vascularization (Torcuator et al., 2009) In a placebo-controlled, randomized study of bevacizumab for the treatment of RT necrosis in 14 brain tumor patients (Levin et al., 2011), there was a decrease in MRI enhancement and improvement in neurological symptoms in all patients treated with bevacizumab A decrease in radiation necrosis on MRI following bevacizumab was also reported in 11 patients with brain metastases treated with stereotactic radiosurgery (Boothe et al., 2013) However, a recent review of the use of bevacizumab for the treatment of RT necrosis suggested that although most studies reported Cognitive Functions in Adults With Cancers a reduction in radiographic volume of necrosis-associated edema, a high rate of serious complications raised concerns about this treatment approach (Lubelski, Abdullah, Weil, & Marko, 2013) Pharmacological treatments for RT-induced cognitive dysfunction have been based primarily on therapies used for other neurological disorders that cause similar symptoms (Kim et al., 2008) Agents such as psychostimulants and acetylcholinesterase inhibitors have been used to treat cognitive dysfunction in patients with brain tumors Comprehensive reviews of studies on interventions for this clinical population indicated that there are several completed and ongoing trials using these and other medications, as well as cognitive rehabilitation and behavioral interventions (Gehring, Aaronson, Taphoorn, & Sitskoorn, 2010; Wefel, Kayl, et al., 2004) A prospective open-label Phase II study was conducted to assess the efficacy of donepezil in the treatment of cognitive dysfunction in 24 patients with primary brain tumors (Shaw et al., 2006) After 24 weeks of treatment there was evidence of improvement in attention, verbal and visual memory, in mood, and QoL A recent open-label randomized pilot study examined the efficacy of four weeks of methylphenidate and modafanil in 24 brain tumor patients either during or following treatment with RT or chemotherapy (Gehring et al., 2012) The results showed a beneficial effect of stimulant treatment in speed of processing and executive functions requiring divided attention, and on patient-reported fatigue and QoL, regardless of the medication used However, the results were interpreted with caution give the small sample size and large proportion of dropouts A recent multicenter double-blind placebo-controlled study including 37 patients with primary brain tumors treated with modafinil for six weeks showed no beneficial effects on cognitive function, fatigue, or mood in comparison to placebo (Boele et al., 2013) The small number of studies using cognitive rehabilitation in brain tumor patients suggests some beneficial effects, but problems with accrual and attrition and methodological problems limit the evaluation of its efficacy (Gehring et al., 2010) In a study involving 13 brain tumor patients (Sherer, Meyers, & Bergloff, 1997), there was a significant increase in functional independence in approximately half of the patients following three to 12 weeks of training in the use of compensatory strategies Locke et al (2008) compared the feasibility of memory and problem solving training in dyads of primary brain tumor patients and caregivers versus a no-intervention control group At the three-month follow-up 50% of patients reported using the strategies, but there was no significant intervention effect on QoL and functional capacity and not enough patients completed the neuropsychological assessment Gehring et al (2008) conducted a randomized controlled trial to assess the efficacy of computer-based attention training and compensatory skills training in 140 patients with gliomas; patients were randomly assigned to the intervention group or to a wait list control 569 group There was a significant improvement in self-reported cognitive function but not on neuropsychological test performance immediately after completion of the seven-week program Conversely, at the six-month follow-up patients showed an improvement in attention and verbal memory, but not on self-reported cognitive function The prevention of cognitive deficits with agents that may protect neurons from treatment-induced damage is an area of growing interest (Kim et al., 2008), and the potential neuroprotective effects of lithium and other agents are under investigation (Gehring et al., 2010; Khasraw, Ashley, Wheeler, & Berk, 2012; Wefel, Kayl, et al., 2004) Non-CNS Cancers Beyond the effects of primary CNS cancers on cognition, non-CNS cancer diagnosis and treatment has also been found to be associated with cognitive dysfunction Among primary cancers, breast cancer is relatively common, with approximately 124 per 100,000 new cases diagnosed each year, and a prevalence of approximately 2.8 million women currently diagnosed in the United States alone (http://seer cancer.gov/statfacts/html/breast.html), with 89% survival rates of five years or more Given its prevalence and survival rates, cognitive changes associated with breast cancer diagnosis and treatment have been most widely studied In this section we review cross-sectional and longitudinal studies assessing neuropsychological outcome and self-reported cognitive dysfunction in individuals diagnosed with breast cancer Contributions of structural and functional imaging that may help to clarify the underlying changes in brain structure and function following treatment are then discussed, followed by potential mechanisms by which treatments may exert an effect on the brain and cognition While terms such as chemo-brain and chemo-fog would indicate a primary role for chemotherapy, recent research has questioned whether chemotherapy exposure alone is either necessary or sufficient for cognitive decline following treatment (Hurria, Somlo, & Ahles, 2007) Treatment varies with stage of disease but includes surgical resection potentially in combination with radiation treatment to the breast, adjuvant chemotherapy in later stages, and endocrine therapies depending on receptor characteristics of tumor cells Surgical resection alone (lumpectomy or mastectomy) may be performed in early stage disease in cases in which the tumor is relatively small and there is no evidence of extended disease either to the lymph nodes or other anatomical sites Adjuvant chemotherapy treatment, in which chemotherapy drugs are delivered following surgical resection, may be used to prevent recurrence or in cases in which the disease is found to extend, i.e., to have metastasized, beyond the primary site Radiation may be used to reduce the size of a tumor prior to resection, and to prevent recurrence following resection, as well as in later stages of the disease Hormonal therapies may be used following primary treatment on an extended basis 1114 Subject Index cognitive functioning: defining 63; genetics and 104–106; mindfulness-based interventions and 1059–1060; multiple sclerosis and 604–608; obsessivecompulsive disorder and 703; systemic lupus erythematosus and 625; visuospatial functioning and 606; see also cognitive development; cognitive impairment Cognitive Genomics consorTium (COGENTI) 105–106 cognitive impairment: affect disorders and 701–702; antiphospholipid syndrome and 637–638; anxiety disorders and 701–702; attention deficit/hyperactivity disorder and 1095; bipolar disorder and 706–708, 1092; brain tumors 569; central nervous system cancers and 560, 569; cerebrovascular disease and 377; chemotherapy and 569, 594–595; depression and 705; epilepsy and 449–450, 460–461; genetics and 104–106; heart failure and 746–747; mild traumatic brain injury and 416, 416–417; moderate and severe traumatic brain injury and 394–396; multiple sclerosis and 606–607, 609–610; non-central nervous system cancers and 569–570; Parkinson’s disease and 513–518; pediatric forensic neuropsychology and identifying 945–947, 946–947; primary Sjögren’s syndrome and 643; rheumatoid arthritis and 641–642; surgical resection and 561; systemic lupus erythematosus and 619–622, 621, 622; toxins in the central nervous system and 595; vascular 367–369, 368, 724; see also cognitive functioning; mild cognitive impairment (MCI) cognitive phenotypes 107 Cognitive Rehabilitation Manual 343 cognitive rehabilitation therapy (CRT): approaches 1079–1082; attention 1079–1080; brain tumors and 569; defining 1078–1079; efficacy of 1082–1085; future directions 1085–1086; historical perspective 1078; memory 1080–1081; mild cognitive impairment and 1083; multiple sclerosis and 610; outcome studies 1082–1085; overview 1078–1079; Parkinson’s disease and 529, 1083; problem solving 1081–1082; stroke and 1084–1085; systemic lupus erythematosus and 633; traumatic brain injury and 1084–1085; see also rehabilitation cognitive reserve 167 cognitive testing 782 cognitive training for pediatric cancer 172–173 coherence factor 908 Collaborative Individualized Assessment (CIA) 1068 Collaborative Therapeutic Neuropsychological Assessment (CTNA): assumptions of 1069; case examples 1072–1076; contemporary developments and adaptations in 1070–1072; defining 1068; development of 1068–1069; feedback in neuropsychology and 1068; feedback session 1070; information gathering and 1069–1070; interview, initial 1069–1070; knowledge of, acquiring 851; model 1069; roots of 1068; traumatic brain injury recovery example 1072–1076 Colorado Family Reading study 304 coma 338–340, 392 Coma Recovery Scale—Revised (CRS-R) 338, 396 combined antiretroviral therapy (CART) 480, 483 communication and traumatic brain injury 395; see also language disorders Community Integration Questionnaire (CIQ) 397 comorbid deployment-related health conditions 802–803 comparative judgment 295 compensatory techniques 1078 competence to stand trial 879–880, 892, 967 competency: ability to consult and 964; amnesia and 967–968; capacity versus 878; to confess 966; in context 965–966; criminal 963–966, 963; factual understanding and 964; forensic neuropsychology and 878–879; measures of 966–967; rational understanding and 964; standing trial and 879–880, 892, 967; unique trial 966 Competency Assessment Instrument (CAI) 966 complementary and alternative medicine (CAM) for children with developmental disabilities: attention deficit/hyperactivity disorder 1035; autism spectrum disorder 1034–1035, 1037, 1039; business of 1036; care mapping and 1037, 1037; considerations in 1039–1040, 1039; efficacy of 1038; evidence of efficacy 1032; families likely to engage in 1034–1035; harm caused by 1038; “homey” care environment promoted by 1036; marketing of 1036; as “natural choice”1036; parents’ decisions and 1037; popularity of 1036–1037; prevalence of 1035; problems treated by 1034; providers’ knowledge of effect treatment and 1036–1037; symptoms addressed by 1036; treatment 1032–1033, 1033; types of 1032–1033, 1033 complex posttraumatic stress disorder (CPTSD) 769–771 computed tomography (CT) 63, 373 Computerized Assessment of Response Bias (CARB) 897, 932 computerized clinical decision support systems (CDSS) 1024 Computerized Test of Information Processing 610–611 concussion: biomarker 664–667; defining 411, 413, 415, 660, 660; in sports literature 415; see also mild traumatic brain injury; sportsrelated concussion (SRC) Concussion Recovery Centers (CRCs) 807, 807 Concussion Symptom Inventory (CSI) 661 cones 70 Conference on Internship Training (1989) 16 Conference on Postdoctoral Training (1993) 16 Conference on Postdoctoral Training in Professional Psychology (1992) 20 confirmatory bias 52 confirmatory factor analysis 27 conformal radiotherapy 561–563 confusional states 337, 340–341, 342 Confusion Assessment Metrics (CAM) 341 Confusion Assessment Protocol (CAP) 342, 396 co-normed batteries 34–35 conscious access 336, 337, 340–341 consciousness: access and 334, 337, 340–341; arousal disorders and 337–340, 337; arousal/vigilance and 333; attention and 336; attention impairment disorders 340–341; autonoetic 336; awareness impairments 344–346, 345–346; complexity of 332; conscious access and 336, 337, 340–341; defining 333; Descartes and 332–333; disorders of 336–346; elements of 333–335, 333; episodic memory and 336–337, 342–343; historical perspective 332–333, 332; inner speech and 335; intransitive 333; level of 72; loss of 411, 423, 659–660, 792, 901; memory and 342–343; neuroimaging 339; neuropsychology’s role in understanding 346; neuroscience of 335–336; overview 346; self-awareness and 335; self-monitoring and 335; self-monitoring impairments and 343–344; semantic memory and 336; sensory perception and 333–334 Consolidated Standards of Reporting Trials (CONSORT) 1009 construct validity 25–26 consultative examinations (CEs) 981 continuous performance test (CPT) 39 contusions 391 conversion 782 conversion disorder 952 co-occurring disorders 800–801 copy number variants/variation (CNV) 195–196 core amnesic syndrome 690, 693 core zone 353 corpus callosum 64–65, 80, 211 cortex 208–209 cortical dementia 720 cortical dysplasia-focal epilepsy syndrome (CDFE) 199 corticobasal degeneration (CBD) 534 corticobasalganglionic degeneration (CBGD) 534–535 corticobasal syndrome (CBS) 534 corticobulbar fibers 80 corticobulbar tract 72, 83 corticospinal fibers 78 corticospinal tract 72 corticosteroids 561 Craig v Orkin Exterminating Co., Inc (2000) 894 cranial nerves (CNs) 70–72, 71 cranial radiation therapy (CRT) 158–160 craniopharyngioma 165, 165 C-reactive protein (CRP) 371, 630 creatine (CR) 634 criminal competencies 963–966, 966 criminal forensics: ability to consult and 964; amnesia and competency and 967–968; Subject Index clinical practice versus 960–961, 961; competency to confess and 966; criminal competencies and 963–966, 963; criminal responsibility and 968–969; dangerousness assessment and 970–971, 971; deathpenalty-related issues and 971–976; diminished capacity and responsibility and 969–970; Dusky v United States and 963–965; ethics and 976–977; evaluation process 962–963, 962; factual understanding and 964; insanity defense and 968–969; malice of aforethought and 969; measures of competency and 966–967; Miranda warning and 962–963, 966; neuropsychological principles applied to 960; overview 960; rational understanding and 964; unique trial competency and 966 criminal justice system and military servicerelated traumatic brain injury 811–812 criminal proceedings and forensic neuropsychology 879–880, 899–901 criminal responsibility 968–969 criterion validity 25, 28–32 Cronbach’s ɑ 24 “crowding” effects 127, 458 cueing 693 cultural differences and differential diagnosis 58–59 cytoarchitectural abnormalities in dyslexia 305 cytokines 202, 630 cytomegalovirus (CMV) 749 cytosine 102, 195, 299 damage claims, neuropsychological analysis of: generalizations about 901; head injury and postconcussion syndrome 901–902; neurotoxic torts 902–903; suboptimal effort and malingering 903–904 dangerousness, assessing criminal 970–971, 971 Daubert v Merrell Dow Pharm., Inc (1993) 10, 859–862, 866–867, 870, 888, 893–897, 893, 906, 914, 916, 938 DBS 528–529, 528 death-penalty-related issues: adaptive function measurement 976; Atkins v Virginia 971–972, 971; Flynn effect 973–976; forensic neuropsychologists and 971; mitigation expertise at sentencing 976; standard error of measurement 972; testretest effects 972–973 decade-nonspecific remote memory disturbance 679 declarative memory 78 deep brain stimulation (DBS) 340, 508 default mode network (DMN) 116, 214, 452, 665–666 Defense Advanced Research Projects Agency (DARPA) 797 Defense and Veterans Brain Injury Center (DVBIC) 793, 802, 806, 812 deficit, defining 136 delay, defining 136 delayed recall effect 29 deletion syndrome 133–134, 290 delirium 340 Delis-Kaplan Executive Function System (DKEFS) 10 dementia: activity-based care and 734; Alzheimer’s disease as cause of 720–724; APA and term of 717; behavioral disturbances in 732–734; clinical criteria 717; cortical 720; in DSM-5717; environment and 733; etiologies 720–730, 732; fronto-temporal 336; frontotemporal lobar degeneration 728–730; future directions 734; generic 719–720; interventions 730–734; with Lewy bodies 507, 525; Lewy body disease 726–728; major neurocognitive disorder 717; mild neurocognitive disorder 717–718; mild traumatic brain injury and 421; mixed 369–370; moderate and severe traumatic brain injury and 394; overview 717, 734; paralysis agitans and 508; Parkinson’s disease with 507, 509, 525; physical factors and 733; primary prevention 730–731; redirection and 734; research criteria 718–720; secondary prevention 731; severity of, assessing 732–733; social factors and 734; subcortical 530, 720; syndromes 717–720; tertiary prevention 731–734; traumatic brain injury and 29, 394; vascular 367–369, 724–726; see also Alzheimer’s disease (AD); mild cognitive impairment (MCI) dementia with Lewy bodies (DLB) 507, 525 dementia pugilistica 668; see also chronic traumatic encephalopathy (CTE) Dementia Rating Scale (DRS) 510 demyelinating conditions 603; see also multiple sclerosis (MS) demyelination 562 dendrites 65 denial 344–346 denial/unawareness of impaired neuropsychological functioning 1045, 1050, 1050–1051 de novo mutations 197 dentate gyrus 78 dentate nuclei 73 Department of Defense (DoD) 793–795, 806–809, 812 Department of Health and Human Services 980, 1011 Department of Labor 994 dephasing 90 depression: bipolar disorder and 1092; after cerebrovascular accident 1045–1048; cerebrovascular disease and 372, 1046–1048; cognitive impairment and 705; electroconvulsive therapy for 705; epilepsy and 461; long-term 450; major depressive disorder 704–706; monoamine theory and 1090; multiple sclerosis and 611–614, 612; neuropathology 614; pain and painrelated disability and 829–830; Parkinson’s disease and 518–520, 519; pharmacological intervention 705, 1090–1092; after stroke 372; trunk and branch model of, in multiple sclerosis 611, 612 descriptive diagnosis 51–52 desychronization 90 1115 developmental delay, defining 136 developmental dyscalculia (DD) 294–295 diabetes/diabetes mellitus 370, 743–744 diagnosis: clinically definite 539; clinically established 539; descriptive 51–52; documented 539; laboratorysupported definite 539; medical 56; neuropsychological, meaning of 51; presumptive 52; see also differential diagnosis; specific disorder diagnostic delay 170 Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5): attention deficit/hyperactivity disorder in 130; autism spectrum disorder in 130, 184, 189; bipolar disorder in 706, 1092; dementia in 717; depressive disorders in 518; educational disability definitions and 136; evidence for mental illness diagnosis and 909; learning disability in 285; learning disorders in 129; malingering in 950; mild cognitive impairment in 717; neurodevelopmental disorders in 129; postconcussion syndrome in 420, 802, 901; posttraumatic stress disorder in 757, 760–771, 761; schizophrenia in 1090; somatic symptom disorders in 846; somatization in 827; vascular dementia in 367 diagnostic threat 426, 429, 805–806, 987, 993 diaschisis 353 diencephalic amnesia 687, 687, 691, 693–694 diencephalon 65, 74–76 differential diagnosis: ABCDE of 59–60; biopsychosocial questions and 59; confirmatory bias and 52; cultural differences and 58–59; with dementia and dementia with Lewy bodies 525; descriptive 51–52; domain-specific differential 53; effort and 57; etymology of 51; factitious disorder and 58; justifying 59; medical history and 54, 54–56; motivation and 57–58, 58; multidomain neuropsychological 53; practice of 51; psychiatric disorders and 56–57; recommendations for 59–60; syndrome analysis and 51, 53, 53 diffuse axonal injury (DAI) 391–392, 411 diffusion tensor imaging (DTI) 70, 80, 212, 302, 356, 373, 391–392, 457, 466, 562, 634–635 diffusion-weighted imaging (DWI) 354, 373 DiGeorge syndrome 290 diminished capacity 969–970 DIRECT technique 1079 disability: APA and 980; cheating concerns and 984–987; for children 980; cogniform disorder 987; constructs 980–981; consultative examinations and 981; deficit and, evolution from 980; defining 129; disability-adjusted life year and 980; factitious disorder and 987; Federal Insurance Contributions Act and 981; Global Burden of Disease metric and 980; informed consent and 983–984, 983–984; intellectual 105, 129, 972; legislative history and 981; malingering and 984–987, 986, 987; medicolegal area and 982–983; 1116 Subject Index military examinations 990–992; other challenges to validity and 987–988; other work-related assessments versus 995–996; in posttraumatic stress disorder, defining 779; private examinations 992–994; private insurance contracts 980; requirements for 989–990, 990; socio-political climate and 981–982; somatic symptom disorders 987; Supplemental Security Income and 980–981; terminology 980–981; validity testing and 988–989, 989; workers’ compensation and 982, 994–995 disability-adjusted life year (DALY) 980 Disability Benefits Questionnaire (DBQ) 991 Disability Determinations Services (DSSs) 981 Disability Rating Scale (DRS) 397 discrepancy between test data 934 discriminant function analysis (DFA) 933 dishabituation 93 disorders of consciousness (DOC) 399; see also consciousness dissociative identity disorder (formerly multiple personality disorder) 1021–1022 distress 779 divalproex 1093 Division 40 3, 14–16, 16 DNA 102–103, 195–196, 562; see also genetics domain-specific differential diagnosis 53 domain-specific hypothesis 106 DOMINION study 521 Donezepil 172 dopamine (DA) 298, 510, 525, 527, 825, 1091, 1095 dopaminergic dysregulation syndrome 521 dorsolateral prefrontal cortex (DLPFC) 92, 824 dose-response relationship 907 double association Down syndrome 131, 195 drugs see pharmacological intervention; specific type DSM-IV-TR 760–771 dualism 62 dual system theory of amnesia 682, 682–683 Due Process hearing 878 Dunedin Multidisciplinary Health and Development Study 592 Dunn’s Sensory Profile 233 dura mater 64 Durham tests 900 Dusky standard 964 Dusky v United States (1960) 880, 963–965 dysarthria 73 dyscalculia 294–295, 308–310 dysgraphia 295–296 dyslexia: cerebellar abnormalities in 305, 311; cytoarchitectural abnormalities in 305; electroencephalography and 307–308; event-related potentials and 307–308; functional neuroimaging and 306–307; genetics of 304–305; magnetoencephalography and 307–308; neural correlates of 305–308; neurobiology of 304–308; neuroimaging 306–307; overview 311; as reading disorder 292–294; structural findings and 305; structural neuroimaging and 306; symptoms 292–294; “triangular” model of 292; types of 292; visual evoked potentials and 308; word blindness and 282 dyslipidemia 370 dysmorphogenesis in autism spectrum disorder 191–192 dysphoria 731 dystonia 539 early infant autism 184 echocardiography 354 Ecologically Oriented Neurorehabilitation Executive (EON-Exec) 1081–1082 Ecologically Oriented Neurorehabilitation of Memory (EON-Mem) program 1081 ecologic validity 31 edema 376 educational intervention 173 Education for All Handicapped Children Act 283 educational testing 136 effective connectivity 213 effort: defining 986; differential diagnosis and 57; forensic neuropsychology and assessment of 859–860, 871, 903–904; suboptimal 871, 903–904; tests of 428 ehrlichiosis 487 e-iatrogenesis 1024 electric seizure (ES) 847 electroconvulsive therapy (ECT) 705 electrocortical stimulation (ECS)/ electrocorticography 465, 467 electro-cortical stimulation mapping (ESM) 467 electroencephalography (EEG) 116–117, 307–308, 339 electronic medical record (EMR) 1024 electrophysiological abnormalities and sportsrelated concussion 666 electrophysiological brain mapping 116–117, 117 embolic shower 354 emboliform nuclei 73 embolism 354 embolization 359 emergent awareness 345, 346 Emerging Consciousness Program 808–809 emotional valence 609 endocrine function 76 endophenotypes 200–201 endovascular treatment 359, 363 enhancers 102 environmental influences on autism spectrum disorder 203–204 enzyme-linked immunosorbent assay (ELISA) 480 ependymal cells 66 Epidemiologic/Epidemiological Catchment Area (ECA) survey 772, 930 epigenetics 194, 200, 299–300 epilepsy: age of onset and 457–458, 459; anterior temporal lobectomy and 454, 463; anxiety and 461, 462; attention deficit/ hyperactivity disorder and 291; benign 458; brain and 449–450; cerebral dominance and 459; chronicity and 458–459; chronological age and 457–458; cognitive impairment and 449–450, 460–461; depression and 461; factors mediating cognitive network reorganization in 457–459, 459; frontallobe 456–457; interaction between cognitive and emotional/behavioral disruptions in 461, 462, 463; medications, cognitive and behavioral impact of 459–460; mesial temporal lobe 450, 461, 463; multifocal deficits in focal 455–457, 455; neuroimaging 465–467; neuropathology of seizure and 449, 451; occipital lobe 457; overview 449; parietal lobe 457; pharmacological intervention 459–460, 460; plasticity and 449–450; progression of cognitive deficits and 460–461; research insights 449; seizure-induced reorganization of cognitive networks and 451–455, 453–454; surgery for, predicting neuropsychological status after 463–465, 463; symptoms 449; temporal lobe 451–452, 453, 454, 456, 459, 463, 463, 1082; see also seizure epileptic encephalopathies 221 episodic memory: Alzheimer’s disease and 723; autism spectrum disorder and 230; consciousness and 336–337, 342–343; Lewy body disease and 728; vascular dementia and 725–726 EQUATOR Network website 1009 equipotential theory 84 erethism 589 error rate, known or potential 896 essential tumor 539 estimation of premorbid cognitive levels 905 ethical practice of clinical neuropsychology: application of resources to challenges 1002–1004; board certification and 1001–1002; challenges 1001–1002; discussions about, increasing 1000; evolution of 1004; Four As of 1002; future directions 1004; ideals 1001–1002; overview 1000; resources 1002 Ethical Principles of Psychologists and Code of Conduct (APA) 58 ethics: APA’s code of 58, 873, 912–913, 942–943, 976, 983–984; criminal forensics and 976–977; expert witness and 873–874; forensic neuropsychology and 873–874, 912–914; pediatric forensic neuropsychology and 942–943; positive 1001; see also ethical practice of clinical neuropsychology Ethyl Cysteinate Dimer (ECD) 112 euthymia 707, 1092 Evaluation of Competency to Stand TrialRevised (ECST-R) 967 event-free survival (EFS) 170 event-related potentials (ERPs) 94–95, 303–304, 307–308, 339 evidence-based decision making 1008 evidence-based medicine 1007 evidence-based practice (EBP) in clinical neuropsychology: APA and 1007–1009; APA Presidential Task Force on 1008–1009, 1015; clinical applications of 1014–1015; dimensions of ideal health care and 1008; evidence-based medicine and 1007; examples of neuropsychology Subject Index research influencing 1015–1016; future directions 1016; health care practice and, evolving 1007–1008; historical perspective of 1007; implementation 1012–1013; in mental health 1011–1012; overview 1007–1016; in psychology 1011; research applications of 1013–1014; resources 1009, 1009; scientific research and 1008 Evidence-Based Practice Centers (EPCs) 1007 evidence-based treatments 1025–1026 evidentiary standards 860–863, 863–866, 866–870 evoked related potentials (ERPs) 666 excitation 114 excitatory amino acids (EEA) neurotransmitters 495 exclusionary criteria 835 executive function: Alzheimer’s disease and 723; at to months 94; at years through adolescence 96–97; at to 12 months 95; at 16 to 24 months 95; autism spectrum disorder and 238–240; bipolar disorder and 707–708; at birth 93–94; fronto-temporal lobar degeneration and 730; moderate and severe traumatic brain injury and 395–396; multiple sclerosis and 606; Parkinson’s disease and 513–514; systemic lupus erythematosus and 624; tests, listing of 27; vascular dementia and 725–726 exercise endurance 633 exons 102 Expanded Paired Associate Test (EPAT) 31 expectancy 826, 889 experimental evidence 908 expert witness: in criminal proceedings 879–880; deceptive attorney behaviors and 872; ethical dilemmas and, responding to 874; ethics and 873–874; for independent medical evaluations 876–877; for independent school evaluations 877–878; in neurotoxin litigation 875–876; objectivity of, importance of maintaining 872–873; other areas of 880; referrals for evaluations of civil competence and 878–879, 879; role of 871–873, 872; sentencing mitigation and 976 explicit memory 230 extended amygdala 688 external capsules 76 external incentives and neuropsychological examination 928 extrapyramidal side effects (EPS) 1090 facial nerves 70–71 Facial Recognition Test 30–31 factitious disorder 58, 952, 987 factor analyses 26–28 Factor C factual understanding 964 failure to keep pace, defining 136 Fake Bad Scale (FBS) 57, 781, 860, 890 false discovery rate (FDR) 104 falsibility 896 familial intracranial aneurysm 362–363 Family Educational Rights and Privacy Act (FERPA) 943 family practice model 134 fasciculi 78 fashionable illnesses 52 fastigial nuclei 73 fasting glucose levels 370–371 fatigue 632 Fatigue Severity Scale 632 fear avoidance 830 Federal Insurance Contributions Act (FICA) 981 Federal Rules of Civil Procedure (FRCP) 894 Federal Rules of Evidence (FRE) 893–896, 895 Feighner criteria 772 fetal alcohol spectrum disorder 133 fetal alcohol syndrome (FAS) 133 fetal mesencephalic cell transplantation 528, 529 F-Family scales 993 first generation antipsychotics (FGA) 1090 fissures 64 Fitness-For-Duty (FDD) examination 995 flight or fight response 76, 78 flocculonodular lobe 73 Florida National Guard survey 801 fluency and naming 723, 726, 729 fluid attenuated inversion recovery (FLAIR) 90, 478, 480, 639 Flynn effect (FE) 137, 973–976 focal anoxic brain injury 500 focal brain ischemia 350 folate deficiency 132 Food and Drug Administration 132, 589, 1024 foramen of Magendie 70 foramen magnum 64 foramen of Monro 70 foramina of Luschka 70 forced-choice tests (FCTs) 931–932; see also symptom validity tests (SVTs) Ford v Wainwright (1986) 880 forensic neuropsychologist (FN) 971; see also criminal forensics; forensic neuropsychology forensic neuropsychology: active answering and 910–911; administrative law and 898; admissibility 859–860, 891–897, 914–915; Admit-Deny tactic 911; adversarial aspect of 857; applicability of norms 870; areas of, key 880–881; assessment process 859–860, 904–906; attribution of facts and 909; biological gradient and 908; capacity and 878; causation analysis and 891; civil court and 898; claimant and 857; clinical versus forensic assessments 889–891; coherence factor and 908; competence to stand trial and 879–880, 892; competency and 878–879; criminal proceedings and 879–880, 899–901; cross-examination 910–911, 911; damage claims and, common issues of 901–904; Daubert case and 893–897; deceptive attorney behaviors and 872; defining 887; discovery and 913; effort assessment and 859–860, 871, 903–904; elements of assessment process 905–906; empirical bases for conclusions based on 860–871; ethics and 873–874, 912–914; evidentiary standards and 860–863, 863–866, 866–870; examples of major activities and roles 874–880; expectancy 1117 and 889; experimental evidence and 908; expert witness role in 871–873, 872; factors influencing emergence of 858; Flynn effect and 975–976; forewarning respondents and 915–916; functional analysis and 908–909; future directions 880–881; health care advances and resulting societal change 858; health care market forces 858–859; hearsay rule and 895; historical perspective 857–860; independent medical evaluations, retained expert for 876–877, 897; independent school evaluations, retained expert for 877–878; insanity plea 880; interpretive process 906–907; interview and 905–906; issues in, key 860–874; law and conflicts with 891, 891; learned treatise and 910, 911; limitations of tests predicting functional outcome 870–871; litigant and 857; litigation consultation and 912–913; malingering assessment and 859–860, 871, 903–904; mental state evaluation and 906; myths of 914–916; normative studies and 870; objectivity and, importance of maintaining 872–873; overview 857, 887, 916–917; performance validity tests and 903; plausibility and 908; plea entry 880; posterior probability and 894; postincident exposures and 889–890; practice effects and 915; premorbid functioning, inferences about 870; prior probability and 894; probate proceedings and 898–989; prominence of, increasing 857, 858, 887; Push-Pull tactic 911; quality of norms 870; raw data disclosure and 913; referrals for evaluations of civil competence 878–879, 878; report writing 907–909; research areas, key 880–881; response bias assessment and 859–860; Rules of the Road for 916, 917; scientist-practitioner model 859; self-report and 890; settings for neuropsychologists, common 898–901; social context of evaluation 889–890; Specialty Guidelines for 976–977; suboptimal effort and 871, 903–904; terminology, basic 887–889; testamentary competence and 899; testimony 892, 909–914, 911; test selection and 906; third-party observers and 897–898; training, need for formal 881; traumatic brain injury and neurotoxin litigation 874–876; traumatic brain injury and rise of 858; validity and, threats to 890–891; weight of evidence and 887, 896; see also pediatric forensic neuropsychology; specific case forensic, term of 887, 942; see also criminal forensics; forensic neuropsychology; pediatric forensic neuropsychology forewarning respondents and forensic neuropsychology 915–916 forgetting, rate of 690–691; see also amnesia fornix 78, 80, 680, 684 Four As of ethical practice 1002 fractional anisotropy (FA) 302, 454, 593 Fragile X mental retardation (FMR 1) gene 131, 193 Fragile X spectrum disorder 131 1118 Subject Index Fragile X syndrome 105, 131, 233 Franz test battery 4, free recall 230 free will 335 frontal lobe epilepsy (FLE) 456–457 fronto-striatal system 300–301 fronto-temporal dementia(FTD) 336 fronto-temporal lobar degeneration (FTLD) 728–730 Frye v United States (1923) 860–863, 893–896, 893 functional adaptation 377 functional analysis 908–909 functional connectivity 213–216 functional connectivity magnetic resonance imaging 115–116, 466–467 functional magnetic resonance imaging (fMRI) 114–115, 466 functional and molecular neuroimaging: attention deficit/hyperactivity and 303; autism spectrum disorder and 213–216; caution about 111; dyslexia and 306–307; electrophysiological brain mapping techniques 116–117, 117; functional transcranial Doppler ultrasonography 118; future directions 119; illness characteristics and 118–119; injury characteristics and 118–119; interpreting, methodological considerations in 118–119; magnetic resonance-based 114–116; multiple sclerosis and 610–611; optical (near-infrared) imaging 118; other technologies 118; overview 111, 119; radioisotope-based 111–114; resting versus activated studies and 111; sports-related concussion and 665–666; see also specific test functional neurological symptom disorder 952 functional neuronal changes and hypoxia of the central nervous system 495 functional reorganization 377 functional somatic syndromes see somatic symptom disorders functional transcranial Doppler ultrasonography 118 funiculi 78 GABA receptors 449–450 Galveston Orientation and Amnesia Scale (GOAT) 390, 396 Gate Control Theory of Pain 824 gender: attention deficit/hyperactivity and 286; autism spectrum disorder and 190–191, 203–204; mild traumatic brain injury and 425; traumatic brain injury and 141 gene networks 106 General Ability Index (GAI) 24–25 general acceptance 896 General Electric Co v Joiner (1997) 861–862, 897, 906, 908 Generalist Gene hypothesis 106 generalized anxiety disorder (GAD) 1093–1094 generalized tonic-clonic seizure (GTCS) 458 genes 103, 195, 298; see also genetics; genomics and phenomics genetic correlations 106 genetic disorders: attention deficit/ hyperactivity disorder and 290; cerebral palsy 131–132; deletion syndrome 133–134; Down syndrome 131; fetal alcohol syndrome 133; Fragile X syndrome 131; prematurity 132, 132; spina bifida 132–133; see also specific type genetics: Alzheimer’s disease and 105; attention deficit/hyperactivity and 297–298; autism spectrum disorder and 192–201, 194, 198, 203–204, 222; classical research 103; cognitive functioning and 104–106; cognitive impairment and 104–106; corticobasalganglionic degeneration and 534–535; dyslexia and 304–305; Huntington’s disease and 536; mild traumatic brain injury and 432–433; Parkinson’s disease and 509–510 genome-wide association studies (GWAS) 103–104, 107, 196–197, 298–299 genomics and phenomics: Alzheimer’s disease and 105; cognitive function/dysfunction and 104–106; domain-specific hypothesis and 106; gene networks and 106; Generalist Gene hypothesis and 106; genetic correlations and 106; Human Connectome Project and 107; overview 102; precision medicine and 108; principles, basic 102–104 Geographic and Racial Differences in Stroke (REGARDS) Study 356 Georgia Court Competency Test (GCCT) 966 Georgia Court Competency Test-Mississippi State Hospital Revision (GCCT-MSH) 966 Geriatric Depression Scale (GDS) 519–520 Gerstmann syndrome 294 giant aneurysms 361–362 Glasgow Coma Scale (GCS) 35, 144–146, 338, 388–389, 411–412, 660, 749, 781 Glasgow Outcome Scale (GOS) 147, 397, 397–398, 433 glia cells 65–66 Glial Fibrillary Acidic Protein (GFAP) 666–667 gliomas 164–165, 164, 560, 563–566; see also brain tumors Global Burden of Disease (GBD) metric 980 Global War on Terror 810 globose nuclei 73 glutamatergic signaling 1094 Goal Management Training (GMT) 1081 Goldstein-Scheerer test battery 6–7, gradient echo (GRE) 90 grammar 237; see also language disorders gray matter (GM) 65, 210–211, 633 great vessels to the neck 66 Gross Stress Reaction 762; see also posttraumatic stress disorder (PTSD) Group Life Insurance Traumatic Injury Protection Program (TSGLI) 803 guanine 102, 195 gyri 64, 80, 85, 91, 309, 685 hallucinations 372–373 Halstead Impairment Index 28 Halstead-Reitan battery (HRB) 4–6, 5, 906, 909, 914, 930 Harvard Trauma Questionnaire 771 headaches 54 head circumference 204–207 health care advances and resulting societal changes 858 health care market forces 858–859 Health Environment Program (HEP) 1059 Health Insurance Portability and Accountability Act (HIPAA) 943, 982 health-related quality of life (HRQOL) 463–464 hearing 71–72 hearsay rule 895 heart disease 371 heart failure 746–747 heavy metals: defining 587; impact of, general 587; lead 587–588, 902; mercury 588–590 hedonistic homeostatic dysregulation syndrome 521, 525 hematomas 376, 391 hemispatial neglect 31 hemodynamics 352–353 hemorrhage 356 hemorrhagic conversion/transformation 376 hemorrhagic stroke 356–357, 356–357 Henry-Heilbronner Index (HHI) 849 Henry M (H M.) case study 678, 680, 682 hepatic encephalopathy (HE) 746 hepatitis C virus (HCV) 482 heritability studies 297–298 herpes simplex encephalitis (HSE): clinical considerations 478; neuropathology 478; neuropsychological implications 478–479; presentation 477–478, 477 heterocyclics 1091 Hexamethyl-propylene Amine Oxime (HMPAO) 112 high blood pressure 53–54, 356, 370–371 high density lipoprotein (HDL) 370 high-grade glioma 563–565 hippocampal sclerosis (HS) 452, 464, 464 hippocampus 78, 680–681 hippocampus proper 78 historical trends in assessment: background information 3; Benton’s tests 6, 7; Boston Process Approach and 9–10; Boston VA test battery and 10, 10; development of methods 3; Franz test battery and 4, 4; Goldstein-Scheerer battery 6–7, 6; Halstead-Reitan battery and 4–6, 5; Montreal Neurological Institute test battery and 9, 9; qualitative approaches 6–10, 7–10; quantitative approaches 3–6, 4–6; Teuber’s battery 9; update on current trends and 10–11 HIV infection see acquired immunodeficiency syndrome H M case study 678, 680, 682 holonomic brain theory 332 homocysteine 371 HONE-In (Health Outcomes and Neuropsychology Efficacy Initiatives) 1014 Hopkins Verbal Learning Test (HVLT) 30 horizontal organization of brain 83–84 hormonal factors and systemic lupus erythematosus 631 Subject Index hormonal therapies 569–570 Horne v Goodson Logging (1986) 892 Houston Conference 16–18 HRB Impairment Index 29, 34 Human Connectome Project 107 human genome 195, 299 human granulocytic anaplasmosis (HGA) 487 Huntington’s disease (HD): biomarkers 718–719; case example of 537–538, 538; cause of 536; epidemiology 536; genetics and 536; neurobehavioral features of 537; neuropathology 537 Huntoon v TCI Cablevision (1998) 892 Hurricane Andrew and posttraumatic stress disorder 775 Hutchison v Am Family Mut Ins (1994) 892–893 hydrocephalus 163, 376 hyperactivity 282; see also attention deficit/ hyperactivity disorder hyperacusis 188 hypercapnia 746 hyperkinesis 282 hyperkinetic disease 282 hypersensitivities 188–189, 232 hypertension 53–54, 356, 370–371 hyperthyroidism 744 hypothalamic dysfunction 165 hypothalamic-pituitary-adrenal (HPA) axis and anxiety 824 hypothalamus 65, 75–76 hypothesis 52 hypothetical ability-focused neuropsychological battery 32 hypothyroidism 744 hypoxemia 494 hypoxia 494, 746 hypoxia of the central nervous system: affective changes and 500; apoptosis and 495; biochemical changes and 495; causes of 494; cognitive impairment and, characterization and treatment of 501–502; focal anoxic brain injury and 500; functional neuronal changes and 495; hypoxic brain injury and 494–495; incidence 494; mechanisms of brain injury and 495, 496; necrosis and 495; neuroimaging 496–499, 497–498; neuropsychological implications 499–500, 501; overview 502; psychiatric changes and 500; reoxygenation injury and 495; reperfusion injury and 495 hypoxic brain injury 494–495 iatrogenesis in neuropsychological assessment: cascade 1023; categories of 1018–1019; defining 1018; dissociative identity disorder and 1021–1022; evidence-based treatments and 1025–1026; medical, reducing 1026–1027; from medications and medical procedures 1022–1024; mild traumatic brain injury and 1019–1020; multiple chemical sensitivities and 1020–1021; objective corroboration of subjective reporting and 1024–1025; overview 1018, 1027; patient pressure and, resisting 1024–1025; postconcussion syndrome and 1019–1020; preventing 1024–1027; technological 1024; undiagnosis and 1025; whiplash injuries and 1020 iatrogenic illness 805–806 idiopathic environmental intolerance 1020–1021 illness anxiety disorder 952 immunoglobulins 202–203 immunological factors and autism spectrum disorder 202–203 Impact of Events Scale (IES) 781 impaired self-awareness (ISA) 1045, 1050, 1050–1051 improvised explosive device (IED) 794–795, 797; see also blast injury impulse control disorders (ICDs) 521 impulsive and related behaviors 521 inattentional blindness 336 in camera evidentiary hearings 888–889 independent medical evaluation (IME) 876–877, 897 independent psychological evaluation (IPE) 876 independent school evaluations 877–878 Index of the Conners Teacher Rating Scale 172 Indiana v Edwards (2008) 966 individual education plan (IEP) 136, 283, 710, 877 individualized quantitative behavioral assessment (IQBA) 338 Individuals with Disabilities Education Act (IDEA) (formerly Education Act of All Handicapped Children) 877–878, 981 Individuals with Disability Act (1990) 189 infantile amnesia 93 inferior occipitofrontal fasciculus 80 inferior prefrontal cortex 309 inflammation 630–631 inflammatory biomarkers 371 informed consent 983–984, 983–984 inhibition and autism spectrum disorder 228 in limine evidentiary hearings 888–889, 893 inner speech 335 in-phase precession 90 Insanity Defense Reform Act (IDRA) (1984) 900, 968–969 insanity plea/defense 880, 909, 968–969 INS/APA Guidelines Report (1987) 14 in silica modeling 107 Institute of Medicine (IOM) 1008 instrumental activities of daily living (IADLs) 514 insula 81 intellectual awareness 345, 346 intellectual development disorder 105, 129 intellectual disability 105, 129, 972 intellectual functioning 137, 225, 513, 606, 973–976; see also IQ scores interdisciplinary model 134–135 interitem consistency 23 interleukin-18 (IL-18) 371 internal capsules 76 internal consistency reliability 23 International Classification of Diseases (tenth edition) (ICD-10) 367, 757, 767–769, 778, 802, 901 1119 International Committee of Medical Journal Editors (ICMJE) 1009 International Conference on Concussion in Sports 662 International Neuropsychological Society (INS) 14 International Primary CNS Lymphoma Collaborative Group (IPCG) 566 International Society for Traumatic Stress Studies 760, 767, 781–782 International Working Party 337 interneurons 65 Interorganizational Council (IOC) for Accreditation of Postdoctoral Programs in Psychology 16 interpretive process in forensic neuropsychology 906–907 interview, clinical 905–906 intracerebral hemorrhage (ICH) 356 intraclass correlation 24 intracranial hematomas 391 intracranial pressure (ICP) 356, 376 intransitive consciousness 333 intraparietal sulcus (IPS) 308–310 introns 102 inverse dose-response relationship 907 “invisible gorilla” experiment 334 Iowa Gambling Task (IGT) 514 IQ scores 34, 58, 129, 143; see also intellectual functioning Iraq war(s) veterans 428–429, 792, 812, 991–992, 1021 irresistible impulse test 900 ischemia 350, 494, 499 ischemic stroke 353–354 island of Reil 81 Jenkins v U.S (1962) 892 John v Im (2002) 894 “junk” DNA 102 “junk science” 860 Kappa values 767 kidney failure 745–746 Killeen (Texas) shooting 774 King-Devick test (KDT) 662 KLOTHO gene 105 Kluver-Bucy syndrome 479 “knock out” test paradigm 465 knowing see semantic memory knowing right from wrong test 899–900 knowledge base thought of training 17 Kuder-Richardson Formula 20 and 21 23–24 Kumho Tire Co v Carmichael (1999) 861–862, 867, 896–897 laboratory-supported definite diagnosis 539 lacunar infarct 350 lacune 350 Lamasa v Bachman (2005) 894 Landau-Kleffner syndrome (LKS) 221 Landers v Chrysler Corporation (1997) 892 Landstuhl Regional Medical Center 799 language development: at to months 94; at years through adolescence 97; at to 1120 Subject Index 12 months 95; at 16 to 24 months 95–96; at birth 94 language disorders: attention deficit/ hyperactivity disorder and 289–290; autism spectrum disorder and 236–238, 289–290; fronto-temporal lobar degeneration and 729–730; grammar 237; moderate and severe traumatic brain injury and 395; multiple sclerosis and 606; orthography 292; Parkinson’s disease and 514–515; phonology 236, 292; pragmatics 238; prosody 236–237; semantics 237–238, 292; source 230; systemic lupus erythematosus and 625 late postconcussion syndrome (LPCS) 901–903 lead exposure 587–588, 902 learned treatise (LT) 910 learning: Parkinson’s disease and 516–517; self-generated 609; systemic lupus erythematosus and 623–624; tests, listing of 27, 32–33 learning difference 282 learning disability (LD): attention deficit/ hyperactivity disorder and 281, 286; clinical profile 285–297; deficits, underlying 291–297; diagnosis 283–285; in DSM-5 285; dyscalculia and 294–295, 308–310; dysgraphia and 295–296; historical perspective 281–283; math disorders and 294–295; neurobiology of 304–310; neuroscience of 297–311; nonverbal 296–297; overview 310–311; presentations 291–297; reading disorders and 292–294; repeat concussions and 667; see also dyslexia learning disorders 129, 282 left hemisphere of brain 83 left-hemisphere damage (LHD) 30–31 lemnisci 78 lenticular nucleus 76 lesions 391, 497–498, 497, 498, 498, 603, 682–683 levodopa 525 Lewy body disease (LBD) 726–728 licensing board evaluations 996 likelihood ratio (LR) 930, 930 Likert scale 661 limbic system 76–78, 78–81, 208, 498 linear predictor 933, 935 Line Orientation Test 31 lithium 707–708, 1092–1093 litigant 857 litigation consultation 912–913 liver failure 746 liver transplant case study 747–754, 748–749, 750–751, 752 local education agency (LEA) 877 localizationist theory 84 locatable region 102 logged odds 933 logic relaxation 1054 logistic regression analysis 196 logit 933 longitudinal organization of brain 83 long-term depression (LTD) 450 long-term potentiation (LTP) 450 loss of consciousness (LOC) 411, 423, 659–660, 792, 901 low density lipoprotein (LDL) 370 low-grade glioma 164–165, 164, 565–566 Luminosity 1079–1080 lung failure 746–747 lupus anticoagulant (LAC) 628 Luria-Nebraska Neuropsychological Battery (LNNB) 906, 914 Lyme arthritis 487 Lyme disease and related disorders: clinical considerations 484, 485; neuropsychological implications 484, 486–487; presentation 484 MacArthur Competency Assessment ToolCriminal Adjudication (MacCAT-CA) 966–967 M’Naghten’s Case (1843) 899–900, 968–969 macroencephaly 191–192, 204–207 Mad Hatter’s disease 589 magnetic resonance angiography (MRA) 373–374, 633–634 magnetic resonance-based imaging: biophysics and 114; functional connectivity magnetic resonance imaging 115–116; functional magnetic resonance imaging 114–115; molecular imaging with MRI 116; overview 114 magnetic resonance imaging (MRI) 63, 373, 465 magnetic resonance spectroscopy (MRS) 116, 374, 634 magnetoencephalography (MEG) 117, 117, 307–308, 310 major depressive disorder (MDD) 704–706, 1090 major neurocognitive disorder (MND) 717, 934 malice of aforethought 969 malingering: definite 950–951; disability and 984–987, 986, 987; in DSM-5950; forensic neuropsychology and assessment of 859– 860, 871, 903–904; pain and 834; pediatric forensic neuropsychology assessment of 950–952, 951; possible 950–951; probable 950–951; testing memory 39, 891, 897, 932, 949, 989 malingering neuropsychological dysfunction (MND) 950–952, 951 mammillary bodies 684–685 mammillothalamic tract (MMT) 687, 687 managed health care 858–859 mania 1092 marijuana 592 material-specific deficits 230–231 math disorders 294–295 matrix metalloproteinases (MMPs) 630 Mattis Dementia Rating Scale (MDRS) 906 maximal medical improvement (MMI) 876, 992 MDMA 592–593 measurement 51–52 measurement error 24–25 medial forebrain bundle 80 medial lemniscus 72 medial limbic circuit 681 medical diagnosis 56 medical history 54, 54–56 medical iatrogenesis 1018, 1026–1027; see also iatrogenesis in neuropsychological assessment medically unexplained symptoms (MUPS) 847, 851 Medical Symptom Validity Test (MSVT) 804, 949 meditation 1054–1055, 1057–1058 medulla 65 medulloblastoma 165–166, 166 megalencephaly 204–207 megencephaly 192 melancholia 508 melatonin 76, 1038 Memantine 633 memory: to months 94; at years through adolescence 96; at to 12 months 94–95; at 16 to 24 months 95; anatomy of 689–690; autism spectrum disorder and 229–231; autobiographical 230; awareness of impairment 344–346; at birth 93; cognitive rehabilitation therapy and 1080–1081; consciousness and 342–343; cueing and 693; declarative 78; denial of impairment 344–346; explicit 230; free recall 230; major depressive disorder and 704; metamemory and 692–693; moderate and severe traumatic brain injury and disorders of 395; multiple sclerosis and 605; Parkinson’s disease and 516–517; processes 229–230; prospective 517, 609; rehabilitation 731; seizure and 452; self-monitoring and 343–344; semantic 336, 342–343; shortterm 97; spatiotemporal context deficits of 691–693; systemic lupus erythematosus and 623–624; temporal lobe and 680–686; for temporal order 691–692; tests, listing of 27, 32–33; see also episodic memory; working memory Memory and Attention Adaptation Training (MAAT) 576 meningitis 477 mens rea principle 889, 899, 969–970 mental health and evidence-based practice 1011–1012 mental retardation (now intellectual disabilities) 105, 129, 980 mental state evaluation (MSE) 904, 906 mental tests, first use of term mercury exposure 588–590 mesial temporal lobe epilepsy(MTL) 450, 461, 463 messenger RNA (mRNA) 102, 195; see also genetics Meta-Analysis Of Observations Studies in Epidemiology (MOOSE) guidelines 707 metabolic autoregulation 353 metabolic disorders: causes of 742; classes of 742, 743; diabetes mellitus 743–744; heart failure 746–747; kidney failure 745–746; liver failure 746; liver transplant case study 747–754, 748–749, 750–751, 752; lung failure 746–747; manifestations of, possible 742, 743; metabolic syndrome 744; phenylketonuria 742–743; prognosis Subject Index 753; symptoms 742–743; thyroid disease 744–745; vitamin B12 deficiency 745 metabolic neuroimaging 213 metabolic syndrome 370–371, 744 metabolism 742 metamemory 692–693 metastatic brain tumors 567–569 methamphetamine 592 methotrexate (MTX) 160 methotrexate-related neurotoxicity 160–162 methylation 299 methylmalonic acidemias (MMA) 747 methylphenidate (MPH) 171–172, 1095 Meyers loop damage 466 Meyers Neuropsychological Battery (MNB) 32 Michigan Compiled Laws Annotated 897 microcephaly 205 microglia 66, 203 micro RNAs (miRNAs) 300 microtubule-associated protein tau (MAPT) 510 midbrain 65 middle cerebral arteries (MCAs) 68, 351–352, 352 Midwest Consortium of Postdoctoral Programs in Clinical Neuropsychology 15 migraine headaches 54 mild cognitive impairment (MCI): Alzheimer’s disease causing 720–721; behavioral disturbance in 732–734; behavioral interventions for 731; cognitive and functional symptoms of 731; cognitive rehabilitation therapy and 1083; in DSM5717; fronto-temporal lobar degeneration and 729; Lewy body disease and 726–727, 727; mood and 731–732; in Parkinson’s disease 507, 517–518, 518; psychological interventions for 731; systemic lupus erythematosus and 618, 620–622 mild head injury (MHI) neuropsychological examination 927–938; external incentives 928; incidence 927–928; integrating information 934; legal implications 937–938; psychosocial influences 929–930; refining diagnostic hypothesis and 930–931; severity of injury 928–929; specialized tests, applying 931–933; test performance patterns, analyzing 933–934; test selection challenges 934–937 mild neurocognitive disorder (mND) 717–718 mild traumatic brain injury: beliefs/ expectations and 425–427; biomarkers 432; chronic traumatic encephalopathy and 433–434; cognitive impairment outcomes 416, 416–417; comorbidities 424–425; complicated 413; context of 427–429; controversies 432–436; dementia and 421; demographics 425; diagnosis 412–415, 412, 901; epidemiology of 412; factors affecting outcomes 421–429, 422; functional outcomes 416–419; future directions 432–436; gender and 425; genetics and 432–433; hospitalization and 794; iatrogenesis in neuropsychological assessment and 1019–1020; litigation and 428; media and 429; medical history and 425; military and 428–429; mood disorders and 419, 424; neuroimaging and 411–412, 417–419; number of injuries and 426–427; overview 436; overview of outcomes 415– 416; pathophysiology of 411–412; politics and 429; posttraumatic stress disorder and 415; psychological outcomes 419; severity of 421–423; sleep and 424; sports and 427– 428; structural outcomes 416–419; studies on outcomes 413, 413–415; subconcussions 434–436; symptom-related outcomes 419–421, 420; terminology 411; testing and 39; treatment 429–432, 430–431 Military Acute Concussion Evaluation 807 military disability examination 990–992 military service-related traumatic brain injury: aging and 813; animal studies on blast injury and 797; barotraumas and 796–797; blast injury 783, 794, 797–799; blast physics and 795–796; chronic traumatic encephalopathy and 813; context of injury 801–802; co-occurring disorders and 800– 801; criminal justice system and 811–812; diagnostic threat and 805–806; differences in blast injury 797–799; Emerging Consciousness Program and 808–809; epidemiology 793–795; evaluation 809–811; external incentives to symptoms and 803–805; follow-up, longitudinal 812–813; historical perspective 793; iatrogenic illness and 805–806; impact of 792; in-theater care 806–807; misattribution bias and 805–806; National Intrepid Center of Excellence and 809; neurocognitive testing and 811; overview 813; physical blast effect and 796–797; postconcussion syndrome and 802–803; programs for 806–809; rehabilitation, acute and subacute 807–809; research 812–813; residential programs and 809; screening 809–811; severity of injury 792–793, 793; symptoms 792 Millon Clinical Multiaxial Inventory (MCMI-III) 847 Minamata disease 589 mindfulness 335, 343–344, 1055 Mindfulness-Based Cognitive Therapy (MBCT) 1056, 1062 mindfulness-based interventions (MBIs): in affective disorders 1060–1061; behavior and 1057–1059; biophysiological functioning and 1059; brain and 1057–1059; cognitive functioning and 1059–1060; cognitive therapy based on 1056, 1062; future research 1064; impact of 1054; meditation 1054–1055, 1057–1058; methodological considerations 1064; neuropsychology and 1062–1064; overview 1054, 1064; rehabilitation and 1062–1064; in stress reduction 1054–1059; stroke and 1062– 1063; traumatic brain injury and 1061–1063 Mindfulness-Based Stress Reduction (MBSR) 1054–1059 mind reading 239 minicolumns 206 Minimal Assessment of Cognitive Function in MS (MACFIMS) 607–608 1121 minimally conscious state (MCS) 338–340 Mini-mental State Exam (MMSE) 356, 377, 510, 528, 564, 625, 707, 991 Minnesota Multiphasic Personality Inventory (MMPI) 671, 781, 833–834, 848, 860, 983 Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI2-RF) 848–849, 1068 Miranda warning 962–963, 966, 971 misattribution bias 805–806 mismatch negativity (MMN) 307 mitigation expertise at sentencing 976 mixed dementia 369–370 mixed episode 706 moderate and severe traumatic brain injury: attention disorders and 395; classification of severity 388–390, 389; cognitive impairment and 394–396; communication and 395; defining 387; dementia and 394; employment after 399; executive function and 395–396; incidence 387–388; independent living outcomes and 400; language disorders and 395; link between 393; memory disorders and 395; motor disorders and 393; neuroanatomical findings following 390–392; neurobehavioral functioning after 394–396; neuropsychological assessment of moderate and severe 396–397; neuropsychological functioning after 394–396; new-onset disability incidence and 141, 387–388; overview 387, 401; posttraumatic amnesia and 389–390, 392–393, 396, 901; predictors of death after 398; predictors of functions after 400, 400; prevalence 387–388; recovery from 392–394, 392; risk factors 387–388 molecular biology/genetics 108, 195–196 molecular imaging with MRI 116 molecular imaging with SPECT and PET 113–114 molecular neuroimaging see functional and molecular neuroimaging Molyneux’s problem 333–334, 333 monoamine (MAO) inhibitors 1091 monoamine oxidase (MAO) enzyme 1091 monoamine theory 1090 Monte Carlo estimation 946 Montreal Cognitive Assessment (MoCA) 356, 377, 625, 748, 751 Montreal Neurological Institute test battery 9, mood disorders: attention deficit/hyperactivity disorder and 289; chemotherapy and 594; mild traumatic brain injury and 419, 424; Parkinson’s disease and 518–525 mood disorders; see also specific type morphometry 310, 456 mossy fiber protection 680 motivation and differential diagnosis 57–58, 58 motor disorders: attention deficit/ hyperactivity disorder and 290–291; autism spectrum disorder and 226–227; moderate and severe traumatic brain injury and 393; see also specific type movement disorders: clinical considerations 540–541, 541; dystonia 539; essential 1122 Subject Index tremor 539; psychogenic 539–540; see also Huntington’s disease (HD); Parkinson’s disease (PD) Movement Disorder Society (MDS) 521 moyamoya disease 366–367, 366 Multi-Data Source Model 976 multidomain neuropsychological diagnosis 53 multifocal axonal injury 411 multiple chemical injuries (MCS) 1020–1021 multiple personality disorder (now dissociative identity disorder) 1021–1022 multiple sclerosis (MS): anxiety disorders and 614; attention and 605; Brief International Cognitive Assessment for MS and 608; Brief Repeatable Battery and 604, 607; Chronic Progressive 604, 607; clinically isolated syndrome and 606; cognitive functioning and 604–608; cognitive impairment and 606–607, 609–610; cognitive rehabilitation therapy and 610; depression and 611–614, 612; diagnosis 603–604; driving and 608; emotional valence and 609; employment and 608–609; epidemiology 603; executive functioning and 606; functional neuroimaging and 610–611; incidence 603; intellectual functioning and 606; language disorders and 606; measurement 607–608; Minimal Assessment of Cognitive Function in MS and 607–608; neuroimaging and 610–611; neuropathology 603; neuropsychological tests in 608–609; overview 614; patterns 604–606; prevalence 604–606; prospective memory and 609; psychiatric issues and 611–614; psychotherapy for 1045, 1048–1049; Relapsing-Remitting 604, 607–608, 610; self-generated learning and 609; symptom onset 603–604; testing effect and 609–610; types of 604; visuospatial functioning and 606 multiple system atrophy: epidemiology 533; genetics and 533; neurobehavioral features of 534; neuropathology 533, 533; parkinsonian form of (MSA-P) 531; preclinical Lewy body disease and 726; symptoms 532; terminology 532 Multiple Trace Theory (MTT) 679 multitasking 343 Munchausen Syndrome 987 myelination 94–95 N-acetyle aspartate (NAA) 634 Nadel v Las Vegas Metro (2001) 894 nadir CD4 cell 480 National Academy of Clinical Neuropsychology 944 National Academy of Neuropsychology (NAN) 16, 57–58, 873, 985–986, 1014 National Alliance of Professional Psychology Providers 767 National Cancer Institute (NCI) 561 National Consortium on Complementary and Alternative Medicine 1033 National Comorbidity Survey (NCS) 772 National Football League (NFL) players study 427 National Health and Nutrition Examination Survey (NHANES) 53 National Institute on Aging (NIA) 718–719 National Institute of Mental Health (NIMH) 107–108, 701, 767 National Institute of Neurological Disorders and Stroke—Association International pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) 367, 368 National Institute of Neurological Disorders and Stroke—Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards 368 National Intrepid Center for Excellence (NCoE) 809 National Joint Committee on Learning Disabilities 284 National Survey on Alcohol and Related Conditions 775 National Vietnam Veterans Readjustment Study 760, 782 necrosis 495 neglect 31 neocortex 80 neomammalian brain 83 nerve cells 65 neural correlates 305–310 neural networks 84 neuroanatomy: central nervous system 63, 63; cognitive functions and 63; divisions, major 63, 63; of higher function 63, 63, 84; historical perspective 62; neuroimaging and 63–64, 63, 87–90, 87–90; overview 62; peripheral nervous system 63, 63; see also brain neurobiology of learning disability: dyscalculia 308–310; dyslexia 304–308 neurodegenerative etiology 720 neurodevelopmental disorders: assessment of 134–135; attention deficit/hyperactivity disorder 289–291; behaviorally defined 129–130; brain-behavior relationships and 127–128; central nervous system alterations and 127; challenges to conceptualization and service provision and 135–137; classification of 128–129, 128; defining 127; developmental neuropsychological formulation for 135; educational testing and, high-stakes 136; Flynn effect and 137; framework for conceptualization of 134; multiple assessments and 136–137; with neurological conditions 130–137; overview 137; practice effects and 137; terminology 136; time-referenced symptom and 127; transition into adulthood and 128; see also specific type neurofibromatosis 105 neuroimaging: acute lymphoblastic leukemia 161; alcohol use 593; antiphospholipid syndrome 639–640; attention deficit/ hyperactivity disorder 130, 303; autism spectrum disorder 213–216; blast injury 797–798; brain tumors 164–166, 560, 562; carbon monoxide exposure 591; cerebrovascular disease 373–374, 377; chemotherapy effects 594; consciousness 339; dyslexia 306–307; epilepsy 465–467; functional 213–216, 306–307, 610–611, 665–666; hypoxia of the central nervous system 496–499, 497–498; meditation 1057–1058; mercury intoxication 589; metabolic 213; mild traumatic brain injury 411–412, 417–419; multiple sclerosis 610–611; neuroanatomy 63–64, 63, 87–90, 87–89; non-central nervous system cancers 573, 574–575, 576; opiate use 593; optic nerves 70, 71; organic solvents exposure 590; posttraumatic stress disorder 783–784; prematurity 132; primary Sjögren’s syndrome 644–645; rheumatoid arthritis 642; sports-related concussion 664–666; structural 210–213, 306, 610, 664–665; systemic lupus erythematosus 633–637; traumatic brain injury 145; white matter 80; see also functional and molecular neuroimaging; specific test neurolaw 858 neurological conditions with neurodevelopment disorders: background information 130; cerebral palsy syndrome 131–132; deletion syndrome 133–134; Down syndrome 131; fetal alcohol syndrome 133; Fragile X syndrome 131; prematurity 132, 132; spina bifida 132–133 neurons 65, 70, 208 Neuron-Specific Enolase (NSE) 666 neuropeptide factors and systemic lupus erythematosus 631 neuroplasticity 449–450 Neuropsychiatric Inventory (NPI) 535 neuropsychiatric manifestations: of antiphospholipid syndrome 637–638; of rheumatoid arthritis 643; of systemic lupus erythematosus 618–619, 620–622 Neuropsychological Assessment Battery (NAB) 32, 397 Neuropsychological Assessment Feedback Intervention (NAFI) 1070 neuropsychological diagnosis, meaning of 51 neuropsychological examination: clinical judgments and 938; diagnostic hypothesis and, refining 930–931; discrepancy between data and 934; external incentives and 928; historical perspective 927–928; injury severity in assessment of effort 928–929; integrating information and 934; legal implications of 937–938; malingering and 927; mild head injury 927–938; overview 927–928; parameter estimates 932–933, 933; performance patterns and, analyzing 933–934; psychosocial influences on 929–930; selecting test, challenge of 934–937; specialized, applying 931–933 neuropsychological implications: of acquired immunodeficiency syndrome 483–484; of aneurysm 363–364; of arteriovenous malformation 359–360; of cavernous malformation 361; of cerebral amyloid angiopathy 364–365; of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy 365–366; of herpes simplex encephalitis 478–479; Subject Index of hypoxia of the central nervous system 499–500, 501; of lead exposure 588; of Lyme disease and related disorders 484, 486–487; of mercury exposure 589; of moyamoya disease 367; of transient ischemic attack 356; of vascular cognitive impairment 369; of vascular dementia 369 neuropsychological screening 135 Neuropsychological Working Group 368 Neuropsychology Task Force of MDS Multiple System Atrophy (MODIMSA) Study 534 neuropsychotherapy 1045 neuroscience: of attention deficit/ hyperactivity disorder 297–311; of autism spectrum disorder 204–216; of learning disability 297–311 neurotoxicity 563 neurotoxin litigation 874–876, 902–903 neurotransmitters 66, 450, 495, 824–827 neurotropic infections: acquired immunodeficiency syndrome 479–484; background information 477; herpes simplex encephalitis 473, 477–479; Lyme disease and related disorders 484, 485, 486–487; meningitis 477; overview 477, 487; viral infections and 477 New Freedom Commission 1011 NIH Toolbox 397 nitric oxide synthase (NOS) 495 N-Methyl-D-Aspartate (NMDA) receptor 450, 478, 628–629 nociception 824 non-central nervous system cancers: chemotherapy for 569, 587; cognitive impairment and 569–570; crosssectional neuropsychological studies posttreatment 570; findings overview 573–574; longitudinal neuropsychological studies pre- and posttreatment 570–573; neuroimaging 573, 574–575, 576; overview 577; treatment 569–570, 576, 587 nonfluent progressive aphasia (PNFA) 728 noninvasive vascular imaging 354 nonstimulants 1095 nonverbal learning disability 296–297 norepinephrine (NE) 825–826, 1090–1091 normative studies 870 nucleotides 102, 195 numerical cognition 294 OARS (open-ended questions, affirmations, reflections, and summaries) 1070 obesity 372, 627, 632–633 obsessive-compulsive disorder (OCD) 703–704, 1093 obstructive hydrocephalus 133 obstructive sleep apnea (OSA) 372, 494, 499–500 occipital-frontal head circumference (OFHC) 205 occipital lobe of brain 85 occipital lobe epilepsy(OLE) 457 occluded carotid artery 353 Office of Disability Adjudication Review (ODAR) 990 Office of the Inspector General (OIG) Fraud Unit 984 Oklahoma City bombings 774 Oklahoma Pre-morbid Intelligence Estimate (OPIE) 33 olfaction 70 olfactory epithelium 70 oligodendrocytes 66 Online Mendelian Inheritance in Man (OMIM) 105 opiates 593 opioids 824–825 oppositional defiant disorder (ODD) 144 opsoclonus myoclonus ataxia (OMA) syndrome 169–170 optical (near-infrared) imaging 118 optic images of letters 282 optic nerves 70, 71 optic radiations 78 orbitofrontal cortex (OFC) 824 Orch-OR theory 332 organic solvents, exposure to 590 orienting, exogenous and endogenous 227 orthnography 292; see also language disorders Overall Test Battery Mean 34 oxygen deprivation, effects of 494; see also hypoxia of the central nervous system oxygen extraction fraction (OEF) 353, 353 pain and pain-related disability: anxiety disorders and 829–830; autoimmune disorders and 632; biopsychosocial intervention models 835–837; catastrophizing and 829; childhood adversity and 827–828; chronic 823; clinical applications 832–837; context factors 830–832; defining pain and 823; depression and 829–830; education 830; fear avoidance and 830; financial incentive effects and 832; Gate Control Theory of Pain and 824; iatrogensis in managing 1023; incidence 823; malingering and 834; neural systems of pain and 824; neuroanatomy 824–827; neurotransmitters and 824–827; occupation and work-related factors 831; overview 823–824, 837; perception of pain and 825; person factors 827–830; physiology 824–827; preprocedure psychological screen and 834–835; psychological management of 836–837; psychological pain evaluations 833–834; psychosocial factors 827–830; satisfaction with care and 831–832; somatization and 827–829; system factors 830–832; treatment delays and 831 paleocortex 80 paleomammalian brain 83 panic disorder (PD) 1093–1094 Papez circuit 78, 78, 80, 684 paraenchymal hematomas 376 parahippocampal region 680–681 paralimbic system 208 parallel form of reliability 23 paralysis agitans 508 parens patriae viewpoint of doctors 878 parental age and autism spectrum disorder 191 parietal lobe 85, 301–302 parietal lobe epilepsy 457 1123 Parkinsonian disorders, atypical: corticobasalganglionic degeneration 534–535; multiple system atrophy 532–534, 533; neuropsychological tests in differentiating among 535–536, 536; progressive supranuclear palsy 529–532, 530–531; see also specific type parkinsonism 507–509 Parkinson’s disease (PD): anxiety disorders and 520; apathy and 520; attention and 513; case example 522–525, 523, 523, 524; cerebrospinal fluid and 511; cognitive impairment and 513–518; cognitive rehabilitation therapy and 529, 1083; with dementia 507, 509, 525; with dementia with Lewy bodies 507, 525; depression and 518–520, 519; diagnosis 507, 507; differential diagnosis with dementia and dementia with Lewy bodies 507, 525; epidemiology 508–509; executive function and 513–514; genetics and 509–510; historical perspective 508; impulsive and related behaviors and 521; intellectual functioning and 513; language disorders and 514–515; learning and 516–517; measuring severity of 51; memory and 516–517; mild cognitive impairment in 507, 517–518, 518; mood disorders and 518–522, 519; multiple system atrophy and 531; neurobehavioral features of 511–517; neuropathology 510–512, 510; NFL football players and 427; overview 507; parkinsonism versus 507–509; pathophysiology 510–512, 512–513; pharmacological intervention 525, 526, 527–528; psychiatric disturbances and 518–522, 521–522; psychosis and 522; spatial functions and 515–516; surgery for 528–529, 528; Sydney Multicenter Study of 511; visuoperceptual functions and 515–516; working memory and 513; see also Parkinsonian disorders, atypical Parkinson’s disease with dementia (PDD) 507, 509, 525 Parsons v State (2007) 968 Participation Assessment with Recombined Tools—Objective (PART-O) 397 parvocellular system 308 Patient Health Questionnaire (PHQ) 781, 848 patterns in test performance 933–934 pediatric bipolar disorder (PBD) 708–710 pediatric cancer: acute lymphoblastic leukemia 157–162, 159, 161; adolescence and 168–169; adult outcomes 166–168; aging and, early 167–168; behavioral intervention 172; brain tumors 162–166, 164–166; chemotherapy 159–160; cognitive reserve and 167; cognitive training for 172–173; educational intervention 173; field of 158; future directions 171; infant ALL and brain tumors 170–171; methotrexate for 160; opsoclonus myoclonus ataxia syndrome 169–170; overview 158; pharmacological intervention 171–172; social intervention 174; survival rates 158, 158, 169, 169; treatment 171–174 1124 Subject Index pediatric forensic neuropsychology: cognitive impairment and, identifying 945–947, 946–947; documentation 952–956; ethics and 942–943; forensic context of 942–945, 943; as mainstay of discipline 942; malingering and 950–952, 951; overview 942, 956; performance validity tests and 948–949; self-report validity tests and 949–950; testimony 952–956; validity testing 947–950, 949 pediatric neuropsychologist (PN) 942; see also pediatric forensic neuropsychology peduncles 78 peer review 896 penultimate testimony 888 penumbra zone 353 perceptual abilities and autism spectrum disorder 231–236 perforant pathway 680 performance validity tests (PVTs): background information 39; case studies 39–40; defining 39; differential diagnosis of actual versus feigned dementia and 42, 43–44, 45–48, 45; evidence from 42; forensic neuropsychology and 903; inconsistency in test scores across cognitive exams 44, 45–48, 45; interpretation of data from multiple 40–42; mismatch between test scores and demonstrated functionality and 45; pediatric forensic neuropsychology and 948; somatic symptom disorders and 847–848; symptom validity tests versus 32; see also specific test perikaryon 65 peripheral nervous system (PNS) 63, 63, 66 Personality Assessment Inventory (PAI) 799, 993 personality disorders 289 personality tests 848–850; see also specific name pervasive development disorder (PDD) 185 pervasive development disorder—not otherwise specified (PDD-NOS) 185 pervasive remote memory disturbance 679 pharmacological intervention: aneurysms 363; anxiety disorders 1093–1094; attention deficit/hyperactivity disorder 1094–1095; bipolar disorder 707–708, 1092–1093; brain tumors 568–569; cerebrovascular disease 375; delirium 341; depression 705, 1090–1092; epilepsy 459–460, 460; extrapyramidal side effects and 1090; iatrogenesis and 1022–1024; Parkinson’s disease 525, 526, 527–528; pediatric cancer 171–172; schizophrenia 1089–1090; seizures 376; systemic lupus erythematosus 633; see also specific drug phenomics 107; see also genomics and phenomics phenylketonuria (PKU) 742–743 phenytoin 376 phonology 236, 292; see also language disorders photons 113 Physical Activity Recall Interview 613–614 pia mater 64 “pick and choose” tests 39 placebo effect 826 planned follow-up assessment 134–135 planum temporale 84 plaques 371, 603 plasticity 92–93, 449–450 plausibility and forensic neuropsychology 908 pleas, entering in criminal proceedings 880 polychlorinated biphenyls (PCBs) 861, 893 polygraph 893 polymerase chain reaction (PCR) 477 polymorphisms 103 Polytrauma Network Sites 808 Polytrauma Rehabilitation Center (PRC) 794 Polytrauma Support Clinics 808 Polytrauma System of Care 808–809 Polytrauma Transitional Rehabilitation Programs 809 pons 65 population stratification 104 positive ethics 1001 positive predictive value (PPV) 985 Positive Romberg signs 662 positron emission tomography (PET) 93, 113, 213, 374, 465, 635 PositScience 1079–1080 postconcussion disorder (PCD) 419 postconcussion/postconcussional/ postconcussive syndrome (PCS) 52, 419–420, 422–423, 425–427, 436, 668, 671, 802–803, 901 Post-Concussion Scale-Revised (PCS-R) 661 Post-Deployment Health Assessment/PostDeployment Health Reassessment (PDH/ PDHRA) 795 postdoctoral residency 17–19 posterior cerebral arteries (PCAs) 351–352, 352 posterior communicating arteries (PCoAs) 67 posterior fossa syndrome (PFS) 163 posterior probability 894 posterior reversible encephalopathy syndrome(PRES) 161–162, 161 postincident exposures 889–890 postinjury testing in sports-related concussion 663, 664 post-Lyme disease syndrome 486 poststroke depression 372 posttraumatic amnesia (PTA): external symptoms 803–805; moderate and severe traumatic brain injury and 389–390, 392–393, 396, 901; symptoms 340–341, 803–805 posttraumatic confusional state (PTCS) 340–342, 390, 393 posttraumatic model (PTM) 1021 posttraumatic stress disorder (PTSD): biomarkers 783–784; blast injury and 783; clinical interview 779–780; clinical population studies 774–775; cognitive testing 782; cohort studies 774–775; comorbid conditions 776–777; complex 769–771; controversy 757; cross-cultural issues 775–776; defining 764–767, 778–779; diagnostic criteria 768; disability in defining 779; dissociative subtype 766–767; in DSM5757, 760–771, 761; from DSM-IV-TR to DSM-5760–771; epidemiology 771–775; establishing 758–760; evaluation 809–811; field trials 767; Hurricane Andrew and 775; hybrid model 778–779; in International Classification of Diseases 757, 767–769, 778; interview 758, 777–782; mild traumatic brain injury and 415; National Center for PTSD study and 757; neurobiology of 783; neuroimaging 783–784; overview 757–760, 782–784; personality changes and 770–771, 770; population studies 772–775; precursor to 762; prevalence 769, 800; psychological testing 780–782; racial issues 775–776; research criteria 768; risk factors 776–777; screening 809–811; stressor and 765–766; as subcategory of anxiety disorders 1093 practice effects (PEs) 137, 915 Prader-Willi syndrome 165 pragmatics 238 precentral gyrus 83, 85 precision medicine 108 prefrontal cortex (PFC) 91, 309 prejudicial relevance of evidence 888 prematurity 132, 132 premorbid functioning, inferences about 870 pre-optic area 688 pre- and perinatal adverse events 201–202 preprocedure psychological screen 834–835 prespecified genes 298 presumptive diagnosis 52 prevalence, defining 930 Preventing Violent Explosive Neurotrauma (PREVENT) 797 primary central nervous system lymphoma (PCNSL) 560, 566–567 primary dyscalculia 294 primary injuries 142 primary legal authority 888 primary progressive aphasia (PPA) 728 primary Sjögren’s syndrome (PSS): biobehavioral correlates of cognitive impairment and 644; cognitive impairment and 643–644; defining 643; epidemiology 643; neuroimaging 644–645; neuropsychiatric 643 prior probability 894 private disability examination 992–994 probate proceedings and forensic neuropsychology 898–899 probative relevance of evidence 888 problem-focused assessment 135 problem solving 1081–1082 process approach 10 processing speed tests 27, 32–33 prodromal Alzheimer’s disease 720–721 professional anosognosia 976 Profile of Mood States (POMS) 520 progressive apraxia of speech (PPAOS) 729 progressive supranuclear palsy (PSP): case study 531–532; epidemiology 529–530; genetics and 529–530; neurobehavioral features 530–531; neuropathology 530, 530–531; neuropsychological testing 532, 532 proliferative zones 92 prosody 236–237; see also language disorders prospective memory (PM) 517, 609 proton density sequences 90 pseudo-dementia 704 Subject Index psychiatric disorders: attention deficit/ hyperactivity disorder and 287; differential diagnosis and 56–57; neuropsychology and 701–702; see also specific type psychiatric disturbances and Parkinson’s disease: anxiety 520; apathy 520; depression 518–520, 519; impulsive and related behaviors 521 psychogenic movement disorder (PMD) 539–540, 847 psychogenic nonepileptic seizures (PNES) 847 psychological iatrogenesis 1018; see also iatrogenesis in neuropsychological assessment psychological pain management 836–837; see also pain and pain-related disability psychological tests and somatic symptom disorders 848–850; see also specific test name psychometric testing: change scores and, reliable 25; defining 22–23; factor analyses of 26–28; interpretation of scores and 32–35; measurement error and 24–25; overview 22, 35; reliability and 23–24; traumatic brain injury and 147; validity and 25–32 psychosis 372–373, 522 psychotherapy: defining 1045–1046; for denial/unawareness of impaired neuropsychological functioning 1045, 1050, 1050–1051; for depression after cerebral vascular accident 1045–1048; dialogue 1045–1046; efficacy of, with patients without brain disorders 1046; importance of 1045; limitations of alliance in 1051; for multiple sclerosis 1045, 1048–1049; overview 1045, 1051–1052; strength of alliance in 1051; see also cognitive behavioral therapy (CBT) published court opinions 888 punch drunk syndrome 433, 668; see also chronic traumatic encephalopathy (CTE) Push-Pull tactic 911 qualitative approaches 6–10, 7–10 Quality Enhancement Research Initiative in Polytrauma and Blast-Related Injury 812–813 quality of life (QoL) evaluations 561 quantitative approaches 3–6, 4–6 quantitative EEG (QEEG) 117–118, 307, 666, 894 quantitative electroencephalography 116–117 quantitative trait loci (QTL) 311 quantity, understanding 308–309 Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease (QUIP) 521 race and autism spectrum disorder 191 radial diffusion (RD) 212 radiation encephalopathy 562 radiation therapy: brain tumor risk and 163; for brain tumors 162, 561–563, 566–568; for craniopharyngioma 165 Radiation Therapy Oncology Group (RTOG) 561 radioisotope-based imaging 111–114 Ragge v MCA/Universal Studios (1995) 898 Rand Corporation study of tort and dollarthreshold states 928 rapid automatic naming (RAN) 292 raw data disclosure 913 Raynaud’s phenomenon 627 RBANS Effort Scale (ES) 46 reactive oxygen species (ROS) 562 reading disorders 292–294 reasonable understanding 964 receiver operating characteristic (ROC) 28, 30 Recognition Memory Test (RMT) 932 records, review of 906 recursive partitioning (RP) 936–937, 937 regions of interest (ROI) 300 regression 136 regressive autism spectrum disorder (RASD) 204, 219–222 regulatory agency evaluations 995–996 rehabilitation: cerebrovascular disease 377–378, 378; memory 731; mindfulnessbased interventions and 1062–1064; neuropsychology and 1062–1064; state vocational 996; stroke 376–377; see also cognitive rehabilitation therapy (CRT) Rehabilitation Act 877–878 Rehabilitation Services Administration (RSA) 284 Reiner v Warren Resort Hotels, Inc (2008) 938 relative standing, defining 136 reliability 23–24 remediation techniques 1078 remembering see episodic memory; memory remote memory disturbance 678–679 REM sleep behavior disorder (RBD) 726 renal disease 745–746 reoxygenation injury 495 reperfusion injury 495 repetitive transcranial magnetic stimulation (rTMS) 340 reporting guidelines 1009 report writing 907–909 repressors 102 reptilian brain 83 Research Diagnostic Criteria 772 Research Domains Criteria (RDoC) (NIMH) 107–108 resective surgery 463–465 residential programs for military servicerelated traumatic brain injury 809 Response Assessment in Neuro-Oncology (RANO) group 565, 568 response bias 428, 859–860, 986 Response Bias Scale (RBS) 849–850, 993 resting-state networks (RSNs) 452 resting studies paradigm 111 restricted and repetitive patterns of behavior (RRBIAs) 185–186, 188–189, 242–243 Restructured Clinical (RC) scales 849 reticular formation 72 retinal ischemia 350 retrograde amnesia 678–679, 691 retrosplenial cortex 685 Rett’s disorder (RD) 185 reuptake inhibitors 1091 1125 reversible ischemic neurologic deficit (RIND) 354 Revised Competency Assessment Instrument (R-CAI) 966 Rey-Osterrieth Complex Figure and Clock Drawing Test 10 rheumatoid arthritis (RA): biobehavioral mechanisms of cognitive dysfunction and 642; cognitive impairment and 641–642; defining 640; epidemiology 640; flares 640; neuroimaging 642; neurologic 640–641; overview 642–643 right hemisphere of brain 84 risk assessment methods of dangerousness 970–971, 971 RNA 102 rods 70 Rohling Interpretive Method (RIM) 34–35 Rolandic fissure 81 Romberg sign 498 Rosa’s Law 980 Rules of Evidence 860, 862, 893–896, 895 St Jude Children’s Research Hospital studies 165 salience network (SN) 215 SBTP 1080 scanning speech 73 scatter 945–946 schizophrenia 57, 708, 906, 1089–1090 Schudel v General Electric (1995) 893 Schwann cells 66 Scientific Brain Training Pro (SBTP) program 1080 scientific expert 859; see also expert witness scientist-practitioner model 859 Scoville and Milner case study 678 secondary injuries 142 secondary legal authority 888 secondary Sjögren’s syndrome 643 second generation of antipsychotics (SGA) 1090 seizure: chronic 458–459; disorders 291; electric 847; generalized tonic-clonic 458; hemorrhagic stroke and 376; memory and 452; neuropathology 449, 451; neurotransmitters associated with 450; pathophysiology of 449; prophylaxis 376; psychogenic nonepileptic 847; see also epilepsy selective reporting bias 104 selective serotonin reuptake inhibitor (SSRI) 704–705, 825, 837, 1091, 1094 self-awareness 335–336 self-generated learning 609 self-monitoring 335 self-monitoring impairments 343–344 self-pay health care 859 self-report 890 self-report validity tests 949–950 self, sense of 334–335 semantic memory 336, 342–343 semantics 237–238, 292; see also language disorders sensorimotor function tests 26–27 sensorimotor regulation 339–340 sensory function 71 1126 Subject Index Sensory Integration Therapy 1038 sensory perception 333–334 sentencing, mitigation expertise at 976 serotonin 72, 825, 1090–1091 serotonin-norepinephrine reuptake inhibitor (SNRI) 825, 837, 1091 serum IgG 202 serum versus CSF studies 630–631 set-shifting and autism spectrum disorder 228–229 severe traumatic brain injury see moderate and severe traumatic brain injury Shaffer collateral pathways 680 Sheehan v Daily Racing Form, Inc (1997) 862 Sheperd Center rehabilitation program for arousal disorders 339 short association fibers 80 short-term memory 97 sideline testing in sports-related concussion 661–662 significance, statistical 103–104 silencers 102 silent stroke 350 Simmons v Mullins (1975) 892 single nucleotide polymorphism (SNP) 103–104, 195–196 single photon emission computed emission tomography (SPECT) 111–113, 374, 465, 635 sinks 117 Sjögren’s Syndrome Foundation 643 skill base thought of training 17 sleep 424, 632, 1038 smoking cigarettes 371–372 social abilities 94 social anxiety disorder (SAD) 1093–1094 social class and autism spectrum disorder 191 social communication and autism spectrum disorder 185–186, 188, 217–218, 240–242 social intervention 174 Social Security Act (1935) 981 Social Security Disability (SSD) 983 Society of Clinical Neuropsychology (formerly Division 40) 14 Society of Neuropsychology (Division 40) 3, 14–16, 16 Society for Traumatic Stress Studies 780 sociocognitive model (SCM) 1021 sodium MR imaging 116 soma 65 somatic symptom disorders: assessment 846–850; associated disorders with 847; cognitive symptoms 847–848; disability and 987; in DSM-5846; intervention 850–851; medically unexplained symptoms and 847, 851; overview 846, 851; pathology 846–847; performance validity tests and 847–848; presentations 846–847; psychological/ personality tests and 848–850; terms for 846 somatization 828–829 somatoform disorders see somatic symptom disorders somatoform tendencies 828 source amnesia 692 source memory 230 sources 117 space, understanding 308–309 spatial functions and Parkinson’s disease 515–516 specialized knowledge 895; see also expert witness Specialty Guidelines for Forensic Psychology 873, 912–914 Specific Problems Scales 850 specific validity tests 903–904 spina bifida 97–98, 132–133 spinothalamic tract 72 split-half reliability 23 Sports Concussion Assessment Tool (SCAT-3) 662, 670 sports-related concussion (SRC): assessment of acute injury effects 661–662; balance testing 662; baseline testing 663–664; biomarker for concussion and, search for 664–667; chronic traumatic encephalopathy and 668–669; clinical effects, acute 660; complications in recovery from 667–669; computerized versus paper-and-pencil testing 663–664; diagnostic challenges and issues 659–660; electrophysiological abnormalities and 666; functional neuroimaging 665–666; incidence 659; initial recovery from 669–670; KingDevick test and 662; laboratory biomarkers 666–667; longer-term effects of 670–671, 670; media and 659; neuroimaging 664–666; neuropsychological assessment 662–664; overview 659, 671–672; postconcussion syndrome 668; postinjury testing, timing of 663, 664; practice recommendations 669–671, 669; recovery from 659–660, 669–670; repeat injury and 667–668; sideline testing 661–662; Sports Concussion Assessment Tool and 662; symptom checklists 661–662 standard error of measurement (SEM) 24, 972 Standardized Assessment of Concussion (SAC) 662 standardized mean effect size 28 stare decisis principle 888, 891 State of California Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) 367 state vocational rehabilitation 996 statistical approaches Steele-Richardson-Olszewski syndrome see progressive supranuclear palsy (PSP) stepdown analysis 935, 935, 936 sterioids 561 steroid treatment 162 stimulants 1095 STrengthening the REporting of Genetic Association (STREGA) studies 103 Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 103 stress and autism spectrum disorder 204 stressor 765–766, 774 striatonigral degeneration (SND) 531 striatum 76 stroke: brain dysfunction analysis and 29; cognitive rehabilitation therapy 1084–1085; complications 376–377; defining 350; depression after 372; hemorrhagic 356–357, 356–357; ischemic 353–354; mindfulnessbased intervention and 1062–1161; prevention 377–378; rehabilitation 376–377; risk factors 370–372; telestroke 375–376; see also cerebrovascular disease structural neuroimaging 210–213, 306, 610, 664–665 structural variations 298–299 structured professional judgment (SPJ) 970–971 subarachnoid hemorrhage (SAH) 361–362, 376 subconcussions 434–436 subcortical dementia 530, 720 subdural hematoma (SDH) 391 subiculum 78 substances of abuse: alcohol 593; amphetamines 592–593; cannabis 592; MDMA 592–593; opiates 593 substance use 287, 289 substantial gainful activity (SGA) 980 subthalamus 76 subtractive processes 92 sulci 64, 91, 308–310 superconducting quantum-interference devices (SQUIDs) 117 superior occipitofrontal fasciculus 80 Supervision Rating Scale (SRS) 397 Supplemental Security Income (SSI) 980–981 supplementary motor cortex (SMC) 301 surgery: ablative 463–465, 528, 528; aneurysms 363; arteriovenous malformation 359; cavernous malformation 360–361; epilepsy 463–465; Parkinson’s disease 528–529; for Parkinson’s disease 528–529, 528; resective 463–465 surgical hematoma evacuation 364 susceptibility-weighted sequence (SWI) 90 Sybil’s case 1021–1022 Sydney Multicenter Study of Parkinson’s disease 511 Sylvian fissure 81 symptom checklists 661–662 symptom validity 986 Symptom Validity Scale (FBS) 849 symptom validity tests (SVTs) 32, 848, 891, 931, 948, 986 synapses 65 synaptogenesis 92 synarchy 16 syndrome analysis 51, 53, 53 systemic lupus erythematosus (SLE): activity of disease and 627; antineuronal antibodies and 628; antiphospholipid antibodies and 629; anti-ribosomal P and 629; attention and 624; autoantibodies and 628; behavioral mechanisms of cognitive impairment 626–633; behavioral mechanisms of 631–633; biobehavioral mechanisms of cognitive impairment and 620, 622; characteristics of disease and 626–629; cognitive functioning and 625; cognitive impairment and 619–625, 621, 622; cognitive rehabilitation therapy and 633; cytokines and 630; defining 618; duration of disease and 626; epidemiology 618; executive function and 624; exercise Subject Index endurance and 632–633; fatigue and 632; hormonal factors and 631; inflammation mediators and 630–631; information processing and 624; language disorders and 625; learning and 623–624; matrix metalloproteinases and 630; medications and 627; memory and 623–624; mild cognitive dysfunction and 618, 620–622; neuroimaging 633–637; neuropeptide factors and 631; neuropsychological screening and 625–626; NMDA receptor antibodies and 628–629; neuropsychiatric 618–619, 620, 622; obesity and 632–633; overview 637; pain and 632; problem solving and 624; psychological factors and 631–632; serum versus CSF studies and 630–631; sleep and 632; treatment 633; visuoconstruction and 624; visuospatial functioning and 624 tactile defensiveness 188, 212 tactile hypersensitivities 188–189 TBI Model Systems 388 T cells 487 technological iatrogenesis 1024 telestroke 375–376 temporal lobe 85, 680–686 temporal lobe amnesia 681–684, 682–683, 686, 693–694 temporal lobe epilepsy (TLE) 451–452, 453, 454, 456, 459, 463, 463, 1082 temporal lobe-limbic system 78 temporally graded remote memory disturbance 679 temporally limited remote memory disturbance 679 temporolimbic system 78 testamentary competence (TC) 899 testing effect 609–610 testing the limits Test of Memory Malingering (TOMM) 39, 891, 897, 932, 949, 989 test performance patterns 933–934 test-retest reliability 23, 767, 972–973 test scores, interpreting 32–35; see also specific test thalamic amnesia 686–687, 687 thalamic radiations 78 thalamus 65, 75, 76, 824 theory of mind (ToM) 239 Therapeutic Assessment (TA) 851, 1068; see also Collaborative Therapeutic Neuropsychological Assessment (CTNA) third-party observers (TPO) 897–898 threshold effect 426, 434–435 threshold of viability 132 thrombolytic therapy 374 thrombosis 354 thrombotic infarcts 354 thymine 102, 195 thyroid disease 744–745 thyroid hormones 744 tick-borne infections 484, 486–487 time-referenced symptoms 127 tissue plasminogen activator (tPA) 375 Tomlin v Holecek (1993) 898 Toronto Test of Acute Recovery After TBI 396 tort 888, 902–903 toxins in the central nervous system: alcohol 593; amphetamines 592–593; cannabis 592; carbon monoxide 590–592; chemotherapy 587, 593–595; cognitive impairment and 595; heavy metals 587–589; lead 587–588; MDMA 592–593; mercury 588–590; opiates 593; organic solvents 590; overview 587, 595; substances of abuse 592–593 tracts 78, 80 training in clinical neuropsychology: APA accreditation and 17–19; APA Division 40 and 14, 16, 16; controversies in 19–20; current developments 19–20; Houston Conference and 16–18; knowledge base thought of 17; in 1980s 14–15; in 1990s 15–16; organizations involved in 14–16, 20; overview 20; postdoctoral residency 17–19; skill base thought of 17 trait anxiety 702 Transcranial Direct Current Stimulation 1086 transcranial Doppler (TCD) sonography 118, 374 transcranial magnetic stimulation (TMS) 377 transcription 102 transcription factors 300, 450 transfer 730 transient ischemic attack (TIA) 350, 354–356 transplantation 528, 529 Trauma Symptom Checklist 771 Trauma Symptom Inventory (TSI) 781 traumatic axonal injury (TAI) 411 traumatic brain injury (TBI): advocacy groups 858; Alzheimer’s disease and 421, 427; assessment 149–150, 149; biomarkers 798; case illustration 148–150, 148, 149; causes of 141, 388; closed 792; cognitive abilities and 143; cognitive development and 145–146; cognitive rehabilitation therapy and 1084–1085; Collaborative Therapeutic Neuropsychological Assessment and recovery from 1072–1076; communication and 395; dementia and 29, 394; demographics and 141; epidemiology 141–143; forensic neuropsychology and rise of 858; functional outcomes 143–144; future directions 150; gender and 141; general outcomes 143–144; incidence 659; injury characteristics and 144; Iraq war veterans and 792; late effects of 142–143; methodological critique 146–148; mild 792; mindfulness-based interventions and 1061–1063; mortality 141–142; neurochemical mechanisms and 142; neuroimaging 145; neurometabolic mechanisms and 142; neuropathology 142–143, 142; neuropsychological testing and 25–26, 29–30; neurotoxin litigation and 874–876; non-injury-related influences 145; pathophysiology 142–143; penetrating 792; predictors of outcomes 144–146, 148; prevalence 141; primary injuries and 142; programs 806–809; psychometric 1127 testing 147; recovery from 147; Screening Questionnaire 795; secondary injuries 142; severity of 792–793; see also mild traumatic brain injury; military service-related traumatic brain injury; moderate and severe brain injury traumatic events 774 treatment see specific type tricyclic antagonists/antidepressants (TCAs) 705, 1091, 1094 trisomy 21 131 trisynaptic circuit 680 “triune” brain 83 Trolano v John Hancock (2003) 898 True Response Inconsistency (TRIN) scale 993 truncal ataxia 73 trunk and branch model of depression in multiple sclerosis 611, 612 Twins Early Development Study (UK) 298 Type I diabetes 370, 744 Type I error 104 Type II diabetes 370, 744 typical antipsychotics 1090 Ubiquitin C-Terminal Hydrolase (UCH-L1) 666–667 U fibers 80 ultimate legal questions 888 ultrasonography 118 uncinate fasciculus 80 unconsciousness 333 undiagnosis 1025 United States v Cameron (1990) 900 unpublished court opinions 888 unresponsive wakefulness syndrome 338 Updated Sapporo Classification Criteria 637 U.S v Andrews (2006) 967 U.S v Pohlot (1987) 970 U.S v Rinchack (1987) 967 U.S v Swanson (1978) 967 validated surrogate marker 783 validity: construct 25–26; criterion 25, 28–32; ecologic 31; psychometric testing and 25–32; testing 947–950, 988–989, 989; see also performance validity tests (PVTs) Valiulis v Scheffeos (1989) 892 valproate 1093 variability of test scores 945–946 Variable Response Inconsistency (VRIN) scale 993 vascular cognitive impairment (VCI) 367–369, 368, 724 vascular dementia (VaD) 367–369, 724–726 vasospasm 376 vegetative state (VS) 338–340, 392, 398 velocardiofacial syndrome 290 ventral anterior (VA) nuclei 73, 75 ventral lateral (VL) nuclei 73, 75 ventral pallidum 688 ventral posterior medial (VPM) 71 ventral striatum 688 ventrical amygdalaofugal (VAF) pathway 687, 687 1128 Subject Index ventricles 65, 68, 69, 70 Ventricle-to-Brain Ratio 499 ventrolateral prefrontal cortex (VLPFC) 824 verbal symbolic abilities tests 26, 32–33 vermis 73 vertical organization of brain 83 very low density lipoprotein (VLDL) 370 vestibular division 71 vestibulocochlear nerve 71 Veterans Affairs 794–795, 806–809, 812–813 Veterans Benefits Administration (VBA) 990 Veterans Health Administration (VHA) 795 Vietnam Veterans Against the War 759 Vietnam Veterans Working Group 759 Vietnam war veterans 429, 758–760 vigilance 333 Villalba v Consol Freightways (2000) 897 Vineland Adaptive Behavior Scales 233, 976 viral infections 477 vision 70, 189 visual evoked potentials (VEPs) 308, 311 visual field deficit (VFD) 466 Visual Form Discrimination Test 31 visualization of the analysis of variance (VISOVA) 107 visualization of variance (ViVA) 107 visual learning tests 27 visuoperceptual functions and Parkinson’s disease 515–516 visuoperceptual judgment tests 26–27, 32–33 visuospatial functioning: Alzheimer’s disease and 723; fronto-temporal lobar degeneration and 730; Lewy body disease and 728; multiple sclerosis and 606; systemic lupus erythematosus and 624; vascular memory and 726 visuospatial judgment tests 26–27, 32–33 vitamin B12 deficiency 745 Von Economo neurons (VENs) 336 voxel-based morphometry (VBM) 300, 456 Walter Reed Army Medical Center 798–799, 809 Washington University group 772 watershed zone 356 Wechsleer Memory Scale (WMS) 10 Wechsler Adult Intelligence Scale (WAIS) 10; WAIS-IV index 33; WAIS Verbal and Performance IQ 30–31 weight of evidence 887, 896 Wernicke-Korsakoff syndrome 684–685, 687 Weschsler Test of Premorbid Function (TOPF) 33 Western Blot Test 484 whiplash injuries 1020 white matter (WM) 65, 73, 78, 80, 210–212, 302, 369, 392, 454, 457, 633 white matter hyperintensities (WMH) 480, 562, 633, 642 WHOADAS (World Health Organization Disability Assessment) 779 whole-brain radiotherapy 561–563 Wilson v United States (1968) 967 Winnie Dunn’s Sensory Profile 233 WMS-IV Indexes 24–25 Woodcock-Johnson tests 294 word blindness 282 workers’ compensation (WC) 982, 994–995 working memory: at to 12 months 95; autism spectrum disorder and 229; cognitive construct of, hypotheses for 107; Parkinson’s disease and 513; tests, listing of 27, 32–33; trait anxiety and 702; vascular memory and 726 World Association of Medical Editors (WAME) 1011 World Health Organization (WHO) 52, 370, 412, 701, 767, 779, 980 yoga 1054 zinc supplementation 1038 zone of proximal development Zurich Consensus Statement on Concussion in Sport 669, 669 ... Neurosurgery, 60 (2) , 27 7 28 3; discussion 28 3 27 4 doi: 10. 122 7/01.NEU.000 024 927 2.64439.B1 Chapman, C H., Nazem-Zadeh, M., Lee, O E., Schipper, M J., Tsien, C I., Lawrence, T S., & Cao, Y (20 13) Regional... 119(1), 22 6 23 2 doi: 10.10 02/ cncr .27 504 Monje, M L., & Dietrich, J (20 12) Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis Behavioural Brain Research, 22 7 (2) ,... Treatment of Cancer Lymphoma Group Phase II Trial 20 9 62 Journal of Clinical Oncology, 21 (24 ), 4483–4488 doi: 10. 120 0/JCO .20 03.03.108 Poppelreuter, M., Weis, J., & Bartsch, H H (20 09) Effects of specific