US 2014O142140A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0142140 A1 Bird (43) Pub. Date: May 22, 2014

(54) PHARMACEUTICAL COMPOSITION FOR Publication Classification NEUROLOGICAL DISORDERS (51) Int. Cl. (75) Inventor: Philip Bird, Maroochydore (AU) A613 L/445 (2006.01) A613 L/466 (2006.01) (73) Assignee: GOSFORTH CENTRE (HOLDINGS) A63L/20 (2006.01) PTY LTD, Maroochydore, Queensland A6II 45/06 (2006.01) (AU) (52) U.S. Cl. CPC ...... A61K 31/445 (2013.01); A61K 45/06 (21) Appl. No.: 14/131,609 (2013.01); A61 K3I/4166 (2013.01); A61 K 31/20 (2013.01) (22) PCT Filed: Jul. 9, 2012 USPC ...... 514/319; 514/391; 514/557: 548/321.1 (86). PCT No.: PCT/EP2012/063419 (57) ABSTRACT S371 (c)(1), An anti-epileptic agent for use in the treatment of a neuro (2), (4) Date: Jan. 8, 2014 logical disorder other than epilepsy characterised in that the anti-epileptic agent is the sole active agent and that the daily (30) Foreign Application Priority Data dose of the anti-epileptic is less than 20% of the minimum daily dose which is effective for mood stabilisation or treat Jul. 8, 2011 (GB) ...... 11117124 ment of epileptic symptoms. US 2014/0142140 A1 May 22, 2014

PHARMACEUTICAL COMPOSITION FOR 0006 When Autism Spectrum Disorder (ASD) co-occurs NEUROLOGICAL DISORDERS with a reading disorder or dyslexia, considerable variation in 0001. The present invention relates to pharmaceutical reading ability can be expected and this relates to the hetero compositions for the treatment of neurological disorders, par geneous natures of ASD and the complex genetic and envi ticularly those associated with cognitive processing, such as ronmental base of dyslexia (Benitez-Burraco, 2010). learning disorders (LD), reading disorders (RD), attention 0007 Whatever the association is between specific lan deficit hyperactivity disorder (ADHD), acquired brain injury guage impairment and autism it is likely that the more effort (ABI), autism, tardive dyskinesia, neurodegenerative disor ful either process the more vulnerable they are to impairment. ders (e.g. dementia and Parkinson's disease), spina bifida It would seem appropriate to hypothesise that both processes (SB), chronic pain, post traumatic stress disorder (PTSD), rely heavily on efficient automatic cognitive functioning. Schizophrenia (SCZ) and visual acuity/fatigue. According to Solomon et al (2009), cognitive control and the 0002 Cognitive processing enables humans to selectively ability to process task-relevant behaviour over competing attend, filter, reflect and prioritise incoming information and information is necessary to guide thoughts and actions that integrate this with thoughts and ideas. These processes are are reflective of internal goals. particularly important for higher executive function. Execu 0008 Attention Deficit Hyperactivity Disorder (ADHD) tive functions are necessary for the planning and sequencing is the most commonly diagnosed neuro-behavioural disorder of goal-directed behaviour. They include the ability to initiate of childhood (Willcutt & Pennington, 2000). It is currently and stop actions, to monitor and change behaviour as needed, defined in the Diagnostic and Statistical Manual of Mental and to plan future behaviour when faced with novel tasks and Disorders Fourth Edition (DSM-IV) (2004) as a disorder of situations. Executive functions include a set of cognitive executive functioning, characterised by short attention span, abilities that control and regulate other abilities and behav impulsivity and excessive activity. In up to 65% of individuals iours, to allow humans to anticipate outcomes and adapt to diagnosed with ADHD there is persistence of some symp changing situations. Further, the ability to form new concepts toms into adulthood which are associated with significant and think abstractly is often considered a component of clinical impairments (Faraone et al., 2006). Results from the executive function. In particular, this includes the cognitive National Comorbidity Survey Replication estimate the preva functions of sequencing, organising and integrating Social lence of adult ADHD in the United States to be 4.4% (Ronald information and appears to be used during the complex inter C Kessler et al., 2006). personal interaction which forms the basis of human Social 0009. Many researchers have reported that the symptoms communication and interaction. Defective or abnormal cog of inattention, hyperactivity and impulsivity are less pro nitive processing can therefore become apparent in behav nounced in adults (Biederman, Faraone, Monuteaux, & Bie iours that are controlled by higher executive functioning. derman, J., Faraone, S.V., & Monuteaux, 2002), and that the Defects in cognitive processing may result in hyper-focusing phenotype in adults is different to that seen in children (Adler on a specific topic during conversation and/or an inability to & Cohen, 2004). Further to these behavioural symptoms, process simultaneously the multiple lines of thought that adults often complain of impairment across a broader spec usually and automatically take place in normal Social inter trum of daily functions including; difficulty in Sustaining action. Instead the individual may select a preferred, more attention for reading, poor motivation, over-reacting to frus comfortable, and probably more familiar topic. As a conse tration, easily bored, procrastination, and an inability to work quence, resistance to or difficulty in following the natural independently (Murphy & Barkley, 1996). Such symptoms flow of conversation is apparent. have been reported to impact significantly on academic and 0003 Learning disorders are categorised by difficulties in work performance and Social functioning (Davids, K is, learning in a typical manner. Such difficulties are thought to Specka, & Gastpar, 2006). arise from an inability of the brain to receive and process 0010. The inventor has noted that many adults diagnosed information in what is considered to be a normal way. with ADHD and receiving adequate, traditional stimulant 0004 Developing an ability to read fluently and compre therapy still remained cognitively and Socially impaired. This hend standard texts is an acquired process familiar to indi may also be related to the increasing executive function viduals who have access to the teaching or learning of literacy demands of adulthood including; having to drive, manage skills. A diagnosis of a reading disorder is usually made when money, take care of others, juggle work and home demands a patient has an impaired ability when it comes to reading, and self-regulate nutrition, exercise, and sleep. Adults plan typically resulting from neurological factors. For reasons and prioritize constantly on both a micro- and macro level related to neurobiological factors, approximately 5-17% of (Weiss et al., 2008). children in the U.S. (Shaywitz & Shaywitz, 2005; Duff & 0011 Unexpectedly and serendipitously improvements Clarke, 2011) develop a specific learning disability associ were noted in individuals with symptoms of ADHD on ultra ated with reading and this condition is referred to as devel low doses of phenyloin which would have not sought to be opmental dyslexia. Reading disorders include developmental therapeutically effective. Not only were the higher doses inef dyslexia, alexia (acquired dyslexia) and hyperlexia. The latter fective, they were also associated with significant cognitive term referring to individuals, who while displaying cognitive side effects. It was only on a dose reduction that the clinical and linguistic deficits function with an advanced ability at improvements were Sustained. word recognition skills (Nation, Clarke, Wright & Williams, 0012 Acquired brain injury (ABI) often results in signifi 2006). cant cognitive defects and/or personality changes. In particu 0005. The difficulties presented with dyslexia are usually lar, patients may become socially withdrawn and/or their characterized by deficits in the phonological components of communication deteriorates. They may also develop repeti language thus making the recognition of written words and tive motor tics and Vocalisations, such as repetitive chanting. spelling and decoding ability quite difficult (Shaywitz & 0013 Acquired brain injury is brain damage caused by Shaywitz ibid; Benitez-Burraco, A. (2010). events after birth. ABI can result in cognitive, physical, emo US 2014/0142140 A1 May 22, 2014

tional, or behavioural impairments that lead to permanent or 1989). However, it is common for both types of injury to exist temporary changes in functioning. These impairments result in a given case (Smith et al., 1989). from either traumatic brain injury (e.g. physical trauma due to 0020. Diffuse injury manifests with little apparent damage accidents, assaults, neuroSurgery, head injury etc.) or non in neuroimaging studies, but lesions can be seen with micros traumatic injury derived from either an internal or external copy techniques post-mortem (D. H. Smith et al., 1989) (Gra Source (e.g. stroke, brain tumours, infection, poisoning, nacher, 2007), and in the early 2000s, researchers discovered hypoxia, ischemia, encephalopathy or Substance abuse). ABI that diffusion tensor imaging (DTI), away of processing MRI does not include damage to the brain resulting from neuro images that shows white matter tracts, was an effective tool degenerative disorders. for displaying the extent of diffuse axonal injury (Kraus et al., 0014 While research has demonstrated that thinking and 2007) (Kumar et al., 2009). Types of injuries considered behaviour may be altered in virtually all forms of ABI, brain diffuse include oedema (Swelling) and diffuse axonal injury, injury is itself a very complex phenomenon having dramati which is widespread damage to axons including white matter cally varied effects where no two persons can expect the same tracts and projections to the cortex (Nahum & Melvin, 2001) outcome or resulting difficulties. The brain controls every (McCrea, 2007). Types of injuries considered diffuse include part of human life: physical, intellectual, behavioural, social concussion and diffuse axonal injury, widespread damage to and emotional. Thus when the brain is damaged, it is likely axons in areas including white matter and the cerebral hemi that some part of a person’s life will be adversely affected. spheres (Nahum & Melvin, 2001). 0015 Consequences of ABI often require a major life 0021 Focal injuries often produce symptoms related to adjustment around the person's new circumstances, and mak the functions of the damaged area (Povlishock, 2008) (Pov ing that adjustment is a critical factor in recovery and reha lishock, 2008). Research shows that the most common areas bilitation. While the outcome of a given injury depends to have focal lesions in non-penetrating traumatic brain injury largely upon the nature and severity of the injury itself, appro are the orbitofrontal cortex (the lower surface of the frontal priate treatment plays a vital role in determining the level of lobes) and the anterior temporal lobes, areas that are involved recovery. in Social behaviour, emotion regulation, olfaction, and deci 0016 Traumatic braininjury (TBI) is defined as damage to Sion-making, hence the common Social/emotional and judg the brain resulting from external mechanical force. Such as ment deficits following moderate-severe TBI (Mattson & rapid acceleration or deceleration, impact, blast waves, or Levin, 1990a) (Bayly et al., 2005) (Cummings, 1993) (Mc penetration by a projectile (Maas, Stocchetti, & Bullock, Donald, Flanagan, Rollins, & Kinch, 2003). Symptoms such 2008). Brain function is temporarily or permanently impaired as hemiparesis oraphasia can also occur when less commonly and structural damage may or may not be detectable with affected areas such as motor or language areas are, respec current technology. tively, damaged (Basso & Scarpa, 1990) (Mohr et al., 1980). 0022. One type of focal injury, cerebral laceration, occurs 0017 TBI is one of two subsets of acquired brain injury: when the tissue is cut or torn (Hardman & Manoukian, 2002). the first is brain damage that occurs after birth; the second is Such tearing is common in the orbitofrontal cortex in particu non-traumatic brain injury, which does not involve external lar, because of bony protrusions on the interior skull ridge mechanical force and examples of this include stroke and above the eyes (Mattson & Levin, 1990b). In a similar injury, infection. All traumatic brain injuries are head injuries, but cerebral contusion (bruising of brain tissue), blood is mixed the latter term may also refer to injury to other parts of the among tissue. head (Blissitt, 2006a) However, the terms head injury and 0023 Symptoms are dependent on the type ofTBI (diffuse brain injury are often used interchangeably. (The Practice of or focal) and the part of the brain that is affected. Uncon Forensic Neuropsychology. Meeting Challenges in the sciousness tends to last longer for people with injuries on the Courtroom (Critical Issues in Neuropsychology), 1996). left side of the brain than for those with injuries on the right Similarly, brain injuries fall under the classification of central (Noggle, 2011). Symptoms are also dependent on the injury's nervous system injuries (Povlishock, 2008) and neurotrauma severity. With mild TBI, the patient may remain conscious or (Neurotrauma: New Insights Into Pathology and Treatment may lose consciousness for a few seconds or minutes. Other (Google eBook), 2007). In neuropsychology research litera symptoms of mild TBI include headache, vomiting, nausea, ture, in general the term “traumatic brain injury' is used to lack of motor coordination, dizziness, difficulty balancing, refer to non-penetrating traumatic brain injuries. lightheadedness, blurred vision or tired eyes, ringing in the 0018 TBI is usually classified based on severity, anatomi ears, bad taste in the mouth, fatigue or lethargy, and changes cal features of the injury, and the mechanism (the causative in sleep patterns (NINDA Traumatic Brain Injury Information forces) (Povlishock, 2008). Mechanism-related classification Page, 2008). Cognitive and emotional symptoms include divides TBI into closed and penetrating head injury (Maas et behavioural or mood changes, confusion, and trouble with al., 2008). A closed (also called nonpenetrating, or blunt) memory, concentration, attention, or thinking. (Blissitt, 2006b) injury occurs when the brain is not exposed 0024. A person with a moderate or severe TBI may have a (Noggle, 2011). A penetrating, or open, head injury occurs headache that does not go away, repeated Vomiting or nausea, when an object pierces the skull and breaches the dura mater, convulsions, an inability to awaken, dilation of one or both the outermost membrane Surrounding the brain (Noggle, pupils, slurred speech, aphasia (word-finding difficulties), 2011). dysarthria (muscle weakness that causes disordered speech), 0019 Systems also exist to classify TBI by its pathological weakness or numbness in the limbs, loss of coordination, features (Povlishock, 2008). Lesions can be extra-axial, (oc confusion, restlessness, or agitation (NINDA Traumatic Brain curring within the skull but outside of the brain) or intra-axial Injury Information Page, 2008). Common long-term symp (occurring within the brain tissue). Damage from TBI can be toms of moderate to severe TBI are changes in appropriate focal or diffuse, confined to specific areas or distributed in a Social behaviour, deficits in Social judgment, and cognitive more general manner, respectively (Smith, Meaney, & Shull, changes, especially problems with Sustained attention, pro US 2014/0142140 A1 May 22, 2014

cessing speed, and executive functioning (McDonald et al., and inhibition. The latter cortical inhibitory circuits are com 2003) (Textbook of Traumatic Brain Injury, 2004) (Kim, prised of interneurons that release GABA onto pyramidal 2002) (Busch, McBride, Curtiss, & Vanderploeg, 2005) (Pon neurons (the principal cells of the neocortex) and cause a sford, Draper, & Schonberger, 2008). Alexithymia, a defi membrane hyperpolarisation that counterbalances excitatory ciency in identifying, understanding, processing, and inputs. describing emotions occurs in 60.9% of individuals with TBI 0031 One factor contributing to this vulnerability may be (Williams & Wood, 2010). Cognitive and social deficits have an intrinsic limit on the recruitment of GABA inhibition, such long-term consequences for the daily lives of people with that rising excitation can build to levels that exceed the capac moderate to severe TBI, but can be improved with appropriate ity of inhibitory mechanisms to contain. Thus, inhibitory rehabilitation (Ponsford et al., 2008). interneurons may play a key role in maintaining the stability 0025. The type, direction, intensity, and duration of forces of cortical network activity. Well-known modulators of inhi all contribute to the characteristics and severity of TBI (Maas bition include agents, which prolong or enhance the actions of et al., 2008). Forces that may contribute to TBI include angu GABA on pyramidal cells; these have found applications as lar, rotational, shear, and translational forces (Hardman & effective anticonvulsants, mood stabilisers, sedatives and Manoukian, 2002). tranquilizers, and examples of which are Valproate, Phe 0026. Even in the absence of an impact, significant accel nobarbital and Clonazepam. (Vicini et al., 1986) (Hashimoto eration or deceleration of the head can cause TBI; however in et al., 2003) most cases a combination of impact and acceleration is prob 0032. However, GABA-enhancing drugs used at usual ably to blame (Hardman & Manoukian, 2002). Forces involv therapeutic doses also produce cognitive impairments, such ing the head striking or being struck by something, termed as amnesia, that presumably result from amplified GABAer contact orimpact loading, are the cause of most focal injuries, gic inhibition impeding normal cortical function (Costa and and movement of the brain within the skull, termed noncon Guidotti, 1996). tact or inertial loading, usually causes diffuse injuries (Pov 0033 Serendipitously we have observed that the GABA lishock, 2008). The violent shaking of an infant that causes enhancing drugs Valproate and Phenyloin used at ultra low shaken baby syndrome commonly manifests as diffuse injury doses appear to act as potential nootropic (cognition-enhanc (Committee on Child Abuse and Neglect, 2001). In impact ing) drugs. These antiepileptic drugs have also been investi loading, the force sends shock waves through the skull and gated as potential neuroprotective agents. If in addition to this brain, resulting in tissue damage (Hardman & Manoukian, they can Successfully modulate these damaged GABA inter 2002). Shock waves caused by penetrating injuries can also neurons this may provide a safe therapeutic treatment provid destroy tissue along the path of a projectile, compounding the ing both an improvement in cognitive function and an addi damage caused by the missile itself. tional neuroprotective intervention. 0027 Damage may occur directly under the site of impact, 0034. It is therefore possible that the Ultra low dose Phe or it may occur on the side opposite the impact (coup and nyloin and Valproate may act as nootropic agents through contrecoup injury, respectively) When a moving object their actions on inhibitory interneurons and thus, they might impacts the stationary head, coup injuries are typical (Morri serve as a new pharmacological approach to boost inhibitory son, King, Korell, Smialek, & Troncoso, 1998), while con cell output and counter states of hyperexcitation. The thera trecoup injuries are usually produced when the moving head peutic action of these inhibitory agents appears to be dose strikes a stationary object (Poirier, 2003). dependent, higher doses associated with impaired neuroplas 0028. The trauma occurring from these injuries can occur ticity; this factor has previously limited their potential as when the head is accelerated and decelerated abruptly in nootropic agents. (Bales, Wagner, & Kline, 2009). Often early space, particularly when accompanied by a torsional head treatment in the course of the recovery can do little to disen movement, and when strainforces are applied to nerve fibers tangle the drug effects from the natural recovery in this period (axons) throughout the brain (Lewis, Volk, & Hashimoto, (Whyte, 2010) 2004) (Costa & Guidotti, 1996). The resulting axonal strain 0035. Autism is a disorder or neural development charac injuries are collectively referred to as diffuse axonal injury terised by impaired social interaction and communication, (DAI), and can contribute to the severity of injury. Axons that and by restricted and repetitive behaviour. project up from the brain stem are particularly Vulnerable, and 0036. The preceding two decades has witnessed a rapid although referred to as diffuse axonal injury, the Supra-tento increase in the worldwide prevalence of Autism or Autistic rial injury usually include functional disturbances marked by Disorder (AD). Autism is derived from the Greek word “auto difficulties with cognitive processing speed, multitasking, meaning “self and this can be ascribed to the active detach and cognitive endurance (Lux, 2007). ment behaviour noted in many individuals with Autism 0029. The cognitive and behavioural manifestations of (Lombardo & Baron-Cohen, 2011). Autism is a severe and TBI are thought to include a number of pathologies including complex neurodevelopmental disorder characterized by a altered neuronal homeostasis due to disruption of the blood triad of core symptoms including impairments in communi brain barrier (BBB), excessive release of excitatory neu cation, ability to interact with others and a preoccupation with rotransmitters, axonal and dendritic disruptions, neuroin routines or repetitive behaviours (Matson et al., 2011; (Go flammation, posttraumatic seizures (PTS), and cell death mot & Wicker, 2012). The effects of Autism commence (Bramlett & Dietrich, 2007: Faden, Demediuk, Panter, & within the first three postnatal years, are pervasive and remain Vink, 1989: Kadhim, Duchateau, & Sébire, 2008; Ommaya & with Some degrees of remission throughout life. Gennarelli, 1974). The somatosensory cortex (neocortex) 0037 Autism is assigned to a spectrum of disorders that seems to be particularly susceptible to the development of are referred to as Autism Spectrum Disorders (ASD) and are unrestrained excitation. distinguishable in the severity of symptoms (Erdmann, 0030 Normal activity in the central nervous system is 2011). Autism represents the most severe manifestations of regulated by the critical balance between synaptic excitation this group that includes Asperger Syndrome and Pervasive US 2014/0142140 A1 May 22, 2014

developmental disorder not otherwise specified (PDD-NOS) 0043 Hussman (2001) has earlier suggested that Sup and ASD is diagnosed on the basis of behavioural symptoms pressed GABAergic inhibition is a common feature of the (Betancur, 2011; (Tager-Flusberg, 2010)). Typically identi autistic brain. Such a problem could also be exacerbated by fied in the preschool years, these diagnostic symptoms abnormal modulatory control of the learning and memory include: unusual eye contact, limitations in facial expression processes that enable and regulate the normal progressive directed to other people, atypical Social engagement and differentiation and elaboration of information processing in responsiveness, difficulty with peer relationships, lack of the developing brain, because progressive functional differ awareness of other peoples thoughts and feelings, poor com entiation increases processing reliability and representational munication skills, difficulty initiating social contacts through salience, and thereby reduces process noise (Zhang, Bao, & Verbal or non-verbal means, rigid or unusual behaviours and Merzenich, 2001) (Tallal, Merzenich, Miller, & Jenkins, restricted interests (Tager-Flusberg, 2010). 1998), (Rubenstein & Merzenich, 2003) Primacy of Communication Possible Evolutionary Perspective 0038. It is well established in the ASD literature of the 0044) A perspective on the evolution of autism is provided limiting effects that ensue from a non-normative developing by the Polyvagal theory (Porges, 2003a). Polyvagal theory repertoire of language and communication function. In a con postulates that through three stages of phylogeny, mammals, firmed diagnosis of ASD, the individual may have to contend especially primates, including humans, have evolved a func with numerous language related deficits that relate to expres tional neural organization that regulates emotions and Social sive language, receptive Vocabulary, comprehension of exten behaviour. The vagus, i.e., the 10th cranial nerve is a major sive directions, the initiation of communication and engaging component of the autonomic nervous system that plays an in reciprocal conversations (Forde, Holloway, Healy & Bro important role in regulating emotions and social behaviour. snan, 2011). 0045. The Polyvagal Theory emphasizes that physiologi 0039. Furthermore this can have a profound effect on the cal states support different classes of behaviour. For example, life trajectory of a person in terms of their ability to socially a physiological state, characterized by a vagal withdrawal, interact with others and their overall quality of life. While would support the mobilization behaviours of fight and flight. symptom severity and comorbidity will be a determining In contrast, a physiological state, characterized by increased factor in the level of language and speech attainment, func Vagal influence (via pathways originating in the nucleus tional communication skills fail to develop for many younger ambiguous) on the heart, would support spontaneous Social individuals with ASD or a related disorder and this in turn can engagement behaviours. Further, the theory emphasizes the progress into adulthood (Forde etal). However adaptive strat functional and structural links between neural control of the egies for these adults may have developed in an attempt to striated muscles of the face and the smooth muscles of the lessen the degree of the communication deficit. viscera (Porges, 2007). This would provide an explanation for the autonomic and involuntary control of the facial muscles Autism and Aetiology involved in non-verbal communication. 0046. The most phylogenetically primitive component, 0040 Autism is a condition of multiple aetiologies distrib the immobilization system, is dependent on the unmyelinated uted across genetic, neuroanatomical, and behavioural vagus, which is shared with most vertebrates. With increased domains that ultimately results in alterations in brain connec neural complexity resulting from phylogenetic development, tivity (Müller, 2007). The cerebellum is an ideal structure to the organisms behavioural and affective repertoire is investigate connectivity due to its simple cytoarchitecture, enriched. The three circuits can be conceptualized as highly ordered topographic circuitry and its multifocal intrin dynamic, providing adaptive responses to safe, dangerous, sic GABAergic neurotransmission. and life-threatening events and contexts. 0041 Multiple lines of evidence, including genetic and 0047. The human nervous system has evolved in line with imaging studies, suggest that the anterior cingulate cortex other mammals to enable Survival in dangerous and life (ACC) and GABA system may be affected in autism. The threatening contexts. To accomplish this adaptive flexibility, benzodiazepine binding site on the GABA receptor complex the humannervous system retained two more primitive neural is an important target for pharmacotherapy and has important circuits to regulate defensive strategies (i.e., fight/flight and clinical implications. These findings suggest that in the autis freeze behaviours) (Porges, 2007). tic group this down regulation of both benzodiazepine sites 0048. It is important to note that social behaviour, social and GABA receptors in the ACC may be the result of communication, and visceral homeostasis are incompatible increased GABA innervations and/or release disturbing the with the neurophysiological states and behaviours promoted delicate excitation/inhibition balance of principal neurons as by the two neural circuits that Support defence strategies. well as their output to key limbic cortical targets. Such dis Thus, via evolution the human nervous system retains three turbances likely underlie the core alterations in Socio-emo neural circuits, which are in a phylogenetically organized tional behaviours in autism (Oblak A, Gibbs T.T. & Blatt G. hierarchy. Porges 2007, suggests that these three circuits are J., 2009). organized and respond to challenges in a phylogenetically 0042. A model for autism has been posited by Rubenstein determined hierarchy consistent with the Jacksonian prin & Merzenich (2003) that suggests an increasing in the ratio of ciple of dissolution (Jackson, 1873). excitation/inhibition in key neural systems, either genetically 0049. Jackson proposed that in the brain, higher (i.e., phy or epigenetically and is a common pathway for causing logenetically newer) neural circuits inhibited lower (i.e., phy autism. An imbalance of excitation and inhibition could be logenetically older) neural circuits and “when the higher are due to increased glutamatergic (excitatory) signalling, or to a suddenly rendered functionless, the lower rise in activity” reduction in inhibition due to a reduction in GABAergic (Taylor, 1958). In this hierarchy of adaptive responses, the signalling. newest circuit is used first, and if that circuit fails to provide US 2014/0142140 A1 May 22, 2014 safety the older circuits are recruited sequentially. Porges has 0.058 Enhanced timing and appropriateness of non-ver proposed (Porges, 1998) (Porges, 2001) (Porges, 2003b) the bal communication in contrast to the frequent delayed neural pathways originating in several cranial nerves that and exaggerated responses characteristic of these con regulate the striated muscles of the face and head (i.e., special ditions, examples of these have included excessive head visceral efferent) and the myelinated vagal fibers from the nodding, Smiling, facial grimacing, use of hands and neural Substrate of the Social Engagement System. arms. These are placed by subtle but more immediate 0050. The social communication system (i.e., Social and responsive movements of the Small muscles of the Engagement System, see below) is dependent upon the func face particularly around the eyes and forehead. These tions of the myelinated vagus, which serves to foster calm are involuntary and reflexive, providing more empathic behavioural states by inhibiting the sympathetic influences to and intuitive interaction. the heart and dampening the HPA axis (Porges, 2009). The 0059 Subsequent descriptions of improvements inabil Social Engagement System controls the cortical upper motor ity to listen and respond verbally with a reduction in the neurons that regulates brainstem nuclei (lower motor neu internal dialogue, this previously had been disabling rons) to control eyelid opening (e.g., looking), facial muscles resulting in extreme difficulty in communicating (e.g., emotional expression), middle ear muscles (e.g., thoughts and ideas. extracting human Voice from background noise), muscles of 0060 Post-traumatic stress disorder (PTSD) affects 8% of mastication (e.g., ingestion), laryngeal and pharyngeal Americans at Some time in their lives and is associated with muscles (e.g., prosody and intonation), and head turning considerable morbidity (R C Kessler, Sonnega, Bromet, muscles (e.g., social gesture and orientation). Collectively, Hughes, & Nelson, 1995). Developing effective treatments these muscles function both to enable social engagement and for PTSD is of critical importance. Large placebo-controlled to filter and thus enhance the information processed (Porges, trials revealed efficacy for the selective serotonin reuptake 2007). inhibitors (SSRI), sertraline (Brady et al., 2000) and parox 0051. The neural pathways that raise the eyelids also tense etine (Tucker et al., 2001) in PTSD, but not all patients the stapedius muscle in the middle ear, which facilitates hear respond optimally to SSRI treatment. ing human voice (Borg & Counter, 1989). Thus, the neural 0061 Although in a recent open study Phenyloin treat mechanisms for making eye contact are shared with those ment resulted in a significant 6% increase in right brain Vol needed to listen to human Voice. As a cluster, difficulties in ume (p<0.05). Increased hippocampal volume was correlated gaze, extraction of human Voice, facial expression, headges with reductions in Symptom severity as measured by the ture and prosody are common features of individuals with Clinician Administered PTSD Scale and improvements in autism and other psychiatric disorders (Porges, 2007). executive function as measured by the Trails Making test. 0052 We have treated many individuals with both autistic However, treatment associated with improvements in spectrum disorders and Social communication disorders. A memory and cognition did not achieve statistical significance. primary impairment associated with these disorders is the These findings suggest that phenyloin treatment may be asso inability to communicate, which can lead to frustration and ciated with changes in brainstructure in patients with PTSD. behavioural disturbance. Many children are diagnosed in Treatment was begun at 300 mg per day divided into three childhood with these conditions and experience significant doses and increased to 400 mg/day if plasma levels were handicap and impairment both socially and educationally. sub-therapeutic. (Bremner et al., 2005). Because of the frequent behavioural disturbance they are commenced on psychotropic medications. Two medications 0062 We have noted that patients with post traumatic which have been approved by the food and drug administra stress disorder have difficulty controlling the intrusive and tion in the United States of America as well as other countries distressing memories. This frequently results in poor concen for the treatment of behavioural disturbance in autism are tration, irritability and frustration. It would appear that they Risperidone and Aripiprazole. Although effective treatments, have a reduced ability to automatically/effortlessly control they are associated with side effects including sedation, cog their re-experiencing phenomena relying on effortful control. nitive impairment, weight gain and metabolic disturbance. This leads to cognitive fatigue and being overwhelmed by Many individuals have experienced these side effects with their memories. This pattern of functioning is not dissimilar only moderate improvement in behaviour with little or no to the failure to habituate noxious stimuli. Although it has improvement in their communication. Many also have a been previously reported that antiepileptic medications are comorbid diagnosis of ADHD and have been treated with useful for the treatment of post-traumatic stress disorder the stimulants and non-stimulants. This has resulted in improve doses used were within the therapeutic range. Unexpectedly ments in attention, concentration and impulsivity, although and contrary to usual clinical practice we have noted that the use of Ultra low dose phenyloin has been associated with again little benefit in their abilities to communicate. significant improvements in functional capacity as well as a 0053. On the addition of Ultra low dose phenyloin we have noted a frequent instant improvement in both their non-verbal reduction in the symptoms of PTSD. and verbal communication. These benefits occurred at Ultra 0063. The presence of schizophrenia as a major mental low doses of phenyloin and in the case of autistic spectrum disorder now affects 1% of the world's population and disorders are frequently below 5 mg. renewed emphasis on cause and treatment modalities have prompted many researchers in the area to realign their former 0054 These have included: psychogenic models of investigation to a neurobiological 0055 Improved eye contact both when listening and structure of inquiry. More specifically, the importance of speaking neurocognitive assessment in determining greater clinician 0056 Enhanced prosody and complexity of speech understanding of cognitive domain deficits has occurred thus 0.057 Improved organisation and sequencing of conver permitting greater accuracy for pharmacological treatment sation provision. According to (Reichenberg, 2005) (Arnott, Sali, & US 2014/0142140 A1 May 22, 2014

Copland, 2011), cognitive deficits remain the key feature of man primates indicate that normal working memory function Schizophrenia and a primary cause of long-term disability. depends upon appropriate GABA neurotransmission in the 0064 Cognitive deficit is a stable, traits like condition, DLPFC, and alterations in markers of GABA neurotransmis independent of psychotic symptoms and mostly unaffected sion are well documented in the DLPFC of subjects with by antipsychotic treatment. Cognitive deficits are associated schizophrenia (Lewis et al., 2004). with social deficits. In a meta-analysis of 37 studies (MF 0069. Despite the advances in our understanding of the Green, Kern, Braff, & Mintz, 2000), it was found that cogni neurocognitive deficits but as yet, not widely applicable, evi tive impairment accounted for 20%-60% of the variance in dence-based treatments are available to the clinician. The site functional outcome for individuals with schizophrenia. of action of phenyloin in its antiepileptic activity appears to Attention, Verbal learning and fluency are related to Success hinge on the inhibition of Voltage-sensitive Na+ channels in ful performance of social skills (Silverstein, Schenkel, Valone the plasma membrane of neurons undergoing seizure activity & Nuernberger, 1998). including the GABA, receptors, which are found on the 0065. Another prominent factor which may affect func GABAergic interneurons (Tunnicliff, 1996). tional outcome in Schizophrenia is impaired facial affect rec ognition. This has been linked to negative symptom severity 0070. It is known that sodium valproate and phenyloin and poor functional outcome (Brekke, Kay, Lee, & Green, appear to exert a negative effect on cognitive functioning 2005; Heimberg, Gur, Erwin, Shtasel, & Gur, 1992; Heim particularly when used at high dosage (Mula & Trimble, berg et al., 1992; Silver, Goodman, Knoll, & Isakov, 2004: 2009). Therefore one would expect that these medications Manuscript et al., 2006; Morris, Weickert, & Loughland, used in Schizophrenia would further increase cognitive 2009). There is increasing evidence from treatment studies impairment. that emotional face recognition deficits may be remediated 0071 Schizophrenia is a mental disorder characterized by (Morris et al., 2009) both by behavioural (Russell, Green, a breakdown of thought processes and by poor emotional Simpson, & Coltheart, 2008) and pharmacological means responsiveness. It most commonly manifests itself as audi (Guastella, Mitchell, & Dadds, 2008) reported that oxytocin tory hallucinations, paranoid or bizarre delusions, or disorga increased the gaze of healthy individuals to the eye region of nized speech and thinking, and it is accompanied by signifi neutral face. Recent evidence Suggests that reduced oxytocin cant Social or occupational dysfunction. The onset of levels may be related to negative symptoms, social with symptoms typically occur in young adulthood, with a global drawal and isolation in Schizophrenia (Keri, Kiss, & Kele lifetime prevalence of about 0.3-0.7% (van Os & Kapur, men, 2009). 2009). Diagnosis is based on observed behaviour and the 0066. The wide-ranging cognitive deficits observed in patient's reported experiences. individuals with Schizophrenia include communication and 0072 Genetics, early environment, neurobiology, and oral language problems. Evidence of Schizophrenia-related psychological and social processes appear to be important reading difficulties has also emerged (e.g. (Manuscript et al., contributory factors; some recreational and prescription 2006)). It has been advanced by Condray and others Crow et drugs appear to cause or worsen symptoms. Current research all 1995, (McNab & Klingberg, 2008), that language disorder is focused on the role of neurobiology, although no single is increasingly understood as an important characteristic of isolated organic cause has been found. The many possible schizophrenia. Patients with schizophrenia, like those with combinations of symptoms have triggered debate about dyslexia, show deficits in early auditory processing includ whether the diagnosis represents a single disorder or a num ing, for example, deficits in tone matching (Daniel C. Javitt, ber of discrete syndromes. Despite the etymology of the term Shelley, Silipo, & Lieberman, 2000), mismatch negativity from the Greek roots skhizein “to split' and phren, “mind', generation (D C Javitt, Doneshka, Grochowski, & Ritter, schizophrenia does not imply a “split personality, or “mul 1995) and the ability to detect phonetic boundaries (Cienfu tiple personality disorder' (which is known these days as egos, March, Shelley, & Javitt, 1999). dissociative identity disorder)—a condition with which it is 0067. Reading deficits are predicted strongly by recent often confused in public perception (Picchioni & Murray, research demonstrating impaired functioning of the magno 2007). Rather, the term means a “splitting of mental func cellular visual pathway in Schizophrenia. The magnocellular tions', because of the symptomatic presentation of the illness. (M) pathway is one of two primary low-level visual pathways in the human brain, and is primarily responsible for process 0073. The mainstay of treatment is antipsychotic medica ing low spatial frequency and motion information, and for tion, which primarily suppresses dopamine (and sometimes organising visual space. Magnocellular processing deficits serotonin) receptor activity. Psychotherapy and Vocational have been extensively linked to dyslexia (Demb, Boynton, and Social rehabilitation are also important in treatment. In Best, & Heeger, 1998); (Talcott JB, Hansen PC, Willis-Owen more serious cases—where there is risk to self and others— C. McKinnell I W. Richardson AJ, 1998); (Romani et al., involuntary hospitalization may be necessary, although hos 2001) (Romani et al., 2001); (Ridder, Borsting, Cooper, pital stays are now shorter and less frequent than they once McNeel, & Huang, 1997). were (Becker & Kilian, 2006). 0068. These disturbances of the cognitive processes, such 0074 The disorder is thought mainly to affect cognition, as working memory, are now regarded as core features of but it also usually contributes to chronic problems with Schizophrenia, but available pharmacological treatments pro behaviour and emotion. People with schizophrenia are likely duce little or no improvement in these cognitive deficits. to have additional (comorbid) conditions, including major These cognitive deficits appear to reflect a disturbance in depression and anxiety disorders; the lifetime occurrence of executive control, the processes that facilitate complex infor substance abuse is almost 50% (Buckley, Miller, Lehrer, & mation processing and behaviour, and that include context Castle, 2009). Social problems, such as long-term unemploy representation and maintenance, functions dependent on the ment, poverty and homelessness, are common. The average dorsolateral prefrontal cortex (DLPFC). Studies in non-hu life expectancy of people with the disorder is 12 to 15 years US 2014/0142140 A1 May 22, 2014

less than those without, the result of increased physical health These differences have been linked to the neurocognitive problems and a higher suicide rate (about 5%) (van Os & deficits often associated with schizophrenia (Michael F Kapur, 2009). Green, 2006). Because neural circuits are altered, it has alter 0075. Many psychological mechanisms have been impli natively been suggested that schizophrenia should be thought cated in the development and maintenance of Schizophrenia. of as a collection of neurodevelopmental disorders (Insel, Cognitive biases have been identified in those with the diag 2010). nosis or those at risk, especially when under stress or in 0078 Particular attention has been paid to the function of confusing situations (Bentall, Fernyhough, Morrison, Lewis, dopamine in the mesolimbic pathway of the brain. This focus & Corcoran, 2007). Some cognitive features may reflect glo largely resulted from the accidental finding that phenothiaz bal neurocognitive deficits such as memory loss, while others ine drugs, which block dopamine function, could reduce psy may be related to particular issues and experiences (Bentallet chotic symptoms. It is also Supported by the fact that amphet al., 2007) (Kurtz, 2005). amines, which trigger the release of dopamine, may 0076. Despite a demonstrated appearance of blunted exacerbate the psychotic symptoms in Schizophrenia affect, recent findings indicate that many individuals diag (Laruelle et al., 1996). The influential dopamine hypothesis nosed with Schizophrenia are emotionally responsive, par of schizophrenia proposed that excessive activation of D2 ticularly to stressful or negative stimuli, and that such sensi receptors was the cause of (the positive symptoms of) Schizo tivity may cause Vulnerability to symptoms or to the disorder phrenia. Although postulated for about 20 years based on the (Cohen & Docherty, 2004) (Horan & Blanchard, 2003). Some D blockade effect common to all antipsychotics, it was not evidence Suggests that the content of delusional beliefs and until the mid-1990s that PET and SPET imaging studies psychotic experiences can reflect emotional causes of the provided Supporting evidence. The dopamine hypothesis is disorder, and that how a person interprets such experiences now thought to be simplistic, partly because newer antipsy can influence symptomatology (B. Smith et al., 2006) (Bell, chotic medication (atypical antipsychotic medication) can be Halligan, & Ellis, 2006). The use of “safety behaviours' to just as effective as older medication (typical antipsychotic avoid imagined threats may contribute to the chronicity of medication), but also affects serotonin function and may have delusions (Freeman et al., 2007). Further evidence for the role slightly less of a dopamine blocking effect (Jones & of psychological mechanisms comes from the effects of psy Pilowsky, 2002). chotherapies on symptoms of Schizophrenia (Kuipers et al., 0079 Interest has also focused on the neurotransmitter 2006). glutamate and the reduced function of the NMDA glutamate 0077 Schizophrenia is often described interms of positive receptor in schizophrenia, largely because of the abnormally and negative (or deficit) symptoms (Professor, 2002). Posi low levels of glutamate receptors found in the post-mortem tive symptoms are those that most individuals do not nor brains of those diagnosed with Schizophrenia (Konradi & mally experience but are present in people with Schizophre Heckers, 2003), and the discovery that glutamate-blocking nia. They can include delusions, disordered thoughts and drugs such as phencyclidine and ketamine can mimic the speech, and tactile, auditory, visual, olfactory and gustatory symptoms and cognitive problems associated with the condi hallucinations, typically regarded as manifestations of psy tion (Lahti, Weiler, Tamara Michaelidis, Parwani, & Tam chosis (Kneisl & Trigoboff, 2008). Hallucinations are also minga, 2001). Reduced glutamate function is linked to poor typically related to the content of the delusional theme (Asso performance on tests requiring frontal lobe and hippocampal ciation, 2000). Positive symptoms generally respond well to function, and glutamate can affect dopamine function, both of medication (Association, 2000). Negative symptoms are defi which have been implicated in Schizophrenia, have Suggested cits of normal emotional responses or of other thought pro an important mediating (and possibly causal) role of cesses, and respond less well to medication (Kneisl & glutamate pathways in the condition (Coyle, Tsai, & Goff, Trigoboff). They commonly include flat or blunted affect and 2003). But positive symptoms fail to respond to glutamatergic emotion, poverty of speech (alogia), inability to experience medication (Tuominen, Tihonen, & Wahlbeck, 2005). pleasure (anhedonia), lack of desire to form relationships 0080 Deficits in social cognition form one of the most (asociality), and lack of motivation (avolition). Research Sug significant areas of impairment associated with schizophrenia gests that negative symptoms contribute more to poor quality and are often characterised as the negative symptoms of of life, functional disability, and the burden on others than do Schizophrenia. There is also evidence Suggesting that there is positive symptoms. People with prominent negative symp an association between childhood autism and the Subsequent toms often have a history of poor adjustment before the onset diagnosis schizophrenia. This evidence together with the bio of illness, and response to medication is often limited (T. logical function of self-awareness and conscious experience, Smith, Weston, & Lieberman, 2010) Schizophrenia is asso and how its disturbance in pathology may account for major ciated with subtle differences in brainstructures, found in 40 symptoms in self-regulatory disorders like autism, ADHD to 50% of cases, and in brain chemistry during acute psy and schizophrenia. Therefore it would not be an unreasonable chotic states. Studies using neuropsychological tests and hypothesis that the deficits in Social cognition are associated brain imaging technologies such as fMRI and PET to examine with conditions such as schizophrenia may well benefit from functional differences in brain activity have shown that dif mood stabilising medication. However, the finding that of the ferences seem to most commonly occur in the frontal lobes, low dose phenyloin improved social cognition was unex hippocampus and temporal lobes (The Boundaries of Con pected at a dose which would not normally be considered sciousness. Neurobiology And Neuropathology (Google effective. eBook), 2006). Reductions in brain volume, smaller than I0081. In individuals with bipolar mood disorder there is those found in Alzheimer's disease, have been reported in evidence of stable and lasting cognitive impairment in all areas of the frontal cortex and temporal lobes. It is uncertain phases of the disorder, including the remission phase, particu whether these Volumetric changes are progressive or pre-exist larly in the following domains: Sustained attention, memory prior to the onset of the disease (Konradi & Heckers, 2003). and executive functions. (Latalova, Prasko, Diveky, & Velar US 2014/0142140 A1 May 22, 2014

tova, 2011) This is not infrequently results in difficulties in Superimposed on a background of neuronal loss related to Social cognition and maintenance of Social relationships. ageing. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyri 0082. A recent review reported significant relationships dine), a contaminant of an illicitly produced pethidine ana between cognitive impairments and functional outcomes logue MPPP (1-methyl-4-phenyl-4-propionoxypiperidine), were reported in 12 of the 13 studies (Wingo, Harvey, & causes irreversible parkinsonism similar to Parkinson's dis Baldessarini, 2009), The quality of which are important to ease. This effect appears to follow conversion by monoamine maintain Support particularly during periods of illness. There oxidase B to the neurotoxic methylphenylpyridinium ion fore treatment which enhances psychosocial functioning may which is selectively concentrated in dopaminergic neurones be associated with a significant positive outcome. Antiepilep in the Substantia nigra. It has been proposed that free radicals tic Mood stabilisers have been a mainstay of treatment for produced during normal metabolism of dopamine in the brain bipolar mood disorder, the typical therapeutic dose for by monoamine oxidase B might be similarly neurotoxic to sodium valproate in the treatment of bipolar disorder is con dopaminergic neurones in the Substantia nigra (the oxidant sidered between 1000 mg and 2000 mg a day, although other stress hypothesis). This has led to concern that use of antiepileptics have been found to be helpful the typical dose is levodopa, by increasing the Supply of dopamine, might there usually considered in a similar range to that required for the fore exacerbate neurodegeneration and hasten the progres treatment of epilepsy. We have noted in some patients with sion of Parkinson's disease but compelling evidence of Such bipolar mood disorder a significant improvement in their an effect is lacking. executive functioning on the addition of a very low dose of 0092 Drug-induced parkinsonism can arise from deple phenyloin. Improvement appears to be consistent that tion of presynaptic dopamine, as with reserpine and tetra observed in other conditions with enhanced organisation, and benazine, or from blockade of postsynaptic dopamine recep sequencing of thought together with enhanced social cogni tors in the striatum, as by antipsychotics and some tion. antiemetics such as metoclopramide. It is generally reversible 0083 Tardive Dyskinesia (TD) is a disorder resulting in on drug withdrawal or dose reduction and may sometimes involuntary, repetitive body movements that have a slow or disappear gradually despite continuous drug therapy. belated onset. The movements often have no purpose and can Although the use of levodopa to overcome antipsychotic include grimacing, tongue protrusion, lip Smacking, pucker induced blockade of dopamine receptors might appear ratio ing and pursing of the lips, and rapid eye blinking. Rapid nal, it has generally been reported to be ineffective or to movements of the extremities may also occur. increase psychiatric symptoms. Antimuscarinics may pro 0084 Neurodegeneration is the progressive loss of struc vide relief from the extrapyramidal symptoms that occur as ture or function of neurons, including the death or functional adverse effects of antipsychotic therapy; however, they do not disablement of neurons in the brain and/or central nervous relieve the symptoms of tardive dyskinesia and should be system. withdrawn if it develops. 0085 Neurodegenerative diseases, including Parkinson's, 0093. There is no cure for Parkinson's disease. Although dementia, Alzheimer's disease and Huntington's disease, are the possibility of using drug therapy to slow neurodegenera discussed in more detail below. tion is being investigated, no drug so far has a proven neuro I0086 Parkinson's disease is characterised by tremor, protective effect. Treatment is palliative and symptomatic and rigidity, akinesia or bradykinesia, and loss of postural consists mainly of drug therapy Supplemented when neces reflexes, associated with reduced dopamine activity in the sary with physical treatment Such as physiotherapy and brain. It may be classified as follows: speech therapy. Surgery is occasionally used and there is I0087 primary (idiopathic) parkinsonism, usually growing interest in the use of transplantation and in electrical referred to as Parkinson's disease (formerly paralysis devices for the control of tremor. agitans) 0094. The most widely used form of treatment is L-dopa in 0088 secondary (acquired) parkinsonism, including various forms. L-dopa is transformed into dopamine in the postencephalitic parkinsonism, drug-induced parkin dopaminergic neurons by L-aromatic amino acid decarboxy Sonism, and symptoms associated with manganese poi lase (often known by its former name dopa-decarboxylase). Soning However, only 1-5% of L-DOPA enters the dopaminergic parkinsonism-plus syndromes where parkinsonism is a fea neurons. The remaining L-dopa is often metabolised to ture of other degenerative diseases of the CNS, such as pro dopamine elsewhere, causing a wide variety of side effects. gressive Supranuclear palsy and multiple system atrophy. Due to feedback inhibition, L-dopa results in a reduction in 0089 Arteriosclerotic parkinsonism” has been used to the endogenous formation of L-dopa, and so eventually describe parkinsonism associated with cerebrovascular dis becomes counterproductive. The majority of patients respond ease, although this may be confusing since vascular brain initially to levodopa and its use has improved the quality and damage is not a cause of Parkinson's disease. duration of life. However, after 2 years or more, benefit is 0090 The term parkinsonism is often used for the idio reduced as the disease progresses and late complications pathic form, that is, Parkinson's disease. Parkinson's disease emerge. Apart from dyskinesias and psychiatric effects, a and postencephalitic parkinsonism have been attributed pri major problem with long-term levodopa treatment is the marily to depletion of striatal dopamine in the basal ganglia as appearance of fluctuations in mobility, the two predominant a result of the loss of neurones in the Substantia nigra. Striatal forms being end-of-dose deterioration (wearing-off effect) dopamine deficiency results in loss of the normal functional and the on-off phenomenon. Thus, views differ as to the best balance between dopaminergic and cholinergic activity and time to start treatment and the dosage to use in order to limit the aim of treatment is to increase the former and/or decrease the long-term complications. the latter. 0.095 Carbidopa and benserazide are dopa decarboxylase 0091. The cause of Parkinson's disease is not established, inhibitors. They help to prevent the metabolism of L-dopa although environmental and genetic factors are probably before it reaches the dopaminergic neurons and are generally US 2014/0142140 A1 May 22, 2014 given as combination preparations of carbidopa/levodopa 0100 Amantadine is a weak dopamine agonist with some (co-careldopa) (e.g. Sinemet, Parcopa) and benseraZide/ antimuscarinic activity although its activity as an antagonist levodopa (co-beneldopa) (e.g. Madopar). There are also con of N-methyl-D-aspartate may also have a beneficial effect in trolled release versions of Sinemet and Madopar that spread Parkinson's disease. It has mild antiparkinsonian effects out the effect of the L-dopa. Duodopa is a combination of compared with levodopa but is relatively free from adverse levodopa and carbidopa, dispersed as a viscous gel. Using a effects. It can improve bradykinesia as well as tremor and patient-operated portable pump, the drug is continuously rigidity although only a small proportion of patients derive delivered via a tube directly into the upper small intestine, much benefit. It is used similarly to antimuscarinics in early where it is rapidly absorbed. Another drug, Stalevo (carbi disease when symptoms are mild, but tolerance to its effects dopa, levodopa and entacapone), is also available for treat can occur rapidly. ment. 0101 If symptoms are mild, drug therapy may not be 0096 Catechol-O-methyltransferase (COMT) inhibitors, required in the early stages of the disease. When symptoms Such as entacapone and tolcapone, are selective and reversible become troublesome but are still relatively mild amantadine inhibitors of COMT, with mainly peripheral actions. They are oran antimuscarinic may be started; antimuscarinics are use given as adjunctive therapy to patients experiencing fluctua ful when tremor predominates but are generally more suitable tions in disability related to levodopa and dopa-decarboxy for younger patients and in drug-induced rather than idio lase inhibitor combinations; because of the risk of serious pathic parkinsonism. Some have begun treatment with sel hepatotoxicity, tolcapone should be restricted to when other egiline immediately, but there have been doubts over whether adjunctive therapy is ineffective or contra-indicated. When it has a neuroprotective effect, as postulated, and also over levodopa is used with a peripheral dopa-decarboxylase long-term safety. There is no consensus on when to start inhibitor, O-methylation becomes the predominant form of dopaminergic treatment or whether to begin with levodopa or metabolism of levodopa; adding a peripheral COMT inhibitor a dopamine agonist. For most patients treatment with can thus extend the duration and effect of levodopa in the levodopa eventually becomes necessary, but many neurolo brain, and allow lower and less frequent doses of levodopa. gists delay initial treatment with levodopa because of the They therefore can help to stabilise patients, especially those increased risk of motor complications. New patients, espe experiencing end-of-dose deterioration. cially younger patients, therefore often begin treatment with a dopamine agonist, with levodopa reserved for the elderly, 0097 Dopamine agonists such as bromocriptine, caber the frail, or those with intercurrent illness or more severe goline, lisuride, pergolide, pramipexole, and ropinirole act by symptoms. direct stimulation of remaining postsynaptic dopamine recep 0102. When levodopa does become necessary, the usual tors. Dopamine agonists are increasingly used in the early practice is to start with Small doses, together with a peripheral treatment of younger patients with parkinsonism in an dopa-decarboxylase inhibitor, and increase slowly to a dose attempt to delay therapy with levodopa (younger patients are which reduces disability to an acceptable level. Variations in at an increased risk of motor complications with levodopa). response and diminishing effectiveness over the years neces However, their efficacy often decreases after a few years. In older patients they may be reserved for adjunctive use when sitate careful adjustment of the size and form of the dose and levodopa is no longer effective alone or cannot be tolerated. the dosage schedule. They are sometimes useful in reducing off periods with 0103 Pramipexole was proposed in late 2009 as an early levodopa and in ameliorating fluctuations in mobility in the stage treatment alternative to Levodopa. 0104 Recently there has been a consensus that younger later stages of the disease. Parkinson's patients first be treated with dopamine agonists 0098. Apomorphine is a potent dopamine agonist, but while older patients should be given levodopa. must be given parenterally and with an antiemetic. Although 0105. Selegiline and rasagiline reduce the symptoms of this restricts its use, it has a role in stabilising patients who Parkinson's disease by inhibiting monoamine oxidase-B suffer unpredictable on-off effects. It is also used in the (MAO-B). MAO-B breaks down dopamine secreted by the differential diagnosis of parkinsonism. Transdermal patches dopaminergic neurons, so inhibiting it will result in inhibition containing rotigotine, another dopamine agonist, are avail of the breakdown of dopamine. Metabolites of selegiline able for use as monotherapy in the treatment of early-stage include L-amphetamine and L-methamphetamine (not to be Parkinson's disease in some countries. confused with the more notorious and potent dextrorotary 0099 Antimuscarinics are considered to have a weak anti isomers). This might result in side effects such as insomnia. parkinsonian effect compared with levodopa. They may Use of L-dopa in conjunction with selegiline has increased reduce tremor but have little effect on bradykinesia. They may mortality rates that have not been effectively explained. be of use alone or with other drugs in the initial treatment of Another side effect of the combination can be stomatitis. One patients with mild symptoms, especially when tremor is pro report raised concern about increased mortality when nounced, or later as an adjunct to levodopa, such as in patients MAO-B inhibitors were combined with L-dopa; however with refractory tremor or dystonias. Antimuscarinic adverse Subsequent studies have not confirmed this finding. Unlike effects, particularly cognitive impairment, occur frequently other non selective monoamine oxidase inhibitors, tyramine and can limit their use. However, Some antimuscarinic effects containing foods do not cause a hypertensive crisis. can ameliorate complications associated with Parkinson's 0106 Dementia is another neurodegenerative condition disease; dry mouth may be an advantage in patients with that is characterized by a progressive decline in cognitive sialorrhoea. There appear to be no important differences in function which may be due to damage or disease in the brain the efficacy of antimuscarinics for Parkinson's disease but beyond what might be expected from normal aging. Areas Some patients may tolerate one drug better than another. particularly affected include memory, attention, judgement, Those commonly used for Parkinson's disease include ben language and problem solving. Dementia typically begins Zatropine, orphenadrine, procyclidine, and trihexyphenidyl. gradually and worsens progressively over several years due to US 2014/0142140 A1 May 22, 2014 neuronal degeneration of the brain and causing gradual but this care. Subjective Cognitive Impairment (SCI) is a mild irreversible loss of function. The causes of dementia depend and variable condition with an identified nonspecific cogni on the age at which symptoms begin. In the elderly population tive impairment. Mild Cognitive Impairment (MCI) is a diag (usually defined in this context as over 65 years of age), a nosis given to individuals who have cognitive impairments large majority of cases of dementia are caused by Alzheimer's beyond that expected for their age and education, but which disease, vascular dementia or both. Dementia with Lewy do not interfere significantly with their daily activities. It is bodies is another fairly common cause, which again may considered to be the boundary or transitional stage between occur alongside either or both of the other causes normal aging and dementia and is seen as a risk factor for 0107. Several agents are currently used for the treatment Alzheimer's disease. The third is Alzheimer's Type Dementia of dementia. (ATD) and associated dementias which represent the most 0108 Acetylcholinesteraseinhibitors: Tacrine (Cognex), severe and end-stage presentation of cognitive impairment in donepezil (Aricept), galantamine (Razadyne), and rivastig the elderly. MCI can present with a variety of symptoms, but mine (Exelon) are approved by the United States Food and when memory loss is the predominant symptom it is termed Drug Administration (FDA) for treatment of dementia “amnesic MCI and is frequently seen as a risk factor for induced by Alzheimer's disease. They may be useful for other Alzheimer's disease. Studies suggest that these individuals similar diseases causing dementia Such as Parkinsons or vas tend to progress towards probable Alzheimer's disease at a cular dementia. rate of approximately 10% to 15% per year. Studies suggest 0109 The medications introduced for the treatment of that individuals with MCI tend to progress towards probable dementia were the cholinesterase inhibitors (ChEI) in 1997. Alzheimer's disease with an 80% conversion rate within five Since this time most clinicians and probably most patients years of onset. SCI is considered a prodromal MCI condition, would consider the cholinergic drugs, donepezil, galantamine and may last up to approximately 15 years. Deterioration in and rivastigmine, to be the first line pharmacotherapy for mild Social cognition and symptoms of higher executive dysfunc to moderate Alzheimer's disease. The individual drugs have tion are commonly cited as potential sensitive markers of later slightly different pharmacological profiles, but they all work progression to more significant cognitive impairment. There by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the fore both SCI and MCI may provide the best opportunities for enzyme acetylcholinesterase. The most that these drugs could clinical intervention, aiming for the possible re-direction or achieve is to modify the manifestations of Alzheimer's dis least delay of the eventual loss of function. ease. N-methyl-D-aspartate Blockers. Memantine (Na 0114. There is no proven treatment or therapy for mild menda) is a drug representative of this class. It can be used in cognitive impairment. As MCI may represent a prodromal combination with acetylcholinesterase inhibitors. Amyloid state to clinical Alzheimer's disease, treatments proposed for deposit inhibitors: Minocycline and Clioquinoline, antibiot Alzheimer's disease, such as antioxidants and cholinesterase ics, may help reduce amyloid deposits in the brains of persons inhibitors, may be useful. In fact, several potential treatments with Alzheimer's disease. are currently under investigation. Two drugs used to treat 0110 Antidepressant drugs: Depression is frequently Alzheimer's disease have been explored in particular, for associated with dementia and generally worsens the degree of their ability to effectively treat MCI or prevent/slow down the cognitive and behavioral impairment. Antidepressants effec progress towards full Alzheimer's disease. Rivastigmine tively treat the cognitive and behavioral symptoms of depres failed to stop or slow progression to Alzheimer's disease or sion in patients with Alzheimer's disease, but evidence for improve cognitive function for individuals with MCI, and their use in other forms of dementia is weak. Donepezil showed only minor, short-term benefits and was 0111 Anxiolytic drugs: Many patients with dementia associated with significant side effects. Recently, there have experience anxiety symptoms. Although benzodiazepines been favourable reports regarding Colostrinin, which confirm like diazepam (e.g. Valium) have been used for treating anxi the drug offers a viable treatment for MCI. ety in other situations, they are often avoided because they 0115 Furthermore, compliance with pharmacotherapy is may increase agitation in persons with dementia and are a long standing and difficult problem with individuals both likely to worsen cognitive problems or are too sedating. Bus with and without attention and concentration impairment. pirone (Buspar) is often initially tried for mild-to-moderate Reduced compliance affects and potentially limits the effi anxiety. There is little evidence for the effectiveness of ben cacy of all interventions, frequently being the most limiting Zodiazepines in dementia, whereas there is evidence for the factor in providing Sustained psychotherapeutic benefit. For effectivess of antipsychotics (at low doses). example, the 12 month compliance rate for use of psycho 0112 Selegiline, a drug used primarily in the treatment of stimulants in adults is approximately 33%. The core areas of Parkinson's disease, appears to slow the development of impairment appear to be in the sequence and organisation of dementia. Selegiline is thought to act as an antioxidant, pre thoughts. This is seen clinically with adults with a diagnosis venting free radical damage. However, it also acts as a stimu of attention deficit hyperactivity disorder (ADHD); a DSM lant, making it difficult to determine whether the delay in IV-TR disorder as described in the Fourth Edition of the onset of dementia symptoms is due to protection from free Diagnostic and Statistical Manual of Mental Disorders radicals or to the general elevation of brain activity from the (American Psychiatric Association, 2000), and Snyder, Nuss stimulant effect. baum, & Robins (Eds.), 2006, ibid (especially Box 2) and 0113. Three areas of cognitive impairment associated with Weiss & Murray, 2003 and most commonly treated with dementia have been targeted for research in recent years, this psychostimulants. The initial and at times dramatic improve is in part due to the enormous cost to Society of caring for a ment frequently gives way to a returning disorganisation, and growing aging and increasingly dependent population thus non-adherence with medication and an eventual cessation of the improvement in function or even the slowing of the illness treatment. Unless there is a concurrent improvement in the process will resultina considerable reduction in the burden of automatic and effortless ability to process Social information, US 2014/0142140 A1 May 22, 2014

the gains in motivation provided by the stimulant will inevi a separate study (Rose & Holmbeck, 2007), it was revealed tably wane resulting in the associated return of symptoms. that attention and executive deficits were predictive of social 0116 Spina Bifida (SB) is the most common and severely adjustment difficulties with a meditational analysis inferring disabling neurogenetic disorder with prevalence studies indi that neurocognitive deficits mediated the association between cating rates of 18 out of every 100 000 births in the U.S. spina bifida Status and Social adjustment difficulty. (Holmbeck, Essner, Kelly, Friedman, DeLucia, Zebracki & 0.120. The higher executive and social functioning deficits Jandasek, 2010), 1 per 1000 in Europe and around 6 per 1000 identified in SB may also reflect similar cognitive difficulties live births in parts of India and China (Oakeshott, Hunt, in other conditions which have been successfully treated with Poulton & Reid, 2009). Theaetiology of SB remains complex Ultra low dose phenyloin. We have noted in the following and produces considerable phenotypic variability (Fletcher & example of a similar pattern of improvements SB to these Brei, 2010) that involves cognition, behaviour, adaptation and other conditions. neurologic dysfunction on multiple organ systems. Major I0121 Chronic neck pain affecting the cervical vertebrae organ affects are related to paralysed or weakened lower region can impose episodes of distress and disability for an extremities that often misguide placement of this condition individual and severely limit a multitude of lifestyle factors. into an orthopaedic category with the associated ambulatory The burden of continuous non-malignant pain is one of the effects (Fletcher & Brei). Urinary and bowel incontinence main precursors for seeking medical care and pain literature problems are an unfortunate and common feature in addition has indicated the important association of poor quality of life to hydrocephalus and learning disorders (Holmbeck et al). outcomes and depression symptomatology (Townsend, 0117 Recent decades have seen prevalence rates and the Sletten, Bruce, Rome, Leutze, & Hodgson, 2005; Demylten survival prognosis of SB alter substantially although this has naere et al., 2007). Furthermore, research into chronic pain not necessarily translated into universal behaviour modifica and comorbidity has urged clinicians to be aware of a wider tion. Dietary fortification including the taking of supplements spectrum of mental disorders that may co-occur in greater containing folic acid prenatally has assisted the decline of frequency with chronic pain such as anxiety and mood disor neural tube deficits although much support and education is ders in addition to alcohol dependency (Demyltennaere etal). required internationally for this to produce the desired pre Inferring both the history of pain and prognostic value, the vention rates (Fletcher & Brei). Prior to the 1960's the pre term chronic pain is defined as pain that persists beyond the dicted life outcome was poor for individuals with SB and the normal time of healing and in the category of non-malignant welcomed developments in neuroSurgical intervention wit pain, three months is a common medically agreed upon time nessed the prognosis to survival at 1 year rise significantly frame to distinguish acute phases of pain to chronic phases from 20% to 80% (Oakeshott et al). Longitudinal cohort (Von Korff & Dunn, 2008: Young Casey, Greenberg, Nicas studies have provided researchers, clinicians and families sio, Harpin & Hubbard, 2008). Although clinical debate con affected by SB with important information relating to mean tinues regarding the Suitability of chronic pain classification age of survival that in the Oakeshott study was 40 years of systems, the duration of pain model for determining chonicity age, in addition to greater understanding of health and dis indicates tissue damage is associated with acute pain signal ability concerns, impact on learning, living independently ling and chronic pain stems from central and peripheral sen and connecting socially. An extension of this has been to more sitization of pain that has Sustained beyond the period when closely examine the influences or impediments to academic nociceptive inputs have diminished (Von Korff & Dunn). learning or social engagement for an individual coping with 0.122 The prevalence of chronic neck pain is often impli this severe spinal dysraphism or split spine and determine if cated by the presence of chronic back pain. Regions of the other conditions co-exist with SB. back and neck invoking debilitating pain responses are 0118. One study of children affected by spina bifida men among the most frequently described pain conditions in gen ingomyelocele with hydrocephalus (SBH) which accounts eral populations of the developed world (Demyltennaere et for 95% of SB and 80-90% having CSF shunting, has con al). The ramifications of Such commonly occurring pain firmed the incidence of ADHD at 31%, significantly higher symptoms from individuals can be extensive in terms of than the prevalence figures of ADHD in the general popula health facility utilization, increasing expenditure and reduced tion of approximately 17% and depicted in this study, the employment participation as indicated by a large population ADHD prevalence rate was 5% in the comparison group and based survey revealing that 29% of adults had experienced 8% in the normative sample (Burmeister, Hannay, Copeland, back or neck pain in the previous month with 50% of this Fletcher, Boudousquie & Dennis, 2005). Furthermore, the group reporting chronic pain (Webb in Von Korff, 2005). authors in this study posited that behaviours associated with Several spinal pain studies (Makela et al., 1991; Bovin et al. distractibility, lack of focus and disorganisation are more 1994; Rajalaetal et al., 1995) from Europe and the U.S. have associated with SBH than hyperactive, impulsive behaviours. indicated that a within a prior 12 month time period, the 0119 Furthermore, a growing body of literature has rec prevalence rates for neck pain were between 12% and 34% (as ognised the important and interacting components of social cited in Demyttenaere et al). skills (Fletcher & Brei: Holmbecket al., 2003; Rose & Holm I0123 Determining a direct patho-aetiology of neck pain beck, 2007) in individuals with SB. In a preadolescent age can be assisted by the reference to broad categories Such as group (8-9 years of age) SB sample, it was revealed that these non-degenerative and degenerative neck pain with the former particular children demonstrated Social immaturity and pas category including a suspected differential diagnosis of frac sisivity, were less inclined to have social contacts outside of ture, Subluxation or dislocation (trauma), infection, neoplas School, indicated an increased dependence on adults for guid tic and vascular and the latter degenerative diagnosis includ ance, reduced likely hood for Scholastic Success, were less ing axial neck pain, cervical radiculopathy and cervical physically active, had a reduced ability to make independent myelopathy (Rogers, 2010). decisions and with an increased tendency to illustrate atten 0.124. According to a study by Young Casey etal involving tion and concentration difficulties (Holmbeck et al., 2003). In an aetiological model of chronic pain and disability in US 2014/0142140 A1 May 22, 2014

patients, the existence of baseline depressive symptoms and I0131. In an embodiment of the invention, the neurological pain permanence beliefs were strong predictors of chronic disorder excludes bipolar disorder and/or ADHD. Addition disability often leading to passive coping and avoidance and ally or alternatively, it may exclude neurodegenerative disor hence exacerbating the disability. ders. 0.125. The ability to control noxious stimuli, either from 0.132. Phenyloin (5,5-diphenylhydantoin), which has been pain or Sound can be seen as the ability to Successfully and in use for 60 years, is still an important antiepileptic drug. Its automatically without effort habituate, or ignore the primary mechanism of action is modulation of the Sustained unwanted stimuli. This can be done temporarily with effort repetitive firing of neurones by direct inhibition and blockage but is very exhausting and cannot be sustained for any length of Voltage-gated Sodium channels in the neuronal cell mem of time. Similarly we have noted that many patients are more brane, and by delay of cellular reactivation. The plasma pro able to ignore sound which was previously intrusive and tein binding of phenyloin is normally between 90% and 95%. distracting on commencement of the ultra low dose pheny The drug is rapidly distributed from the blood to the tissues loin. The invasive and distressing nature of the cervical pain and is almost completely metabolized in the liver. The plasma was reduced with unexpected efficacy and rapidity. phenyloin concentration normally reaches the steady-state 0126 Antiepileptic medications are commonly used for level within 1-2 weeks. The half-life of phenyloin is less than the control of chronic and neuropathic pain. Furthermore, it 20h in low doses, but is prolonged in high doses. has been has been described that sodium channel blockers 0.133 Based on this description and mechanism of action Such as phenyloin exhibit analgesic effects (Lai, Porreca, one would not consider it likely that a dose of less than 2.5% Hunter, & Gold, 2004). Certain antiepileptic medication can of the therapeutic dose for epilepsy/bipolar mood disorder be used effectively to control pain and some of these medi would be effective. Particularly in the context of the high cations, such as pregabalin, have approved indications foruse plasma protein binding the rapid action and response noted in in treatment in neuropathic pain. However, the rapidity of the the oral and sublingual routes would not be expected to be response at less than 2.5% of the usual therapeutic doses inconsistent with the above pharmacokinetics. would not be anticipated based on the current knowledge of I0134. The dose of the anti-epileptic agent is less than 20% phenyloin. of the minimum daily dose which is effective for mood sta bilisation or treatment of epileptic symptoms, for example, 0127. Despite the fact that there are many agents that can less than 10%. In certain embodiments, the dose of the anti be used alone or in combination to treat neurological disor epileptic agents is a low dose. Such as for example, less than ders, there is a need for improving treatment of these diseases. 7.5% or less than 5% of the minimum daily dose which is These improvements may relate to the efficacy of the treat effective for mood stabilisation of epilepsy or epileptic symp ment (e.g. in terms of patient outcomes such as quality of life toms. In further embodiments, the dose of the anti-epileptic is and amelioration of symptoms), reduction or elimination of an ultra low dose, such as for example, less than 2.5%, less side-effects and/or the cost of treatment, although without than 2%, less than 1.5% or less than 1% of the minimum daily limitation thereto. dose which is effective for mood stabilisation of epilepsy or 0128. According to a first aspect of the invention, there is epileptic symptoms. Suitably, the amount of the antiepileptic provided an anti-epileptic agent for use in the treatment of a equates to an ultra low dose. neurological disorder other than epilepsy, characterised in 0.135 Suitably, the daily dose of the anti-epileptic agent is that the anti-epileptic agent is the sole active agent and that the greater than 0.001% of the minimum daily dose which is daily dose of the anti-epileptic is less than 20% of the mini effective for mood stabilisation or treatment of epileptic mum daily dose which is effective for mood stabilisation or symptoms. treatment of epileptic symptoms. 0.136. In low dose embodiments, the dose may be admin 0129. In the context of the present invention, neurological istered daily, at multiple time each day or at pre-determined disorders include disorders associated with impaired, abnor times during the week. Thus, the anti-epileptic agent may be mal or reduced cognitive processing, particularly that which administered one, two, three, four, five or six times per week, enables higher executive functioning. Neurodegenerative rather than daily or more than once per day. Where the medi conditions, such as dementia, Parkinson's disease, Alzhe cament is administered in accordance with a dosage regimen imer's disease and Huntington's disease are included within of less than one dose per day (e.g. where the medicament is the neurological disorders of the present invention. In addi administered one, two, three, four, five or six times per week), tion to the neurodegenerative conditions mentioned above, the medicament may be formulated as a controlled release or the neurological disorders of the present invention include a Sustained release pharmaceutical composition. learning disorders, reading disorders, acquired brain injury, 0.137 According to a second aspect of the invention, there autism, tardive dyskinesia (TD), attention deficit hyperactiv is provided a pharmaceutical composition comprising a Sub ity disorder (ADHD), spina bifida (SB), chronic pain, post therapeutic dose of an anti-epileptic agent as the Sole active traumatic stress disorder (PTSD), schizophrenia and visual agent within the composition, together with a pharmaceuti acuity/fatigue. cally acceptable carrier, diluent and/or excipient, wherein the 0130 Thus, the neurological disorders of the invention are sub-therapeutic dose is less than 20% of the minimum daily Suitably selected from the group consisting of neurodegen dose of the anti-epileptic agent which is effective for mood erative conditions, such as dementia, Parkinson's disease, stabilisation or treatment of epileptic symptoms. Alzheimer's disease and Huntington's disease; learning dis 0.138. The amount of the anti-epileptic agent present in the orders; reading disorders; acquired brain injury; autism (in composition may be such that the composition is able to cluding autistic spectrum disorders or ASD); tardive dyski deliver the desired daily dose as discussed above. Thus, for nesia; attention deficit hyperactivity disorder (ADHD); spina compositions adapted to be delivered as a single daily dose, bifida; chronic pain; post traumatic stress disorder (PTSD); the amount of the anti-epileptic agent present may be as Schizophrenia; and visual acuity/fatigue. discussed above. However, for compositions adapted to be US 2014/0142140 A1 May 22, 2014

administered more than once per day, the amount of the is suitably more than 0.001% of the minimum daily dose anti-epileptic present in the composition would be corre which is effective for mood stabilisation or treatment of epi spondingly lower. leptic symptoms. 0139. It has been found that transdermal administration, 0148 Similar to the second aspect of the invention, there is particularly via the oral mucosa, is an efficient mode of also provided a fifth aspect of the invention which provides a administration for the compositions according to the second pharmaceutical composition comprising: aspect of the invention. An example of transdermal delivery 0.149 (a) a sub-therapeutic dose of an anti-epileptic via the oral mucosa is a sub-lingual composition. Thus, trans agent, dermal compositions, including in particular compositions 0.150 (b) an active selected from a stimulant, an anti adapted to be delivered across the oral mucosa, Such as pow Parkinson's agent, an analgesic and an acetylcholinest ders, capsules, tablets, lozenges or pastilles are Suitable forms erase inhibitor; and for delivering the anti-epileptic agent. Alternative transder 0151 (c) a pharmaceutically acceptable carrier, diluent mal compositions include patches or dressings which are and/or excipient, adapted to be secured (e.g. temporarily adhered) to the skin of wherein the sub-therapeutic dose is less than 2.5% of the a patient. Thus, an adhesive patch containing a composition minimum daily dose which is effective for mood stabilisation accordingly to the invention forms an embodiment of the or treatment of epileptic symptoms. invention. 0152. As with the second aspect of the invention, the 0140. In embodiments where the intended route of admin amount of the anti-epileptic agent present in the composition istration is oral, the pharmaceutical composition may be for may be such that the composition is able to deliver the desired mulated as an immediate release formulation or it may be daily dose as discussed above. Thus, for compositions formulated as a controlled release formulation, Sustained adapted to be delivered as a single daily dose, the amount of release formulation or a delayed release formulation. the anti-epileptic agent present may be as discussed above. 0141 Furthermore, the composition may be a combina However, for compositions adapted to be administered more tion of immediate release and controlled release, Sustained than once per day, the amount of the anti-epileptic present in release and/or delayed release. For example, the composition the composition would be correspondingly lower. Similarly, may comprise an immediate release layer or compartment the composition may in a transdermal form (e.g. formulated and a controlled release, Sustained release and/or delayed for Sub-lingual administration or as a patch) as discussed release layer or compartment. above. 0142. According to a third aspect of the invention, there is 0153. The pharmaceutical composition may be formu provided a method of treating a neurological disorder other lated as an immediate release formulation or it may be for than epilepsy in a Subject in need thereof, including the step of mulated as a controlled release formulation, Sustained release administering to the Subject an anti-epileptic agent as the sole formulation or a delayed release formulation. Furthermore, active agent, wherein the daily dose of the anti-epileptic agent the composition may be a combination of immediate release is less than 20% of the minimum daily dose which is effective and controlled release, Sustained release and/or delayed for mood stabilisation or treatment of epileptic symptoms. release. For example, the composition may comprise an 0143. The skilled person will appreciate that the amount of immediate release layer or compartment and a controlled the anti-epileptic agent used in the method according to the release, Sustained release and/or delayed release layer or third aspect of the invention will be as discussed in connection compartment. with the first aspect of the invention. Additionally, the skilled 0154 According to a sixth aspect of the invention, there is person will appreciate that the neurological disorder may be a provided a method of treating a neurological disorder other neurological disorder as defined or mentioned herein. than epilepsy in a Subject in need thereof, including the step of administering to the Subject a combination of (a) an anti 0144. In addition to use of the anti-epileptic as a sole epileptic agent, and (b) an active selected from a stimulant, an active, it may be used in combination with a second active anti-Parkinson's agent, an analgesic and an acetylcholinest selected from a stimulant, an anti-Parkinson's agent, an anal erase inhibitor, wherein the daily dose of the anti-epileptic gesic and an acetylcholinesterase inhibitor. Thus, according agent is less than 2.5% of the minimum daily dose which is to a fourth aspect of the invention, there is provided a com effective for mood stabilisation or treatment of epileptic bination of symptoms. 0145 (a) an anti-epileptic agent; and 0.155. In an embodiment of the invention as defined in any 0146 (b) an active selected from a stimulant, an anti of the aspects detailed above, the anti-epileptic agent may be Parkinson's agent, an analgesic and an acetylcholinest selected from brivaracetam, carbamazepine, clobazam, clon erase inhibitor azepam, dantrolene, eslicarbazepine acetate, ethoSuximide, for use in the treatment of a neurological disorder other than eZogabine, felbamate, gabapentin, ghrelin, lacosamide, lam epilepsy, characterised in that the daily dose of the anti otrigine, levetiracetam, oXcarbazepine, phenobarbital, phe epileptic agent is less than 2.5% of the minimum daily dose nyloin, pregabalin, primidone, retigabine, rufinamide, Safina which is effective for mood stabilisation or treatment of epi mide, seletracetam, talampanel, tiagabine, tizanidine, leptic symptoms. topiramate, valproate, vigabatrin, Zonisamide, 2-(1H-Benzo 0147 The skilled person will appreciate that the fourth triazol-1-yl)-N'-substituted acetohydrazides, 4-aminopyri aspect of the invention uses an ultra low dose of the anti dine, benzodiazepines, barbiturates and sedative hypnotics. epileptic agent, which is less than 2.5%, such as less than 2%, 0156. In embodiments of the invention where a stimulant less than 1.5% or less than 1% of the minimum daily dose is included, the stimulant may be selected from Adrafinil, which is effective for mood stabilisation or treatment of epi Amantadine, Armodafinil, Carphedon, Modafinil, 4-Fluoro leptic symptoms. As with the first aspect of the invention, the amphetamine, 4-Fluoromethamphetamine, 4-Methylmeth amount of the anti-epileptic agent present in the combination cathinone, 4-MTA, C.-PPP, Amphechloral, Amphetamine, US 2014/0142140 A1 May 22, 2014

Dextroamphetamine, Adderall, Amphetaminil, BenZphet understood by one of ordinary skill in the art (e.g. in pharma amine, Bupropion, Cathinone, Chlorphentermine, Cloben ceutical chemistry and medicine, including psychiatry). Zorex, Clortermine, Cypenamine, Diethylpropion, 0.161 Unless contraindicated or noted otherwise, in these Dimethoxyamphetamine, Dimethylamphetamine, Dimethyl descriptions and throughout this specification, the terms “a cathinone, Diphenyl prolinol, Ephedrine, Epinephrine, Eth and “an' mean one or more, the term 'or' means and/or. cathinone, Ethylamphetamine, Fencamfamine, Fenethylline, Fenfluramine, Fenproporex, Feprosidinine, Furfenorex, (0162 Unless defined otherwise, all technical and scien Levomethamphetamine, Lisdexamfetamine, L-lysine-d-am tific terms used herein have the same meaning as commonly phetamine, MDMA, Mefenorex, Methamphetamine, Meth understood by one of ordinary skill in the art (e.g. in pharma cathinone, Methoxyphedrine, Methylone, Octopamine, ceutical chemistry). Parahydroxyamphetamine, PMA, PMEA, PMMA, PPAP 0163. By “comprising is meant including, but not limited Phendimetrazine, Phenmetrazine, Phentermine, Phenyleph to, whatever follows the word “comprising”. Thus, use of the rine, Phenylpropanolamine, Prolintane, Propylamphetamine, term “comprising indicates that the listed elements are Pseudoephedrine, Selegiline, Synephrine, Tenamphetamine, required or mandatory, but that other elements are optional Xylopropamine; piperazines, BZP, MeOPP, MBZP, mCPP, and may or may not be present. 2C-B-BZP, Tropanes, Brasofensine, CFT, Cocaethylene, 0164. By “consisting of is meant including, and limited Cocaine, Dimethocaine, Lometopane, PIT, PTT, RTI-121, to, whatever follows the phrase “consisting of Thus, the Tesofensine, Troparil, WF-23, WF-33, Cholinergics, phrase “consisting of indicates that the listed elements are Arecoline, Cotinine, Convulsants, Bicuculline, Gabazine, required or mandatory, and that no other elements may be Pentetrazol, Picrotoxin, Strychnine, Thujone; Phenylami present. nooxazoles, 4-Methyl-aminorex, Aminorex, Clominorex, 0.165. By “consisting essentially of is meant including Fenozolone, Fluminorex, Pemoline, Thozalinone, Aminept any elements listed after the phrase, and limited to other ine, Bemegride, BPAP. Clenbuterol, Clofenciclan, Cyclopen elements that do not interfere with or contribute to the activity tamine, Cyprodenate, Desoxypipradrol, Ethylphenidate, or action specified in the disclosure for the listed elements. Ethamivan, Gilutensin, GYKI-52895, Hexacyclonate, Indian Thus, the phrase “consisting essentially of indicates that the orex, Indatraline, Isometheptene, Mazindol, MDPV. Meso listed elements are required or mandatory, but that other ele carb, methylphenidate, Dexmethylphenidate, Naphthyliso ments are optional and may or may not be present depending propylamine, Nikethamide, Nocaine, Nomifensine, upon whether or not they affect the activity or action of the Phacetoperane, Phthalimidopropiophenone, Pipradrol, Pro listed elements. lintane, Propylhexedrine, Pyrovalerone, Tuamine, Vanox (0166 As used herein, “subject” or “individual” or erine, Yohimbine, Zylofuramine, Deanol, Diethylaminoetha “patient” refers to any subject for whom or which therapy is nol, Dimefline Hydrochloride, Etilamfetamine desired, and generally refers to the recipient of the therapy to Hydrochloride, Fencamfamin Hydrochloride, Fenetylline be practiced according to the invention. The Subject can be Hydrochloride, Fenfluramine Hydrochloride, Fenproporex any vertebrate, but will suitably be a mammal. If a mammal, Hydrochloride, Lobeline Hydrochloride, Pentetrazol, and the subject will suitably be a human, but may also be a Propylhexedrine. domestic livestock, laboratory subject or pet animal. The O157. In further embodiments of the invention where a Subject is most Suitably a human adult, child or infant, who is second active is present (i.e. according to the fourth, fifth or or has been the subject of treatment, observation or experi sixth aspects), the anti-Parkinson's agent may be selected ment. from apomorphine, benserazide, benzatropine, bromocrip 0.167 As used herein, unless the context demands other tine, cabergoline, carbidopa, clozapine, domperidone, enta wise, the term “treat,” “treating,” or “treatment’ means to capone, levodopa, lisuride, orphenadrine, pergolide, piribe counteract a medical condition (e.g., a neurological disorder) dil, pramipexole, procyclidine, quetiapine, rasagiline, to the extent that the medical condition is improved according rivastigmine, ropinirole, rotigotine, selegiline, tolcapone, tri to clinically acceptable standard(s). For example, “to treat a hexyphenidyl, a dopamine agonist, a dopamine decarboxy neurological disorder” means to improve the disorder or lase inhibitor, a catechol O methyl transferase (COMT) relieve symptoms of the particular disorder in a patient, enzyme inhibitor, a monoamine oxidase-B inhibitor and an wherein the improvement and relief are evaluated with a N-methyl-D-aspartate blocker. clinically acceptable standardised test (e.g., a patient self 0158. Instill further embodiments of the invention accord assessment scale) and/oran empirical test. "Treat,” “treating.” ing to the fourth, fifth or sixth aspects, the acetylcholinest or “treatment as used herein also includes prophylactic treat erase inhibitor is selected from tacrine, donepezil, galan ment unless the context requires otherwise. tamine and rivastigmine. 0.168. As used herein, the term “active agent”, “active' or "agent’ means any Substance which can affect any physical or 0159. The skilled person will appreciate that the term biochemical properties of a biological system, pathway, mol 'anti-epileptic agent can include two or more different com ecule, or interaction relating to an organism, including but not ponents or compounds which are effective in the treatment of limited to animals and humans. In particular, as used herein, epilepsy or epilepsy-related symptoms, or it can comprise a agents include but are not limited to any Substance intended single active component or compound. In the case where the for diagnosis, cure, mitigation, treatment, or prevention of agent comprises two or more different active components, the disease in humans or other animals, or to otherwise enhance daily dose for each of the components is less than the speci physical or mental well-being of humans or animals. fied amount of that component which is effective for mood Examples of biologically active molecules include, but are stabilisation of epilepsy or epileptic symptoms. not limited to, peptides, proteins, enzymes and Small mol 0160 Unless defined otherwise, all technical and scien ecule drugs. Classes of active agents that are Suitable for use tific terms used herein have the same meaning as commonly with the methods and compositions described herein include, US 2014/0142140 A1 May 22, 2014 but are not limited to, drugs, prodrugs, radionuclides, imag fies the relevant compounds or agents useful within the inven ing agents, polymers and the like. tion. Thus, AEDs of diverse chemical classes are useful and 0169 Certain agents, biologically-active molecules and relevant (with Suitable adjustments of dose) according to the other active compounds according to this invention may exist invention. as enantiomers. Where they possess two or more chiral cen 0.175. In embodiments of the invention, the amount of ters, they may additionally exist as diastereomers. It is to be anti-epileptic agent(s), when used as the sole active, is less understood that all such isomers and mixtures thereof are than 20% of the daily dose of anti-epileptic agent typically encompassed within the scope of the present invention. Fur effective in mood stabilization or in treating epileptic symp thermore, Some of the crystalline forms for the agents or toms. In particular embodiments, the amount of anti-epileptic compounds may exist as polymorphs and as such are intended agentis less than 10%, 5%, 2.5%, 2%, 1.5% or 1% of the daily to be included in the present invention. In addition, some of dose of anti-epileptic agent typically effective in mood stabi the agents or compounds may form Solvates with water (i.e., lization or in treating epileptic symptoms. Suitably, the daily hydrates) or common organic solvents, and Such Solvates are dose of the AED is at least 0.001% of the daily dose of also intended to be encompassed within the scope of this anti-epileptic agent typically effective in mood stabilization invention. or in treating epileptic symptoms. 0170 It will also be appreciated that the term "agent', whether in the context of an anti-epileptic agent or an agent 0176 Particular examples of AEDs include sodium val for treating a neurological disease, disorder or condition, may proate (sodium di-n-propylacetic acid) and derivatives be in the form of a pharmaceutically effective or acceptable thereof (valproic acid, valproate pivoxil, semi-sodium val salt. proate, divalproex, valproylamides such as Valpromide, 0171 As used herein, the terms “co-therapy' and “com Depakene, Depakote, Depakote ER), tiagabine, ethoSuxim bination therapy” shall mean treatment of a subject in need ide, Zonisamide, carbamazepine, oXcarbazepine, lamot thereof by administering one or more anti-epileptic agent(s) rigine, tiagabine, gabapentin, pregabalin, phenyloin, primi and one or more agents for treating a neurological, disease, done, phenobarbitone, phenobarital, topiramate, diazepam disorder or condition by any suitable means, simultaneously, and related compounds, and levetiracetam. sequentially, separately or in a single pharmaceutical formu 0177. In particular embodiments the AED is selected from lation or combination. When administered in separate dosage the group consisting of brivaracetam, carbamazepine, cloba forms, the number of dosages administered per day for each Zam, clonazepam, ethoSuximide, felbamate, gabapentin, component may be the same or different. The anti-epileptic lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phe agent(s) and one or more agents for treating a neurological, nobarbital, phenyloin, pregabalin, primidone, retigabine, disease, disorder or condition may be administered via the rufinamide, Safinamide, seletracetam, talampanel, tiagabine, same or different routes of administration. topiramate, valproate, vigabatrin, Zonisamide, benzodiaz 0172. As hereinbefore described, the invention provides epines, barbiturates and sedative hypnotics. sole or combination therapy of a neurological disease, disor der or condition, wherein an anti-epileptic agent alone or a 0.178 Particularly suitable AEDs are sodium valproate combination of one or more anti-epileptic drugs and one or and derivatives thereof, tiagabine, topiramate, carbam more further active therapeutically effective in the treatment azepine, oXcarbazepine, ethotoin, phenyloin, gabapentin, of a neurological disease disorder or condition is adminis pregabalin, and rufinamide. In another embodiment, the anti tered to a Subject to thereby treat the neurological disease, convulsant or anti-epileptic agent(s) is selected from the disorder or condition, Non-limiting examples of neurological group consisting of carbamazepine, clobazam, clonazepam, diseases, disorders or conditions include learning disorders, ethoSuximide, felbamate, gabapentin, lamotrigine, levetirac reading disorders, acquired brain injury, tardive dyskinesia, etam, oXcarbazepine, phenobarbital, phenyloin, pregabalin, Subjective cognitive impairment (SCI), mild cognitive primidone, retigabine, rufinamide, talampanel, tiagabine, impairment (MCI), dementia (including Alzheimer's Type topiramate, valproate, vigabatrin and Zonisamide. Dementia (ATD)), Parkinson's disease, Huntington's dis 0179. In another embodiment, the AED, anti-convulsant ease, pervasive development and communication disorders, oranti-epileptic agent(s) is selected from the group consisting autism (including ASD), attention deficit hyperactivity disor of carbamazepine, lamotrigine, phenobarbital, phenyloin, der (ADHD), spina bifida (SB), chronic pain, post traumatic topiramate, valproate and Zonisamide. Suitably, the anti-con stress disorder (PTSD), schizophrenia and visual acuity/fa Vulsant or anti-epileptic agent(s) is selected from the group tigue. consisting of carbamazepine, gabapentin, lamotrigine, leve 0173 As used herein, unless otherwise noted, the term tiracetam, oXcarbazepine, phenyloin, pregabalin, rufinamide, “anti-epileptic agent” and the abbreviation AED will be valproate and topiramate. More Suitably, the anti-convulsant used interchangeably with the terms “anti-convulsantagent'. oranti-epileptic is selected from the group consisting of gaba “anticonvulsant’ “anti-epileptic mood stabilizer”, “mood sta pentin, lamotrigine, levetiracetam, pregabalin, rufinamide, bilizer, and “anti-epileptic' and refer to an agent capable of valproate and topiramate. In a further embodiment, the anti treating, inhibiting or preventing seizure activity or ictogen epileptic is selected from the group consisting of Valproate, esis and/or achieving mood stabilisation when the agent is rufinamide, topiramate, and phenyloin. administered to a subject or patient. 0.174 While not wishing to be bound by any particular 0180. In particular embodiments, examples of anti-con theory, it is believed that the exact chemical class of AED is Vulsant oranti-epileptic agents include, but are not limited to, not determinative of the utility of any specific AED in the the following, described non-exclusively by either mode of compositions and methods of the invention. Rather, it is the action or chemical class: efficacy of AEDs in treatment of epileptic, pre-epileptic, or 0181 (a) AMPAantagonists such as AMP-397, E-2007, ictogenic events, convulsions, mood stabilization that identi NS-1209, talampanel, perampanel, and the like: US 2014/0142140 A1 May 22, 2014 16

0182 (b) Benzodiazepines such as diazepam, 0206 (y) eugenols such as (4-Allyl-2-Methoxyphenol), lorazepam, clonazepam, clobazam, clorazepate, mida phenyleugenol, benzyleugenol, and phenylethyleu Zolam, nimetazepam, nitrazepam, temasepam, and the genol; like: 0207 (Z) epalons such as ganaxolone and the like; and 0183 (c) Barbiturates such as phenobarbital, amobar 0208 (za) neuroleptics such as ghrelin and the like. bital, methylphenobarbital, primidone, Barbexaclone 0209. In one embodiment, the mood stabiliser is a gamma sodium, metharbital, pentobarbital, and the like: aminobutyric acid (GABA) enhancer, i.e. a GABAergic 0.184 (d) Valproates (including fatty acid derivatives) agent. Such as valproic acid, Valproate semisodium, Valpro mide, divalproex, valnoctamide, and the like; 0210. In further examples, a variety of AEDs have been 0185 (e) GABA related agents such as gabapentin (2- described in the art and useful as anti-epileptics and mood 1-(aminomethyl)cyclohexyl)acetic acid), pregabalin stabilizers. For example, those mentioned in the following ((S)-3-(aminomethyl)-5-methylhexanoic acid), published patents or patent applications describe, in relation vigabatrin, and the like; to the agent they disclose, both suitable methods for their 0186 (f) AEDs such as losigamone, retigabine, rufina preparation and doses for their administration. These publi mide (1-(2,6-difluorophenyl)methyltriazole-4-car cations are herein incorporated by reference. 0211 EP-0021121-A discloses a group of 3,5-diamino-6- boxamide), SPD-421 (DP-VPA), T-2000, XP-13512, (substituted phenyl)-1,2,4-triazines which are active in the and the like; treatment of central nervous system (CNS) disorders, for 0187 (g) Iminostilbenes such as carbamazepine, oxcar example in the treatment of epilepsy. One Such triazine is baZepine, eslicarbazepine acetate and the like; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine which is 0188 (h) Hydantoins such as phenyloin sodium, Phe alternatively called lamotrigine. EP-0372934-A discloses nyloin, mephenyloin, fosphenyloin Sodium, ethotoin, pyrimidine compounds useful in the treatment of CNS disor and the like; ders. Example 18 of EP-0372934-A discloses 2,4-diannino 0189 (h) NMDA antagonists such as harkoseride, and 5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine. the like: 0212 WO 97/09317 discloses the R(-) enantiomer of this (0190 (i) Sodium channel blockers such as BIA-2093, compound, R(+2,4-diamino-5-(2,3-dichlorophenyl)-6-fluo CO-102862, lamotrigine, and the like: romethylpyrimidine, Substantially free of the corresponding 0191 () Succinimides such as methSuximide, ethosux S(+) enantiomer. WO98/38174 discloses pyrazine deriva imide, and the like; tives, including rufinamide, useful in the treatment of CNS 0.192 (k) Carboxylic acids such as tiagabine, and the disorders such as epilepsy. WO99/32462 relates to a triazine like: compound which is useful in the treatment of central nervous 0193 (1) AEDS such as acetazolamide, clomthiazole system (CNS) diseases and disorders, i.e. the compound edisilate, Zonisamide, felbamate, topiramate, tiagabine, 5-amino-6-2,3,5-trichlorophenyl-1,2,4-triazine and phar levetiracetam, briveracetam, GSK-362115, GSK maceutically acceptable derivatives thereof. WO00/12488 406725, ICA-69673, CBD cannabis derivative, isoval relates to pyrazine compounds useful in the treatment of CNS eramide (NPS-1776), RWJ-333369 (carisbamate), Safi diseases and resulting disorders. namide, Seletracetam, soretolide, stiripentol, 0213. As used herein “one or more agents effective in the valrocemide, and the like; treatment of a neurological condition or disorder includes 0194 (m) oxazolidinediones such as trimethadione, any agent useful in the treatment of neurodegenerative disor paramethadione, ethadione and the like; ders including Parkinson's disease and dementia. 0.195 (n) succinimides such as ethosuximide, phensux 0214 Non-limiting examples of agents useful in treating imide, mesuXimide, and the like; Parkinson's disease include apomorphine, benserazide, ben 0.196 (o) pyrrolidines such as levetiracetam, and the Zatropine, bromocriptine, cabergoline, carbidopa, clozapine, like: domperidone, entacapone, levodopa, lisuride, orphenadrine, 0.197 (p) sulphonamides, such as acetazolamide, met pergolide, piribedil, pramipexole, procyclidine, quetiapine, haZolamide, Zonisamide, Sultiame, and the like; rasagiline, rivastigmine, ropinirole, rotigotine, selegiline, tol 0198 (c) aminobutyric acids and the like: capone and trihexyphenidyl, 0199 (r) sulfamate-substituted monosaccharides such 0215. In one embodiment for treating Parkinson's disease, as topiramate (2.3:4.5-Bis-O-(1-methylethylidene)- the agent is L-dopa or levodopa. beta-D-fructopyranose sulfamate)), and the like: 0216. In another embodiment for treating Parkinson's dis 0200 (s) carboxamides such as carbamazepine, oxcar ease, the agent is a dopamine agonist. Non-limiting examples baZepine, rufinamide, and the like; include bromocriptine, pergolide, pramipexole, ropinirole, 0201 (t) aromatic allylic alcohols such as stiripentol, piribedil, apomorphine, cabergoline, lisuride and pramipex and the like; ole. 0202 (u) ureas such as phenacemide, pheneturide, and 0217. In an additional or alternative embodiment for treat the like: ing Parkinson's disease the agent is a dopamine decarboxy 0203 (v) phenyltriazines such as lamotrigine, and the lase inhibitor. Non-limiting examples include carbidopa and like: benserazide 0204 (w) carbamates such as emylcamate, felbamate, 0218. In further additional or alternative embodiment for meprobamate, and the like; treating Parkinson's disease, the agent inhibits the catechol O 0205 (x) pyrrolidines such as brivaracetam, levetriac methyl transferase (COMT) enzyme. Non-limiting examples etame, nefiracetam, selectracetam, and the like; include tolcapone and entacapone. US 2014/0142140 A1 May 22, 2014

0219. In a yet further additional or alternative embodiment BiphentinTM in Canadian Patents 2355854 and 2355644. for treating Parkinson's disease, the agent is a monoamine Though not technically an amphetamine, methylphenidate oxidase-B inhibitor, Non-limiting examples include sel functions in a similar way in the CNS or brain. Methylpheni egiline and rasagiline. date typically has a relatively short duration of action (2 to 4 0220 Inayet still further additional or alternative embodi hours). Hence, slow release or continual release formulations ment for treating Parkinson's disease, the agent is a N-me or methods of delivery have been developed, e.g. ConcertaTM thyl-D-aspartate blocker. Non-limiting examples include and the transdermal patch, marketed as Daytrana T.M. Further Memantine (Namenda). examples of slow or controlled release formulations are 0221. In embodiments relating to treatment of dementia, known in the art, for example as described in published US the agent is preferably an acetylcholinesterase inhibitor. Non patent application no. 2007/0059349. limiting examples include tacrine, donepezil, galantamine 0227 Typical doses for these medications are described in and rivastigmine. Wilens and Dodson, 2004, Clin. Psychiatry 65: 1301-1313 0222. As used herein, unless otherwise noted, the term (methylphenidate juveniles: 0.6 to 1.0 mg/kg/day; adults 20 “stimulant”, “psychostimulant’ or “psychostimulant agent' to 100 mg per day, amphetamine juveniles: 0.3 to 1.5 and the terms “central nervous system stimulant' and “CNS mg/kg/day; adults 10 to 70 mg/day, pemoline juveniles: 1.0 stimulant will be used interchangeably and refer to an agent capable of producing an increase or enhancement in psycho to 3.0 mg/kg/day; adults 75 to 150 mg/day). motor activity. However, and as known to those of skill in the 0228. Additional examples useful in the invention include: art and as herein defined, the terms “psychostimulant' and Eugeroics such as Adrafinil, Armodafinil, Carphedon, “CNS stimulant’ as used herein do not refer to agents such as Modafinil; Phenethylamines such as 4-Fluoroamphetamine, caffeine and nicotine, which are not considered to be psycho 4-Fluoromethamphetamine, 4-Methylmethcathinone, stimulants, at least because they do not enhance locomotor 4-MTA, C.-PPP, Amphechloral, Amphetamine (Dextroam behavior in rodents (Sulzer, D., et al. Prog. Neurobio. 75(6): phetamine, Adderall), Amphetaminil, BenZphetamine, 406-433). Bupropion, Cathinone, Chlorphentermine, Clobenzorex, 0223) A large number of pyschostimulants are known in Clortermine, Cypenamine, Diethylpropion, Dimethoxyam the art and suitable for use in the invention. While not wishing phetamine, Dimethylamphetamine, Dimethylcathinone, to be bound by any particular theory, it is believed that the Diphenyl prolinol, Ephedrine, Epinephrine, Ethcathinone, exact chemical class of psychostimulant is not determinative Ethylamphetamine, Fencamfamine, Fenethylline, Fenflu of the utility of any specific psychostimulant in the composi ramine, Fenproporex, Feprosidinine, Furfenorex, tions and methods of the invention. Rather, it is the efficacy of Levomethamphetamine, Lisdexamfetamine (VyvanceTM) psychostimulants in increasing or enhancing psychomotor (L-lysine-d-amphetamine), MDMA, Mefenorex, Metham activity that is encompassed by the invention. Thus, psycho phetamine, Methcathinone, Methoxyphedrine, Methylone, stimulants of diverse chemical classes are equally useful and Octopamine, Parahydroxyamphetamine, PMA, PMEA, relevant (with suitable adjustments of dose) in combination PMMA, PPAP, Phendimetrazine, Phenmetrazine, Phenter with similarly diverse classes of AEDs within the scope of the mine, Phenylephrine, Phenylpropanolamine, Prolintane, Pro invention. Indeed, clinical examples are provided that dem pylamphetamine, Pseudoephedrine, Selegiline, Synephrine, onstrate effectiveness and relevance of diverse classes of psy Tenamphetamine, Xylopropamine; piperazines Such as BZP, chostimulants in combination with diverse classes of AEDs. MeOPP, MBZP, mCPP, 20-B-BZP; Xanthines such as Ami 0224 Psychostimulants useful for the compositions on the nophylline, Paraxanthine. Theobromine, Theophylline; Tro invention include, but are not limited to: methylphenidate panes Such as Brasofensine, CFT, Cocaethylene, Cocaine, (Ritalin) administered at about 0.01 to about 2.5 mg/kg/day; Dimethocaine, Lometopane, PIT, PTT, RTI-121, dextroamphetamine (Dexedrine) administered at about 0.07 Tesofensine, Troparil, WF-23, WF-33; Cholinergics such as to about 1.5 mg/kg/day; amphetamine (Adderall) adminis Arecoline, Cotinine; Convulsants such as Bicuculline, Gaba tered at about 0.05 to about 1.5 mg/kg/day; and pemoline zine, Pentetrazol, Picrotoxin, Strychnine, Thujone; Pheny (Cylert) administered at about 0.1 to about 2.0 mg/kg/day. laminooxazoles such as 4-Methyl-aminorex, Aminorex, Clo 0225. Examples of psychostimulants with use in the minorex, Fenozolone, Fluminorex, Pemoline, Thozalinone; invention include the class of compounds identifiable as Others such as Amantadine, Amineptine, Bemegride, BPAP. amphetamines. The term "amphetamine' as understood by Clenbuterol, Clofenciclan, Cyclopentamine, Cyprodenate, those of skill in the art, typically contains an alpha-methyl Desoxypipradrol, Ethylphenidate, Ethamivan, Gilutensin, phenethyl-amine motif. Exemplary amphetamines are GYKI-52895, Hexacyclonate, Indanorex, Indatraline, amphetamine, methamphetamine, and dextroamphetamine Isometheptene, Mazindol, MDPV. Mesocarb, methylpheni or “dexamphetamine'. Dextroamphetamine or “D-amphet date, Dexmethylphenidate, Naphthylisopropylamine, amine' or “dexamphetamine' is the dextrorotary (D) stereoi Nikethamide, Nocaine, Nomifensine, Phacetoperane, Phthal Somer of amphetamine. Amphetamines in pharmaceutical imidopropiophenone, Pipradrol, Prolintane, Propyl form include, for example, dextroamphetamine Sulphate hexedrine, Pyrovalerone, Tuamine, Vanoxerine, Yohimbine, (DexaminTM, DextrostatTM, DexadrineTM), dexamphetamine Zylofuramine, Deanol, Diethylaminoethanol, Dimefline or mixed amphetamine salts (Adderall XRTM)) and pemoline Hydrochloride, Etilamfetamine Hydrochloride, Fencam (CylertTM)). famin Hydrochloride, Fenetylline Hydrochloride, Fenflu 0226 Methylphenidate is typically formulated for phar ramine Hydrochloride, Fenproporex Hydrochloride, maceutical use as the hydrochloride (e.g. RitalinTM Ritaline Lobeline Hydrochloride, Pentetrazol, Propylhexedrine. LATM, FocalinTM, ConcertaTM, Methylin, AttentaTM, Loren 0229 Combinations of two or more pyschostimulants tinTM, DaytranaTM, TranquilynTM, EquasymTM, Ripheni may be used. References to all pyschostimulant described dateTM, RubifenTM, Metadate CDTM BiphentinTM). Meth herein include pharmaceutically acceptable salts thereof, as ylphenidate is described in U.S. Pat. No. 2,957,880 and appropriate, and slow release and extended release formula US 2014/0142140 A1 May 22, 2014 tions, as well as prodrugs of the listed active agents. An lation of Drug Dosage and Body Surface Area of Children: example of Such a prodrug is lisdexamfetamine (L-lysine-d- British Journal of Anaesthesia, 1997: 78: 601-605, for amphetamine). example. 0230. Therapeutic combinations of the invention com 0236. These dosages in relation to sodium valproate and prise, in addition to an anti-epileptic agent, one or more of a derivatives thereof represent, at the upper end, less than 20% stimulant, an anti-Parkinson's agent, an analgesic or a cho of the lower end of the normal therapeutic dose range for linesterase inhibitor (hereinafter referred to as “the further mood stabilisation or treating epileptic symptoms, and at the active'), effective in combination to provide enhanced treat lower end, about 0.001% of the normal therapeutic dose range ment of one or more neurological diseases, conditions or for treating epilepsy or bipolar disorder. In certain embodi disorders, or symptoms or another underlying cause of the ments, the upper range of the dose is less than 2.5%, namely, symptom(s), in comparison with either agent alone. The less than 25 mg/day. These dosages can be used as a guide for therapeutically effective amount of co-therapy comprising calculating the relative dosages of other mood Stabilizers that administration of one or more of the further active and an would constitute a sub-therapeutic dose. anti-epileptic agent would include an amount of the further 0237 For example, in the case of carbamazepine, a suit active and the anti-epileptic agent that, when taken together or able sub-therapeutic dose is in the range of from 1 to less than sequentially, have a combined effect that is therapeutically 80 mg/day, such as more than 2, 5 or 7.5 mg/day but less than effective. 80 or 50 mg/day. In certain embodiments, the upper level of 0231. In certain embodiments of therapeutic combina carbamazepine is less than 2.5%, namely less than 10 mg/day. tions and combination formulations or dosage regimes, par 0238. In the case of topiramate, a suitable sub-therapeutic ticularly those utilized in particular methods of the invention dose is in the range of from 0.5 to less than 20 mg/day, Such described herein, the dose administered of the anti-epileptic is as at least 1 or 1.5 mg/day but less than 15 or 10 mg/day. In less than 2.5% of the minimum daily dose which is effective certain embodiments, the upper level of topiramate is less for mood Stabilization, controlling seizures or mania. This than 2.5% of the normal dose to treat epilepsy, namely less means that the dose administered is below the dose range that than 2.5 mg/day would be administered to epileptics and individuals with 0239. In the case of phenyloin, a suitable sub-therapeutic bipolar disorders to achieve mood stabilization, control of dose is in the range of from 1 mg to less than 40 mg/day. Such seizures or control of mania, as appropriate. As mentioned as at least 1.5 or 2 mg/day but less than 40 or 30 mg/day. In above, the use of Such sub-therapeutic dosages is advanta certain embodiments, the upper level of phenyloin is less than geous for the treatments described herein. 2.5% of the normal dose to treat epilepsy, namely less than 5 0232. Therapeutically effective dosage levels and dosage mg/day. regimens for the anti-epileptic agents disclosed herein may be 0240. In the case of pregabalin, a suitable sub-therapeutic readily determined by one of ordinary skill in the art. For dose is in the range of from 1 to less than 60 mg/day. Such as example, therapeutic dosage amounts and regimens for phar more than 2 or 4 mg/day but less than 60 or 50 mg/day. In maceutical agents approved for sale are publicly available, for certain embodiments, the upper level of pregabalin is less example as listed on packaging labels, in standard dosage than 2.5% of the normal dose to treat epilepsy, namely less guidelines, in standard dosage references such as the Physi than 7.5 mg/day. cian's Desk Reference (Medical Economics Company or 0241. In the case of rufinamide a suitable sub-therapeutic online at http://www.pdrel.com) and other sources. dose is in the range of from 1 to less than 80 mg/day. Such as more than 2 or 4 mg/day but less than 80 or 70 mg/day. In 0233. In the case of sodium valproate, the product infor certain embodiments, the upper level of rufinamide is less mation for Epilim (Sanofi-Aventis) states that, for the treat than 2.5% of the normal dose to treat epilepsy, namely less ment of mania (e.g. bipolar disorder) in adults, control of than 10 mg/day. symptoms typically occurs within the range of 1,000 to 2,000 0242 Preferably, the sub-therapeutic dose is less than mg/day, (i.e. approximately 14 to 29 mg/kg/day based on a 70 20%, such as less than 10% of the minimum dose that would kg adult). In the case of carbamazepine, a typical dose for be administered to epileptics to achieve mood stabilization, treating epileptic seizures is in the range of from 400 to 800 control of seizures or control of mania, as appropriate. In mg/day. In the case of topiramate, the target dose for control certain embodiments, the Sub-therapeutic dose is an ultra low ling epileptic seizures is between 100 to 500 mg/day. dose which is less than 2.5% of the minimum dose that would 0234. By contrast, in relation to sodium valproate (and be administered to epileptics and individuals with bipolar derivatives thereof), a sub-therapeutic dose with respect to disorders to achieve mood stabilization, control of seizures or mood stabilization is considered in this context to be less than control of mania, as appropriate. 200 mg/day or 2.86 mg/kg/day (based on an adult weighing 0243 The following is a non-limiting, exemplary list of 70 Kg), a suitable dose being less than 150 mg/day, less than some AED with their usual minimum mood stabilisation or 100 mg/day, less than 50 mg/day, or less than 25 mg/day. The anti-convulsant doses to illustrate a calculation of an initial minimum dose is typically at least 1 mg/day, Such as at least sub-therapeutic AED dose. A sub-therapeutic dose for mood 2.5, 5 or 10 mg/day. The doses are expressed both indepen stabilization in the context of the present invention is there dently of patient weight and based on patient weight since fore less than 20% of the minimum dosages listed below for minimum and maximum doses can apply. each particular agent e.g. for Ethotoin, a sub-therapeutic dose 0235 Typically, the mg/kg/day is more commonly applied is less than 200 mg/day. The minimum dose to be adminis in relation to children whereas the total mg/day may be more tered in the context of the present invention is suitably at least appropriate for adults. The skilled person is able to calculate 0.01, 0.05, 0.1, 0.5 or 1% of the minimum therapeutic dose for an appropriate amount for a child based on the Suggested mood stabilization listed below, e.g. in the case of Ethotoin, at adult dose. A number of different techniques are available for least 1, 5 or 10 mg/day. In the case of rufinamide, a dose Such conversions and some of these are discussed in Calcu within the Sub-therapeutic range for antiepileptic therapy or US 2014/0142140 A1 May 22, 2014

mood stabilization is less than 20% of the minimum thera example, a single tablet or unit dose. Such a dose may be peutic dose for mood stabilization listed below, i.e. less than formulated or effective as a single, daily dose, or may be 80 mg/day. repeated a number of times in a day, for example to result in a total daily dose of 80 mg of AED and 120 mg of further active. 0247 The units of measure of each agent may be divided Minimum typical dose day effective for mood as convenient into steps of 0.01, 0.5, 1.0, 2.0, 5.0 mg and the stabilisation or treatment of like. The units are not constrained by any particular step value Agent epileptic symptoms or events and all possible values between the minimum and maximum Aminoglutethimide 125 mg doses for each agent are contemplated. Thus, the dimensions Barbexaclone 200 mg in divided doses of the matrix row relevant to any particular AED are formed Belcamide 1 mg by its minimum and maximum contemplated doses along Brivaracetam 100 mg with the desired step values. Similarly, the matrix column Carbamazepine 400 mg Clobazam 5 mg/kg daily dimensions are formed by the minimum and maximum con Clonazepam 1 mg templated doses of further active along with the desired step Ethadione 1000 mg values. To include two or more AEDs or further active in a Ethosuximide 1000 mg combination the matrix dimensions are increased by the addi Ethotoin 1000 mg Felbamate 1200 mg tion of a dimension corresponding to the further agent. Fosphenytoin Sodium 10 mg/kg Hence, a 3 dimensional matrix would list all contemplated Gabapentin 900 mg combination of three active agents. All combination unit Lacosamide 200 mg doses and pharmaceutical compositions so described are Lamotrigine 100 mg Levetiracetam 1000 mg within the scope of the invention. Losigamone 1500 mg 0248 AEDs, alone or in combination with a further active, Mephenytoin 200 mg may be administered in the form of a pharmaceutical compo Methoin 1000 mg sition, which further comprises a pharmaceutically accept Methsuximide 300 mg Oxcarbazepine 600 mg able carrier, diluent and/or excipient. Paramethadione 300 mg 0249. In a particular aspect, the invention provides a phar Perampanel 2ng maceutical composition comprising, in combination, one or a Phenacemide 500 mg plurality of anti-epileptic agents, and either one or a plurality Pheneturide 600 mg Phensuximide 1000 mg of further active, orpharmaceutically acceptable salts thereof. Phenytoin 200 mg 0250 In another particular aspect, the invention provides a Pregabalin 300 mg pharmaceutical kit comprising a first pharmaceutical compo Primidone 750 mg sition comprising (i) one or a plurality of anti-epileptic agents Retigabine 600 mg Rufinamide 400 mg or a pharmaceutically acceptable salt thereof, together with a Sultiame 200 mg pharmaceutically acceptable carrier or diluent and (ii) a sec Tiagabine Hydrochloride 30 mg ond pharmaceutical composition comprising one or a plural Topiramate 100 mg ity of further active together with a pharmaceutically accept Trimethadione 900 mg Vigabatrin 1000 mg able carrier, diluent or excipient. Zonisamide 200 mg 0251. The kit according to the invention may include a starter pack adapted for titration of the composition to the desired amount for a patient; and a maintenance pack adapted 0244. In some embodiments, the dosage administered of to maintain the dose of the composition at the pre-determined AED is sub-therapeutic for mood stabilization for the entire, amount. or at least substantially the entire, treatment period. In other 0252) Examples of routes of administration for which the words, it is suitable that the dosage administered of mood pharmaceutical composition may be suitable include, but are stabiliser does not exceed the maximum stated Sub-therapeu not limited to, oral, intravenous (iv), intramuscular (inn), tic dosages described above throughout the treatment. Subcutaneous (sc), transdermal (including via the oral 0245 Particularly suitable combinations of AEDs and the mucosa), and rectal. Compositions may also be administered further active: (i) one or more of sodium valproate and deriva directly to the nervous system including, but not limited to, tives thereof, topiramate, carbamazepine, oXcarbazepine, intracerebral, intraventricular, intracerebroventricular, phenyloin, gabapentin or pregabalin; together with either (ii) intrathecal, intracisternal, intraspinal or peri-spinal routes of one or more psychoStimulants, (iii) one or more cholinest administration by delivery via intracranial or intravertebral erase inhibitors for treating dementia or (iv) one or more of needles or catheters with or without pump devices. The fur levodopa and dopamine agonists. For combination formula ther active and the anticonvulsant or anti-epileptic agent(s) tions comprising an AED and a further active, the intended may be administered according to simultaneous or alternating daily dose of AED may range from 0.001% to less than 2.5% regimens, at the same or different times during the course of of the minimum dosages for treatment of epilepsy or mood the therapy, concurrently in divided or single forms. disorder for each particular AED, while the normal, recom 0253 Pharmaceutical compositions containing one or mended amount of the further active is used. more of the agents described herein can be prepared by inti 0246 Particular doses for particular combinations may be mately mixing the compound or compounds with a pharma created using a matrix formed by rows of AED doses with ceutical carrier, diluent and/or excipient according to conven columns of further active doses. For example, an entry of (20 tional pharmaceutical compounding techniques. mg of AED, 30 mg of furtheractive) in a matrix denotes 20 mg 0254 As used herein, “pharmaceutically acceptable car of AED and 30 mg of further active compounded as, for rier' includes any material which, when combined with an US 2014/0142140 A1 May 22, 2014 20 active ingredient of a composition, allows the ingredient to include the following: acids including acetic acid, 2,2-dichlo retain biological activity and without causing disruptive reac roactic acid, acylated amino acids, adipic acid, alginic acid, tions in the Subject. Examples include, but are not limited to, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic any of the standard pharmaceutical carriers such as a phos acid, 4-acetamidobenzoic acid, (+)-camphoric acid, cam phate buffered saline solution, water, emulsions such as oil phorsulfonic acid, (+)-(1S)-camphor-10-Sulfonic acid, capric and water emulsion, and various types of wetting agents. acid, caproic acid, caprylic acid, cinnamic acid, citric acid, Preferred diluents for aerosol or parenteral administration are cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic phosphate buffered saline or normal (0.9%) saline. Compo acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, sitions comprising such carriers are formulated by well formic acid, fumaric acid, galactaric acid, gentisic acid, glu known conventional methods (see, for example, Remington's coheptonic acid, D-gluconic acid, D-glucoronic acid, Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Pub L-glutamic acid, alpha-oxo-glutaric acid, glycolic acid, lishing Col. Easton Pa. 18042, USA). hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L- 0255. The carrier may take a wide variety of forms lactic acid, (...+-)-DL-lactic acid, lactobionic acid, maleic depending upon the desired route of administration (e.g., oral, acid, (-)-L-malic acid, malonic acid, (..+-)-DL-mandelic parenteral). Thus, for liquid oral preparations such as Suspen acid, methanesulfonic acid, naphthalene-2-sulfonic acid, sions, elixirs and solutions, Suitable carriers and additives naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic include water, glycols, oils, alcohols, flavoring agents, pre acid, nicotinc acid, nitric acid, oleic acid, orotic acid, oxalic servatives, stabilizers, coloring agents and the like; for Solid acid, palmitric acid, pamoic acid, phosphoric acid, L-pyro oral preparations, such as powders, capsules and tablets, Suit glutamic acid, salicylic acid, 4-amino-salicylic acid, Sebaic able carriers and additives include starches, Sugars, diluents, acid, Stearic acid, Succinic acid, Sulfuric acid, tannic acid, granulating agents, lubricants, binders, disintegrating agents (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and the like. Solid oral preparations may also be coated with and undecylenic acid; and bases including ammonia, L-argi Substances such as Sugars or be enteric-coated so as to modu nine, benethamine, benzathine, calcium hydroxide, choline, late major site of absorption. For parenteral administration, deanol, diethanolamine, diethylamine, 2-(diethylamino)- the carrier will usually consist of sterile water and other ethanol, ethanolamine, ethylenediamine, N-methyl-glucam ingredients may be added to increase solubility or preserva ine, hydrabamine, 1H-imidazole, L-lysine, magnesium tion. Injectable Suspensions or Solutions may also be prepared hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, utilizing aqueous carriers along with appropriate additives. potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sec 0256 Transdermal preparations typically includeanadhe ondary amine, sodium hydroxide, triethanolamine, sive patch which is adapted to be temporarily adhered to the tromethamine and Zinc hydroxide. skin. 0260 Optionally, the oral solid dosage form includes a 0257 For use in medicine, the salts of the agents of this sustained release carrier that effects the sustained release of invention refer to non-toxic pharmaceutically acceptable the AED, or both the AED and the further active when the salts.” Other salts may, however, be useful in the preparation dosage form contacts gastrointestinal fluid. The Sustained of compounds according to this invention or of their pharma release dosage form may comprise a multiplicity of substrates ceutically acceptable salts. Suitable pharmaceutically accept and carriers that include the agents. The Substrates may com able salts of the compounds include acid addition salts which prise matrix spheroids or may comprise inert pharmaceuti may, for example, be formed by mixing a solution of the cally acceptable beads that are coated with the agents. The compound with a solution of a pharmaceutically acceptable coated beads are then preferably overcoated with a sustained acid Such as hydrochloric acid, Sulfuric acid, fumaric acid, release coating comprising the Sustained release carrier. The maleic acid. Succinic acid, acetic acid, benzoic acid, citric matrix spheroid may include the Sustained release carrier in acid, tartaric acid, carbonic acid orphosphoric acid. the matrix itself, or the matrix may comprise a simple disin 0258. Furthermore, where the compounds of the invention tegrating or prompt release matrix containing the drugs, the carry an acidic moiety, Suitable pharmaceutically acceptable matrix having a coating applied thereon which comprises the salts thereof may include alkali metal salts, e.g., sodium or Sustained release carrier. In yet other embodiments, the oral potassium salts; alkaline earth metal salts, e.g., calcium or Solid dosage form comprises a tablet core containing the magnesium salts; and salts formed with Suitable organic agents within a normal or prompt release matrix with the ligands, e.g., quaternary ammonium salts. Thus, representa tablet core being coated with a sustained release coating tive pharmaceutically acceptable salts include the following: comprising the Sustained release carrier. In yet further acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, embodiments; the tablet contains the agents within a Sus bitartrate, borate, bromide, calcium edetate, camsylate, car tained release matrix comprising the Sustained release carrier. bonate, chloride, clavulanate, citrate, dihydrochloride, ede tate, edisylate, estolate, esylate, fumarate, gluceptate, glucon 0261. In yet further embodiments, the tablet contains the ate, glutamate, glycolylarsanilate, hexylresorcinate, AED within a sustained release matrix, and the further active hydrabamine, hydrobromide, hydrochloride, hydroxynaph coated into the tablet as an immediate release layer. thoate, iodide, isothionate, lactate, lactobionate, laurate, 0262. In some embodiments of the invention, the pharma malate, maleate, mandelate, meSylate, methylbromide, meth ceutical compositions containing the further active and AED ylnitrate, methylsulfate, mucate, napsylate, nitrate, N-meth agents set forth herein are administered orally. Such oral ylglucamine ammonium salt, oleate, pamoate (embonate), dosage forms may contain one or all of the agents in imme palmitate, pantothenate, phosphate/diphosphate, polygalac diate or Sustained release form. The oral dosage forms may be turonate, salicylate, Stearate, Sulfate, Subacetate. Succinate, in the form of tablets, troches, lozenges, aqueous, Solid or tannate, tartrate, teoclate, tosylate, triethiodide and Valerate. semi-solid solutions or mixtures, or oily Suspensions or solu 0259 Representative acids and bases which may be used tions, dispersible powders or granules, emulsions, multipar in the preparation of pharmaceutically acceptable salts ticulate formulations, syrups, elixirs, and the like. US 2014/0142140 A1 May 22, 2014

0263. In other embodiments, a pharmaceutical composi powder, injection, teaspoonful and the like, an amount of the tion containing the AED(S) and further active can be admin active ingredients necessary to deliver an effective dose as istered in dosage form as a topical preparation, a solid state described herein. and or depot type transdermal delivery device(s), a Supposi 0268 Preferably these compositions are in unit dosage tory, abuccal preparation, Sub-lingual preparation, oran inha forms from Such as tablets, pills, capsules, powders, granules, lation formulation Such as a controlled release particle for sterile parenteral Solutions or Suspensions, metered aerosol or mulation or spray, mist or other topical vehicle, intended to be liquid sprays, drops, ampoules, autoinjector devices or Sup inhaled or instilled into the sinuses. positories; for oral parenteral, intranasal, Sublingual or rectal administration, or for administration by inhalation or insuf 0264. The pharmaceutical compositions containing the flation. Alternatively, the composition may be presented in a agents set forth herein may alternatively be in the form of form Suitable for once-weekly or once-monthly administra microparticles such as microcapsules, microspheres and the tion; for example, an insoluble salt of the active compound, like, which may be injected or implanted into a human Such as the decanoate salt, may be adapted to provide a depot patient, or other implantable dosage forms known to those preparation for intramuscular injection. skilled in the art of pharmaceutical formulation. 0269. For preparing solid compositions such as tablets, the 0265 For administration orally, the compounds may be principal active ingredient is mixed with a pharmaceutical formulated individually or in combination as Sustained carrier, e.g. conventional tableting ingredients such as corn release preparations. If formulated individually, different starch, lactose, Sucrose, Sorbitol, talc, Stearic acid, magne release times or bioavailability may be afforded each active sium Stearate, dicalcium phosphate or gums, and other phar agent though they may ultimately be compounded or mixed maceutical diluents, e.g. water, to form a solid preformulation together into one unit dose. Numerous examples of tech composition containing a homogeneous mixture of a com niques for formulating Sustained release preparations are pound of the present invention, or a pharmaceutically accept described in the following references: U.S. Pat. Nos. 4,891, able salt thereof. When referring to these preformulation 223; 6,004,582: 5,397.574:5,419,917;5,458,005; 5,458,887; compositions as homogeneous, it is meant that the active 5,458,888; 5,472,708; 6,106,862: 6,103,263; 6,099,862: ingredient is dispersed evenly throughout the composition So 6,099,859; 6,096,340; 6,077,541; 5,916,595; 5,837,379; that the composition may be readily subdivided into equally 5,834,023; 5,885,616; 5,456,921; 5,603,956; 5,512,297; effective dosage forms such as tablets, pills and capsules. This 5,399,362; 5,399,359; 5,399,358; 5,725,883; 5,773,025; solid preformulation composition is then subdivided into unit 6,110,498; 5,952,004; 5,912,013; 5,897,876; 5,824,638: dosage forms of the type described above. 5,464,633; 5,422,123; and 4,839,177; WO 98/47491; and 0270. In the context of combination unit doses, a pharma U.S. Patent Application Publications 2005/0266078; 2008/ ceutical composition comprising the active agents may be 0057123; 2008/0026070; 2008/00757769; and 2008/ formulated with distinct halves or further subdivisions, each 0031946, all of which are incorporated herein by reference. half or Subdivision comprising primarily one agent. Scoring or pre-division of the halves or subdivisions thereby allow 0266. As an example of how certain embodiments of the easy modulation of dose of each active agent. pharmaceutical compositions of this invention are prepared, 0271 The tablets or pills of the novel composition can be one or more of the further active and one or more of the coated or otherwise compounded to provide a dosage form anticonvulsant or anti-epileptic agents are intimately affording the advantage of prolonged action. For example, the admixed with a pharmaceutical carrier according to conven tablet or pill can comprise an inner dosage and an outer tional pharmaceutical compounding techniques, which car dosage component, the latter being in the form of an envelope rier may take a wide variety of forms depending of the form of over the former. The two components can be separated by an preparation desired for administration, e.g., oral or parenteral enteric layer which serves to resist disintegration in the stom Such as intramuscular. In preparing the compositions in oral ach and permits the inner component to pass intact into the dosage form, any of the usual pharmaceutical media may be duodenum or to be delayed in release. A variety of material employed. Thus, for liquid oral preparations, such as for can be used for Such enteric layers or coatings, such materials example, Suspensions, elixirs and solutions, Suitable carriers including a number of polymeric acids with Such materials as and additives include water, glycols, oils, alcohols, flavouring shellac, cetyl alcohol and cellulose acetate. agents, preservatives, coloring agents and the like; for Solid 0272. The liquid forms in which the novel compositions of oral preparations such as, for example, powders, capsules, the present invention may be incorporated for administration caplets, gelcaps and tablets, suitable carriers and additives orally or by injection include, aqueous solutions, Suitably include starches, Sugars, diluents, granulating agents, lubri flavored syrups, aqueous or oil suspensions, and flavored cants, binders, disintegrating agents and the like. Because of emulsions with edible oils such as cottonseed oil, Sesame oil, their ease in administration, tablets and capsules represent the coconut oil or peanut oil, as well as elixirs and similar phar most advantageous oral dosage unit form, in which case solid maceutical vehicles. Suitable dispersing or Suspending pharmaceutical carriers are obviously employed. If desired, agents for aqueous Suspensions, include synthetic and natural tablets may be Sugar coated or enteric coated by standard gums such as tragacanth, acacia, alginate, dextran, Sodium techniques. carboxymethylcellulose, methylcellulose, polyvinyl-pyrroli 0267 For parenterals, the carrier will usually comprise done or gelatin. sterile water, through other ingredients, for example, for pur 0273. In an additional embodiment, one or more of the poses Such as aiding solubility or for preservation, may be further active may be separately formulated or compounded, included. Injectable Suspensions may also be prepared, in then coated or embedded in one or more of the anticonvulsant which case appropriate liquid carriers, Suspending agents and oranti-epileptic agents or formulations thereof. Alternatively, the like may be employed. The pharmaceutical compositions the anticonvulsant or anti-epileptic agents or formulations herein will contain, per dosage unit, e.g., tablet, capsule, thereof may be embedded in or otherwise bound to the further US 2014/0142140 A1 May 22, 2014 22 active or their formulations. Thus, the two or more active 0279. In this regard, methods may further include, prior to agents may be compounded separately but ultimately pro administration of the anti-epileptic agent alone or in combi vided together in one unit dose as a combination. Each, sepa nation with the second active, determining whether said Sub rately compounded agent may thus be provided in timed ject is, or may be, in need of prophylactic or therapeutic release, slow release, or other suitable formulation specifi treatment for the neurological disorder. This step may be cally advantageous to that agent, though ultimately provided performed by clinical assessment, genetic testing or genetic as a single unit dose. counseling, alone or in combination. 0274. In particular embodiments, one or a plurality of 0280 Preferably, patients, subjects or individuals treated AEDs alone, or AEDs in combination with a further active, by the method may be adult, juvenile, adolescent, child or may be administered in the form of a pharmaceutical compo infant humans. sition, including but not limited to the particular pharmaceu 0281. In one embodiment, the neurological disorder is tical compositions hereinbefore described. associated with an impairment or deficiency in higher order 0275. In view of the teachings of the invention, optimal executive functioning. The executive system is a theorized dosages and schedules to be administered may be readily cognitive system in psychology that controls and manages determined by those skilled in the art, and will vary with the other cognitive processes. It is also referred to as the executive particular compound used, the mode of administration, the function, Supervisory attentional system, or cognitive control. strength of the preparation, the mode of administration, and 0282. The concept is used by psychologists and neurosci the advancement of the disease condition. In addition, factors entists to describe a loosely defined collection of brain pro associated with the particular patient being treated, including cesses which are responsible for planning, cognitive flexibil patient age, weight, diet and time of administration, will ity, abstract thinking, rule acquisition, initiating appropriate result in the need to adjust dosages. Where a subject of patient actions and inhibiting inappropriate actions, and selecting proves to be particularly sensitive to an agent or combination relevant sensory information. therapy, doses can be appropriately adjusted, or alternative 0283 Higher order executive functioning is thought to be choice of agent(s) made within the teaching of the invention. heavily involved in handling novel situations outside the 0276 One skilled in the art will recognize that a therapeu domain of some of our automatic psychological processes tically effective dosage of the combinations of the present that could be explained by the reproduction of learned sche invention can include repeated doses within a prolonged mas or set behaviors. Psychologists have outlined five types treatment regimen that will yield clinically significant results. of situation where routine activation of behavior would not be Advantageously, combinations of the present invention may sufficient for optimal performance: be administered in a single daily dose, or the total daily 0284 (i) those that involve planning or decision making; dosage may be administered in divided doses of two, three or 0285 (ii) those that involve error correction or trouble four times daily. Furthermore, compounds for the present shooting: invention can be administered in intranasal form via topical 0286 (iii) situations where responses are not well-learned use of Suitable intranasal vehicles, or via transdermal skin or contain novel sequences of actions; patches well known to those of ordinary skill in that art. To be 0287 (iv) dangerous or technically difficult situations: administered in the form of a transdermal delivery system, the and/or dosage administration will, of course, be continuous rather 0288 (V) situations which require the overcoming of a than intermittent throughout the dosage regimen. The com strong habitual response or resisting temptation. binations may be administered through a single transdermal 0289. In another embodiment, the neurological disorder is patch, or via Subdivided transdermal patches or even separate not a developmental disorder or a disorder usually diagnosed transdermal patches, as may be desired. in infancy, childhood or adolescences. 0277 Determination of effective dosages is typically 0290. In yet another embodiment, the neurological disor based on animal model studies followed up by human clinical der is a degenerative disorder. Examples of degenerative dis trials and is guided by determining effective dosages and orders include Mild Cognitive Impairment (MCI), Alzhe administration protocols that significantly reduce the occur imer's Disease, Amyotrophic Lateral Sclerosis, Corticobasal rence or severity of targeted exposure symptoms or condi Degeneration, Creutzfeldt-Jakob Disease, Dementia with tions in the subject. Suitable models in this regard include, for Lewy Bodies, Frontotemporal Dementia, Huntington's Dis example, murine, rat, porcine, feline, non-human primate, ease, Progressive Supranuclear Palsy, Vascular Dementia, and other accepted animal model Subjects known in the art. movement disorders such as Parkinson's disease, dementia Alternatively, effective dosages can be determined using in associated with multiple Sclerosis and motor neurone disease. vitro models. Using such models, only ordinary calculations 0291. In still yet another embodiment, the neurological and adjustments are typically required to determine an appro disorder is a psychotic disorder. Non-limiting examples are priate concentration and dose to administer a therapeutically Schizophrenia and psychotic disorders and/or behaviour effective amount of the biologically active agent(s) (e.g., resulting from causes including brain tumors, drug abuse with amounts that are intranasally effective, transdermally effec amphetamines, cocaine, cannabis, alcohol etc., brain damage tive, intravenously effective, or intramuscularly effective to (acquired or otherwise), bipolar disorder (manic depression), elicit a desired response). severe clinical depression, severe psychosocial stress, sleep 0278. It will be generally understood that therapeutic deprivation, Some focal epileptic disorders especially if the methods may be practiced preventatively to prophylactically temporal lobe is affected, exposure to Some traumatic event treat a neurological disorder, or may be used to treat an (e.g. violent death, road accident), abrupt or over-rapid with existing, recurring or on-going neurological disorder. Pro drawal from certain recreational or prescribed drugs, neuro phylactic treatments may be appropriate where, for example, logical disorders, including: brain tumour, dementia with a subject has a genetic predisposition and/or family history of Lewy bodies, multiple Sclerosis, sarcoidosis, Alzheimer's a neurological disorder. Disease and Parkinson's Disease. US 2014/0142140 A1 May 22, 2014

0292. In still yet another embodiment, the neurological underlying phonological processing deficits. Psychiatry disorder is associated with reduced adherence, or non-com research, 187(1-2), 6-10. Elsevier Ireland Ltd. doi:10. pliance, with a medication regime that includes the adminis 1016/j.psychres.2010.11.025 tration of a therapeutic agent other than, or in addition to, a 0302 Association, A.P. (2000). Diagnostic and Statistical psychostimulant. This embodiment in particular relates to Manual of Mental Disorders, Fourth Edition. DSM-IV long-time, multiple or complex medication regimes, such as TR(R) (p. 943). American Psychiatric Pub. Retrieved from those used in the treatment of hypertension, elevated choles http://books.google.com/books?id=w terol/lipids and diabetes (e.g. insulin). For example, compli HaMnjxwC&pgis=1 ance with long-term treatment for chronic asymptomatic con (0303 Bales, J. Wagner, A., & Kline, A. (2009). Persistent ditions such as hypertension is on the order of 50%. cognitive dysfunction after traumatic brain injury: A (Loghman-Adham 2003. dopamine hypothesis. Neurosci Biobehav Rev., 33 (7), 981 0293. In a further embodiment, the neurological disorder 1003. doi:10.1016/j.neubiorev.2009.03.011. Persistent is an eating disorder. Non-limiting examples include Anor 0304 Basso, A., & Scarpa, M.T. (1990). Traumatic apha exia Nervosa and Bulimia Nervosa. sia in children and adults: a comparison of clinical features 0294. In other particular embodiments, treatment of and evolution. Cortex, a journal devoted to the study of the dementia and sleep disorders are particularly suited to AED nervous system and behavior; 26(4), 501-14. Retrieved therapy without a further active, wherein two or more differ from http://www.ncbi.nlm.nih.gov/pubmed/1706973 ent AEDs are administered. (0305 Bayly, P. V., Cohen, T. S. Leister, E. P., Ajo, D., 0295. In certain embodiments, the present invention is Leuthardt, E. C., & Genin, G. M. (2005). Deformation of particularly Suited to treating a neurological disorder selected the human brain induced by mild acceleration. Journal of from the group consisting of degenerative disorders and/or neurotrauma, 22(8), 845-56. doi:10.1089/neu.2005.22. movement disorders such as Parkinson's disease, dementia 845 and Mild Cognitive Impairment addiction; reduced adher (0306 Becker, T., & Kilian, R. (2006). Psychiatric services ence; eating disorders such as Anorexia Nervosa and Bulimia for people with severe mental illness across western Nervosa, and personality disorders. Europe: what can be generalized from current knowledge 0296. In other particular embodiments of the invention, about differences in provision, costs and outcomes of men the neurological disorder is selected from the group consist tal health care? Acta psychiatrica Scandinavica. Supple ing of: Communication Disorders; Pervasive Development mentum, (429), 9-16. doi:10.1111/j.1600-0447.2005. Disorders; and Anxiety Disorders. OO711X 0297 Particular, non-limiting examples of these embodi 0307 Bell, V., Halligan, P. W., & Ellis, H. D. (2006). ments include neurological disorders that fall within the Explaining delusions: a cognitive perspective. Trends in DSM-IV-TR classification: Communication Disorders (e.g. cognitive sciences, 10(5), 219-26. doi:10.1016/j.tics.2006. Expressive Language Disorder, Mixed Receptive-Expressive O3.004 Language Disorder, Phonological Disorder, Stuttering, Com (0308 Bentall, R. P. Fernyhough, C., Morrison, A. P. munication Disorder NOS (Not Otherwise Specified); Per Lewis, S., & Corcoran, R. (2007). Prospects for a cogni vasive Development Disorders (Autistic Spectrum Disorders tive-developmental account of psychotic experiences. The such as Autistic Disorder and Asperger's Disorder: Rett's British journal of clinical psychology/the British Psycho Disorder, Childhood Disintegrative Disorder and Pervasive logical Society, 46(Pt 2), 155-73. doi:10.1348/ Developmental Disorder NOS); and Anxiety Disorders (e.g. O14466506X123O11 Generalized Anxiety Disorder). 0309 Betancur, C. (2011). Etiological heterogeneity in 0298. In view of the teachings of the invention, optimal autism spectrum disorders: more than 100 genetic and dosages and schedules to be administered may be readily genomic disorders and still counting. Brain research, determined by those skilled in the art, and will vary with the 1380, 42-77. doi:10.1016/j.brainres. 2010.11.078 particular compound used, the mode of administration, the 0310 Biederman, J., Faraone, S.V., Monuteaux, M. C., & strength of the preparation, the mode of administration, and Biederman, J., Faraone, S. V., & Monuteaux, M. (2002). the advancement of the disease condition. In addition, factors Differential effect of environmental adversity by gender: associated with the particular patient being treated, including Rutter's index of adversity in a sample of boys and girls patient age, weight, diet and time of administration, will with and without ADHD. American Journal of Psychiatry, result in the need to adjust dosages. Where a subject of patient 159(9), 1556-1563. American Psychiatric Assn. doi:10. proves to be particularly sensitive to an agent or combination 1176/appi.ajp. 159.9.1556 therapy, doses can be appropriately adjusted, or alternative 0311 Blissitt, P. A. (2006a). Care of the critically ill choice of agent(s) made within the teaching of the invention. patient with penetrating head injury. Critical care nursing 0299 The skilled person will appreciate that where a com clinics of North America, 18(3), 321-32. doi:10.1016/j. ponent is stated as being present in an amount below a defined ccel1.2006.05.006 threshold level, this means that the component is present in a 0312 Blissitt, P. A. (2006b). Care of the critically ill measurable amount and that amount is less than the defined patient with penetrating head injury. Critical care nursing maximum. clinics of North America, 18(3), 321-32. doi:10.1016/j. ccel1.2006.05.006 REFERENCE LIST 0313 Borg, E., & Counter, S.A. (1989). The middle-ear 0300 Adler, L. A., & Cohen, J. (2004). Diagnosis and muscles. Scientific American, 261(2), 74-80. Retrieved evaluation of adults with attention deficit hyperactivity from http://www.ncbi.nlm.nih.gov/pubmed/2667133 disorder. Psychiatry Clinic, 27, 187-214. 0314 Brady, K., Pearlstein, T., Asnis, G. M., Baker, D., 0301 Arnott, W., Sali, L., & Copland, D. (2011). Impaired Rothbaum, B., Sikes, C. R., & Farfel, G. M. (2000). Effi reading comprehension in Schizophrenia: evidence for cacy and safety of Sertraline treatment of posttraumatic US 2014/0142140 A1 May 22, 2014 24

stress disorder: a randomized controlled trial. JAMA: the pathway deficit in dyslexia. Vision research, 38(11), 1555 journal of the American Medical Association, 283 (14), 9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 1837-44. Retrieved from http://www.ncbi.nlm.nih.gov/ 9.747491 pubmed/10770145 0328 Erdmann, J. (2011). Broad collaborations bring new 0315 Bramlett, H. M., & Dietrich, W. D. (2007). Progres energy to autism therapeutics. Chemistry & biology, 18(2), sive damage after brain and spinal cord injury: patho 142-3. doi:10.1016/j.chembiol.2011.02.006 mechanisms and treatment strategies. Progress in brain 0329. Faden, A., Demediuk, P., Panter, S., & Vink, R. research, 161, 125-41. doi:10.1016/S0079-6123(06) (1989). The role of excitatory amino acids and NMDA 61009-1 receptors in traumatic brain injury. Science, 244(4906), 0316 Brekke, J., Kay, D. D., Lee, K. S., & Green, M. F. 798-800. doi:10.1126/science.2567056 (2005). Biosocial pathways to functional outcome in 0330 Faraone, S.V., Biederman, J., Spencer, T., Mick, E., schizophrenia. Schizophrenia Research, 80(2-3), 213-225. Murray, K., Petty, C., Adamson, J. J., et al. (2006). Diag Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ nosing adult attention deficit hyperactivity disorder: are 16137859 late onset and subthreshold diagnoses valid? The American 0317 Bremner, J. D., Mletzko, T., Welter, S., Quinn, S., journal of psychiatry, 163(10), 1720-9: quiz, 1859. doi:10. Williams, C., Brummer, M., Siddiq, S., et al. (2005). 1176/applajp. 163.10.1720 Effects of phenyloin on memory, cognition and brainstruc 0331. Forde, I., Holloway, J., Healy, O., & Brosnan, J. ture in post-traumatic stress disorder: a pilot study. Journal (2011). A dyadic analysis of the effects of setting and of psychopharmacology (Oxford, England), 19(2), 159-65. communication partner on elicited and spontaneous com doi:10.1177/O269881 105048996 munication of children with Autism Spectrum Disorder 0318 Buckley, P. F., Miller, B.J., Lehrer, D.S., & Castle, and typically developing children. Research in Autism D.J. (2009). Psychiatric comorbidities and schizophrenia. Spectrum Disorders, 5(4), 1471-1478. Schizophrenia bulletin, 35(2), 383-402. doi:10.1093/sch 0332 Freeman, D., Garety, P. A., Kuipers, E., Fowler, D., bulfsbn 135 Bebbington, P. E., & Dunn, G. (2007). Acting on persecu tory delusions: the importance of safety seeking. Behav 0319 Busch, R. M., McBride, A., Curtiss, G., & Vander iour research and therapy, 45(1), 89-99. doi:10.1016/j. ploeg, R. D. (2005). The components of executive func brat.2006.01.014 tioning in traumatic brain injury. Journal of clinical and 0333 Gomot, M., & Wicker, B. (2012). A challenging, experimental neuropsychology, 27(8), 1022-32. doi:10. unpredictable world for people with Autism Spectrum Dis 1080/13803390490919263 order. International journal of psychophysiology: official 0320 Cienfuegos, A., March, L., Shelley, A. M., & Javitt, D.C. (1999). Impaired categorical perception of synthetic journal of the International Organization of Psychophysi speech Sounds in Schizophrenia. Biological psychiatry, ology, 83(2), 240-7. doi:10.1016/j.ijpsycho.2011.09.017 45(1), 82-8. Retrieved from http://www.ncbi.nlm.nih.gov/ 0334 Granacher, R. P. (2007). Traumatic Brain Injury: pubmed/98.94579 Methods for Clinical and Forensic Neuropsychiatric Assessment (Google eBook) (p. 560). CRC Press. 0321) Cohen, A. S., & Docherty, N. M. (2004). Affective 0335 Green, M. F. Kern, R. S., Braff, D. L., & Mintz, J. reactivity of speech and emotional experience in patients (2000). Neurocognitive deficits and functional outcome in with schizophrenia. Schizophrenia research, 69(1), 7-14. schizophrenia: are we measuring the “right stuff? Schizo doi:10.1016/S0920-9964(03)00069-0 phrenia bulletin, 26(1), 119-36. Retrieved from http:// 0322 Committee on Child Abuse and Neglect. (2001). www.ncbi.nlm.nih.gov/pubmed/10755673 Shaken Baby Syndrome: Rotational Cranial Injuries Tech 0336 Green, Michael F. (2006). Cognitive impairment nical Report. PEDIATRICS, 108(1), 206-210. doi:10. and functional outcome in Schizophrenia and bipolar dis 1542/peds. 108.1.206 order. The Journal of clinical psychiatry, 67(10), e12. 0323 Costa, E., & Guidotti, A. (1996). Benzodiazepines Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ on trial: a research strategy for their rehabilitation. Trends 17107235 in pharmacological sciences, 17(5), 192-200. Retrieved 0337 Guastella, A. J., Mitchell, P. B., & Dadds, M. R. from http://www.ncbi.nlm.nih.gov/pubmed/8669126 (2008). Oxytocin increases gaze to the eye region of human 0324 Coyle, J.T., Tsai, G., & Goff, D. (2003). Converging faces. Biological psychiatry, 63(1), 3-5. doi:10.1016/j.bi evidence of NMDA receptor hypofunction in the patho opsych. 2007.06.026 physiology of schizophrenia. Annals of the New York Acad 0338 Hardman, J. M., & Manoukian, A. (2002). Pathol emy of Sciences, 1003,318-27. Retrieved from http://www. ogy of head trauma. Neuroimaging clinics of North incbi.nlm.nih.gov/pubmed/14684455 America, 12(2), 175-87, vii. Retrieved from http://www. 0325 Cummings, J. L. (1993). Frontal-subcortical cir neuroimaging...theclinics.com/article/S1052-5149(02) cuits and human behavior. Archives of neurology, 50(8), 00009-6/fulltext 873-80. Retrieved from http://www.ncbi.nlm.nih.gov/ 0339 Hashimoto, T., Volk, D. W. Eggan, S. M., Mirnics, pubmed/8352676 K., Pierri, J. N., Sun, Z. Sampson, A.R., et al. (2003). Gene 0326 Davids, E., K is, B., Specka, M., & Gastpar, M. expression deficits in a subclass of GABA neurons in the (2006). A pilot clinical trial of oxcarbazepine in adults with prefrontal cortex of subjects with schizophrenia. The Jour attention-deficit hyperactivity disorder: Progress in neu nal of neuroscience: the official journal of the Society for ropsychopharmacology biological psychiatry (Vol. 30, pp. Neuroscience, 23(15), 6315-26. Retrieved from http:// 1033-1038). www.ncbi.nlm.nih.gov/pubmed/12867516 0327 Demb, J. B., Boynton, G.M., Best, M., & Heeger, D. (0340 Heimberg, C., Gur, R. E., Erwin, R. J., Shtasel, D. J. (1998). Psychophysical evidence for a magnocellular L., & Gur, R. C. (1992). Facial emotion discrimination: III. US 2014/0142140 A1 May 22, 2014

Behavioral findings in schizophrenia. Psychiatry research, 0354 Kuipers, E., Garety, P., Fowler, D., Freeman, D., 42(3), 253-65. Retrieved from http://www.ncbi.nlm.nih. Dunn, G., & Bebbington, P. (2006). Cognitive, emotional, gov/pubmed/1496057 and social processes in psychosis: refining cognitive (0341 Horan, W. P., & Blanchard, J.J. (2003). Emotional behavioral therapy for persistent positive symptoms. responses to psychosocial stress in Schizophrenia: the role Schizophrenia bulletin, 32 Suppl 1, S24-31. doi:10.1093/ of individual differences in affective traits and coping. Schbulfsb1014 Schizophrenia research, 60(2-3), 271-83. Retrieved from 0355 Kumar, R. Husain, M., Gupta, R. K., Hasan, K. M., http://www.ncbi.nlm.nih.gov/pubmed/12591589 Haris, M., Agarwal, A. K., Pandey, C. M., et al. (2009). 0342. Insel, T. R. (2010). Rethinking schizophrenia. Serial changes in the white matter diffusion tensor imaging Nature, 468(7321), 187-93. Nature Publishing Group. doi: metrics in moderate traumatic brain injury and correlation 10.1038/nature09552 with neuro-cognitive function. Journal of neurotrauma, 0343 Jackson, J. H. (1873). ON THE ANATOMICAL & 26(4), 481-95. doi:10.1089/neu.2008.0461 PHYSIOLOGICAL LOCALISATION OF MOVE 0356. Kurtz, M. M. (2005). Neurocognitive impairment MENTS IN THE BRAIN. The Lancet, 101 (2581), 232 across the lifespan in Schizophrenia: an update. Schizo 235. doi:10.1016/50140-6736(02)63385-9 phrenia research, 74(1), 15-26. doi:10.1016/j.schres.2004. 0344 Javitt, DC, Doneshka, P. Grochowski, S., & Ritter, 07.005 W. (1995). Impaired mismatch negativity generation 0357 Kéri, S., Kiss, I., & Kelemen, O. (2009). Sharing reflects widespread dysfunction of working memory in secrets: oxytocin and trust in Schizophrenia. Social neuro schizophrenia. Archives of general psychiatry, 52(7), 550 science, 4(4), 287-93. doi:10.1080/17470910802319710 8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 0358 Lahti, A. C., Weiler, M.A., Tamara Michaelidis, B. 7598.631 A., Parwani, A., & Tamminga, C. A. (2001). Effects of 0345 Javitt, Daniel C. Shelley, A.-M., Silipo, G., & Lie ketamine in normal and Schizophrenic Volunteers. Neurop berman, J. A. (2000). Deficits in Auditory and Visual Con sychopharmacology: official publication of the American text-Dependent Processing in Schizophrenia. ARCH GEN College of Neuropsychopharmacology, 25(4), 455-67. doi: PSYCHIATRY 57, 1131-1137. 10.1016/50893-133X(01)00243-3 0346 Jones, H. M., & Pilowsky, L. S. (2002). Dopamine 0359 Lai, J., Porreca, F., Hunter, J. C., & Gold, M. S. and antipsychotic drug action revisited. The British journal (2004). Voltage-gated Sodium channels and hyperalgesia. of psychiatry: the journal of mental science, 181, 271-5. Annual review of pharmacology and toxicology, 44, 371 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 97. doi:10.1146/annurev.pharmtox.44.101802.121627 1235.665O 0360 Laruelle, M., Abi-Dargham, A., van Dyck, C. H., (0347 Kadhim, H. J., Duchateau, J., & Sébire, G. (2008). Gil, R., D'Souza, C. D., Erdos, J., McCance, E., et al. Cytokines and brain injury: invited review. Journal of (1996). Single photon emission computerized tomography intensive care medicine, 23(4), 236-49. doi:10.1177/ imaging of amphetamine-induced dopamine release in O885O666.083 18458 drug-free schizophrenic Subjects. Proceedings of the 0348 Kessler, RC, Sonnega, A., Bromet, E., Hughes, M., National Academy of Sciences of the United States of & Nelson, C.B. (1995). Posttraumatic stress disorder in the America, 93(17), 9235-40. Retrieved from http://www. National Comorbidity Survey. Archives of general psy pubmedcentral.nih.gov/articlerender. chiatry, 52(12), 1048-60. Retrieved from http://www.ncbi. fcgi?artid=38625&tool-pmcentrez&render type-abstract nlm.nih.gov/pubmed/7492257 Latalova, K., Prasko, J., Diveky, T., & Velartova, H. (2011). (0349 Kessler, Ronald C, Adler, L., Barkley, R., Bieder Cognitive impairment in bipolar disorder. Biomedical man, J., Conners, C. K., Demler, O., Faraone, S. V., et al. Papers, 155(1), 19-26. doi:10.5507/bp.155.2011.003 (2006). The prevalence and correlates of adult ADHD in 0361 Lewis, D. a, Volk, D. W., & Hashimoto, T. (2004). the United States: results from the National Comorbidity Selective alterations in prefrontal cortical GABA neu Survey Replication. The American journal of psychiatry, rotransmission in Schizophrenia: a novel target for the 163(4), 716-23. doi:10.1176/applajp. 1634.716 treatment of working memory dysfunction. Psychophar 0350 Kim, E. (2002). Agitation, aggression, and disinhi macology, 174(1), 143-50. doi:10.1007/s00213-003 bition syndromes after traumatic brain injury. NeuroReha 1673-X bilitation, 17(4), 297-310. Retrieved from http://www. 0362 Lux, W. E. (2007). A neuropsychiatric perspective incbi.nlm.nih.gov/pubmed/12547978 on traumatic brain injury. The Journal of Rehabilitation 0351 Kneisl, C. R., & Trigoboff, E. (2008). Contempo Research and Development, 44(7), 951-962. doi:10.1682/ rary Psychiatric-Mental Health Nursing (2nd Edition) (p. JRRD2007.O1.OOO9 1024). Prentice Hall. Retrieved from http://www.amazon. 0363 Maas, A.I.R., Stocchetti, N., & Bullock, R. (2008). com/Contemporary-Psychiatric-Mental-Health-Nursing Moderate and severe traumatic brain injury in adults. Lan Edition/dp/013243489X cet neurology, 7(8), 728-41. doi:10.1016/S1474-4422(08) 0352 Konradi, C., & Heckers, S. (2003). Molecular 7O164-9 aspects of glutamate dysregulation: implications for 0364. Manuscript, A., Revheim, N., Butler, P. D., Schizophrenia and its treatment. Pharmacology & thera Schechter, I., Jalbrzikowski, M., Silipo, G., & Javitt, D.C. peutics, 97(2), 153-79. Retrieved from http://www.ncbi. (2006). Reading impairment and visual processing deficits nlm.nih.gov/pubmed/12559388 in schizophrenia. Schizophrenia research, 87(1-3), 238-45. 0353 Kraus, M. F., Susmaras, T., Caughlin, B. P. Walker, doi:10.1016/j.schres.2006.06.022 C.J., Sweeney, J. A., & Little, D. M. (2007). White matter 0365 Matson, J. L., Kozlowski, A. M., Worley, J. A., integrity and cognition in chronic traumatic brain injury: a Shoemaker, M.E., Sipes, M., & Horovitz, M. (2011). What diffusion tensor imaging study. Brain: a journal of neurol is the evidence for environmental causes of challenging ogy, 130(Pt 10), 2508-19. doi:10.1093/brain/awm216 behaviors in persons with intellectual disabilities and US 2014/0142140 A1 May 22, 2014 26

autism spectrum disorders? Research in developmental 0379 Neurotrauma: New Insights Into Pathology and disabilities, 32(2), 693-8. doi:10.1016/j.ridd.2010.11.012 Treatment (Google eBook). (2007). (p. 443). Elsevier. 0366 Mattson, A.J., & Levin, H. S. (1990a). Frontal lobe 0380 Noggle, C. A. (2011). The Encyclopedia of Neurop dysfunction following closed head injury. A review of the sychological Disorders (p. 804). Springer Publishing literature. The Journal of nervous and mental disease, 178 Company. Retrieved from http://books.google.com/ (5), 282-91. Retrieved from http://www.ncbi.nlm.nih.gov/ books?id=Q30 QeaGVLYC&pgis=1 pubmed/2187053 (0381. Oblak A, Gibbs T.T. & Blatt G.J. (2009). Decreased 0367 Mattson, A.J., & Levin, H. S. (1990b). Frontal lobe GABAA receptors and benzodiazepine binding sites in the dysfunction following closed head injury. A review of the anterior cingulate cortex in autism. Autism Research, 204), literature. The Journal of nervous and mental disease, 178 205-219. doi:10.1002/aur.88. Decreased (5), 282-91. Retrieved from http://www.ncbi.nlm.nih.gov/ 0382 Ommaya, A. K., & Gennarelli, T. A. (1974). Cere pubmed/2187053 bral concussion and traumatic unconsciousness. Correla 0368 McCrea, M.A. (2007). Mild Traumatic Brain Injury tion of experimental and clinical observations of blunt head and Postconcussion Syndrome. The New Evidence Base for injuries. Brain: a journal of neurology, 97(4), 633-54. Diagnosis and Treatment (Oxford Workshop Series: Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ American Academy of Clinical Neuropsychology) (p. 4215541 224). Oxford University Press, USA. Retrieved from http:// (0383 Picchioni, M. M., & Murray, R. M. (2007). Schizo www.amazon.com/Traumatic-Brain-Injury-Postconcus phrenia. BMJ (Clinical research ed.), 335(7610), 91-5. sion-Syndrome/dp/0195328299 doi:10.1136/bmj.39227.616447.BE 0369 McDonald, S., Flanagan, S. Rollins, J., & Kinch, J. 0384 Poirier, M. P. (2003). Concussions: assessment, (2003). TASIT: A new clinical tool for assessing social management, and recommendations for return to activity. perception after traumatic braininjury. TheJournal of head Clinical Pediatric Emergency Medicine, 4(3), 179-185. trauma rehabilitation, 18(3), 219-38. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/128021.65 doi:10.1016/S1522-8401(03)00061-2 (0385 Ponsford, J., Draper, K.,& Schönberger, M. (2008). 0370. McNab, F., & Klingberg, T. (2008). Prefrontal cor Functional outcome 10 years after traumatic brain injury: tex and basal ganglia control access to working memory. its relationship with demographic, injury severity, and cog Nature neuroscience, 11(1), 103-7. doi:10.1038/nn2024 nitive and emotional status. Journal of the International 0371 Mohr, J. P. Weiss, G. H., Caveness, W. F., Dillon, J. Neuropsychological Society. JINS, 14(2), 233-42. doi:10. D., Kistler, J. P., Meirowsky, A. M., & Rish, B. L. (1980). Language and motor disorders after penetrating head 101.7/S135561 7708080272 injury in Viet Nam. Neurology, 30(12), 1273-9. Retrieved 0386 Porges, S.W. (1998). Love: an emergent property of from http://www.ncbi.nlm.nih.gov/pubmed/71928.08 the mammalian autonomic nervous system. Psycho 0372 Morris, R. W., Weickert, C. S., & Loughland, C. M. neuroendocrinology, 23(8), 837-61. Retrieved from http:// (2009). Emotional face processing in schizophrenia. Cur www.ncbi.nlm.nih.gov/pubmed/9924740 rent opinion in psychiatry, 22(2), 140-6. doi:10.1097/ (0387 Porges, S.W. (2001). The polyvagal theory: phylo YCO.ObO13e328324f&95 genetic Substrates of a Social nervous system. International 0373) Morrison, A. L., King, T. M., Korell, M. A. Smi journal of psychophysiology: official journal of the Inter alek, J. E., & Troncoso, J. C. (1998). Acceleration-decel national Organization of Psychophysiology, 42(2), 123 eration injuries to the brain in blunt force trauma. The 46. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ American journal of forensic medicine and pathology, 11587772 19(2), 109-12. Retrieved from http://www.ncbi.nlm.nih. (0388 Porges, S. W. (2003a). The Polyvagal Theory: phy gov/pubmed/9662103 logenetic contributions to social behavior. Physiology & 0374) Mula, M., & Trimble, M. R. (2009). Antiepileptic behavior; 79(3), 503-13. Retrieved from http://www.ncbi. drug-induced cognitive adverse effects: potential mecha nlm.nih.gov/pubmed/12954445 nisms and contributing factors. CNS drugs, 23(2), 121-37. (0389 Porges, S. W. (2003b). Social engagement and Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ attachment: a phylogenetic perspective. Annals of the New 19173372 York Academy of Sciences, 1008, 31-47. Retrieved from 0375 Murphy, K. R., & Barkley, R.A. (1996). Prevalence http://www.ncbi.nlm.nih.gov/pubmed/14998870 of DSM-IV symptoms of ADHD in adult licensed drivers: 0390 Porges, S. W. (2007). The polyvagal perspective. Implications for clinical diagnosis. Journal of Attention Biological psychology, 74(2), 116–43. doi:10.1016/j.biop Disorders, 1(3), 147-161. Sage Publications. doi:10.1177/ sycho.2006.06.009 1087054796OO10O303 0391 Porges, S. W. (2009). The polyvagal theory: new 0376 Müller, R.-A. (2007). The study of autism as a dis insights into adaptive reactions of the autonomic nervous tributed disorder. Mental retardation and developmental system. Cleveland Clinic journal of medicine, 76 Suppl disabilities research reviews, 13(1), 85-95. doi:10.1002/ 2(April), S86-90. doi:10.3949/ccjm.76.s2.17 mrdd.20141 0392 Povlishock, J.T. (2008). The classification of trau 0377. NINDA Traumatic Brain Injury Information Page. matic brain injury (TBI) for targeted therapies. Journal of (2008). National Institute of Neurological Disorders and neurotrauma, 25(7), 717-8. doi:10.1089/neu.2008.9964 Stroke. Retrieved from http://www.ninds.nih.gov/disor 0393 Professor, A. C. P. S. M. M. Frcp. F. & E. (2002). derS/tbi/tbi.htm Symptoms in the Mind: An Introduction to Descriptive 0378 Nahum, A. M., & Melvin, J. (2001). Accidental Psychopathology (p. 430). Saunders Ltd. Retrieved from Injury: Biomechanics and Prevention (Google eBook) http://www.amazon.co.uk/Symptoms-Mind-Introduction (Vol. 2001, p. 637). Springer. Descriptive-Psychopathology/dp/0702026271 US 2014/0142140 A1 May 22, 2014 27

0394 Reichenberg, A. (2005, January). Cognitive impair 0407 Tallal, P., Merzenich, M., Miller, S., & Jenkins, W. ment as a risk factor for psychosis. Dialogues in clinical (1998). Language learning impairment: integrating neuroscience. Retrieved from http://www.ncbi.nlm.nih. research and remediation. Scandinavian journal of psy gov/pubmed/21946.140 chology, 39(3), 197-9. Retrieved from http://www.ncbi. 0395. Ridder, W. H., Borsting, E., Cooper, M., McNeel, nlm.nih.gov/pubmed/98.00537 B., & Huang, E. (1997). Not all dyslexics are created equal. (0408 Taylor, J. J. (1958). Selected Writings of John Optometry and vision science: official publication of the Hughlings Jackson. (J.J. Taylor, Ed.) (pp. 45-118). Lon American Academy of Optometry, 74(2), 99-104. don: Staples Press. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 04.09 Textbook of Traumatic Brain Injury. (2004). (p. 90973.26 792). American Psychiatric Publishing, Inc. Retrieved 0396 Romani, A., Conte, S., Callieco, R., Bergamaschi, from http://www.amazon.com/Textbook-Traumatic-In R., Versino, M., Lanzi, G., Zambrino, C. A., et al. (2001). jury-Jonathan-Silver/dp/1585621056 Visual evoked potential abnormalities in dyslexic children. 0410 The Boundaries of Consciousness: Neurobiology Functional neurology, 16(3), 219-29. Retrieved from And Neuropathology (Google eBook). (2006). (p. 585). http://www.ncbi.nlm.nih.gov/pubmed/11769867 Elsevier. Retrieved from http://books.google.com/ 0397 Rubenstein, J. L. R., & Merzenich, M. M. (2003). books?id=YHGacGKyVbYC&pgis=1 Model of autism: increased ratio of excitation/inhibition in 0411. The Practice of Forensic Neuropsychology. Meet key neural systems. Genes, brain, and behavior, 205), 255 ing Challenges in the Courtroom (Critical Issues in Neu 67. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ ropsychology). (1996). (p. 240). Springer. 14606691 0412 Tucker, P. Zaninelli, R., Yehuda, R., Ruggiero, L., 0398 Russell, T. A., Green, M. J., Simpson, I., & Colth Dillingham, K., & Pitts, C. D. (2001). Paroxetine in the eart, M. (2008). Remediation of facial emotion perception treatment of chronic posttraumatic stress disorder: results in Schizophrenia: concomitant changes in visual attention. of a placebo-controlled, flexible-dosage trial. The Journal Schizophrenia research, 103(1-3), 248-56. doi:10.1016/j. of clinical psychiatry, 62(11), 860-8. Retrieved from http:// Schres.2008.04.033 www.ncbi.nlm.nih.gov/pubmed/11775045 0399. Silver, H., Goodman, C., Knoll, G., & Isakov, V. 0413 Tunnicliff, G. (1996). Basis of the antiseizure action (2004). Brief emotion training improves recognition of of phenyloin. General pharmacology, 27(7), 1091-7. facial emotions in chronic schizophrenia. A pilot study. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ Psychiatry research, 128(2), 147-54. doi:10.1016/j.psy 8981053 chres. 2004.06.002 0414 Tuominen, H. J., Tihonen, J., & Wahlbeck, K. 0400 Silverstein, S. M., Schenkel, L. S., Valone, C., & (2005). Glutamatergic drugs for Schizophrenia: a system Nuernberger, S.W. (1998). Cognitive deficits and psychi atic review and meta-analysis. Schizophrenia research, atric rehabilitation outcomes in schizophrenia. The Psychi 72(2-3), 225-34. doi:10.1016/j.schres.2004.05.005 atric quarterly, 69(3), 169-91. Retrieved from http://www. 0415 Vicini, S., Alho, H., Costa, E., Mienville, J. M., incbi.nlm.nih.gov/pubmed/9682284 Santi, M. R., & Vaccarino, F. M. (1986). Modulation of gamma-aminobutyric acid-mediated inhibitory synaptic 0401 Smith, B., Fowler, D.G., Freeman, D., Bebbington, currents in dissociated cortical cell cultures. Proceedings P. Bashforth, H., Garety, P., Dunn, G., et al. (2006). Emo of the National Academy of Sciences of the United States of tion and psychosis: links between depression, self-esteem, America, 83(23), 9269-73. Retrieved from http://www. negative schematic beliefs and delusions and hallucina pubmedcentral.nih.gov/articlerender. tions. Schizophrenia research, 86(1-3), 181-8. doi:10. fcgi?artid=387117&tool-pmcentrez&rende 1016/j.schres.2006.06.018 rtype-abstract 0402 Smith, D. H. Meaney, D. F., & Shull, W. H. (1989). 0416 Weiss, M., Safren, S. a, Solanto, M.V., Hechtman, Diffuse axonal injury in head trauma. The Journal of head L., Rostain, A. L., Ramsay, J. R. & Murray, C. (2008). trauma rehabilitation, 18(4), 307-16. Retrieved from Research forum on psychological treatment of adults with http://www.ncbi.nlm.nih.gov/pubmed/16222 127 ADHD. Journal of attention disorders, 11(6), 642-51. doi: 0403 Smith, T., Weston, C., & Lieberman, J. (2010). 10.1177/1087054708315063 Schizophrenia (maintenance treatment). American family 0417. Whyte, J. (2010). Pharmacological treatment of physician, 82(4), 338-9. Retrieved from http://www.ncbi. cognitive and behavioural sequele of traumatic brain nlm.nih.gov/pubmed/20704164 injury: practicing in the absence of strong evidence. EURJ 0404 Solomon, M., Ozonoff, S.J., Ursu, S., Ravizza, S., PHYS REHABILMED, 46(4), 557-562. Cummings, N., Ly, S., & Carter, C. S. (2009). The neural 0418 Willcutt, E. G., & Pennington, B. F. (2000). Comor Substrates of cognitive control deficits in autism spectrum bidity of reading disability and attention-deficit/hyperac disorders. Neuropsychologia, 47(12), 2515-26. doi:10. tivity disorder: differences by gender and subtype. Journal 1016/j.neuropsychologia 2009.04.019 of Learning Disabilities, 33(2), 179-191. doi:10.1177/ 04.05 Tager-Flusberg, H. (2010). The origins of social OO222 194OOO33OO2O6 impairments in autism spectrum disorder: Studies of 0419 Williams, C., & Wood, R. L. (2010). Alexithymia infants at risk. Neural networks: the official journal of the and emotional empathy following traumatic brain injury. International Neural Network Society, 23(8-9), 1072-6. Journal of clinical and experimental neuropsychology, doi:10.1016/j.neunet.2010.07.008 32(3), 259-67. doi:10.1080/13803390902976940 0406 Talcott J. B. Hansen PC, Willis-Owen C. McKinnell 0420 Wingo, A. P. Harvey, P. D., & Baldessarini, R. J. I W. Richardson A. J. S. J. (1998). Visual magnocellular (2009). Neurocognitive impairment in bipolar disorder impairment in adult developmental dyslexics. Neuro-Oph patients: functional implications. Bipolar disorders, 11(2), thalmology, 20, 187-201. 113-25. doi:10.111141399-5618.2009.00665.X US 2014/0142140 A1 May 22, 2014 28

0421 Zhang, L.I., Bao, S., & Merzenich, M. M. (2001). 0434 Blissitt, P. A. (2006a). Care of the critically ill Persistent and specific influences of early acoustic environ patient with penetrating head injury. Critical care nursing ments on primary auditory cortex. Nature neuroscience, clinics of North America, 18(3), 321-32. doi:10.1016/j. 4(11), 1123-30. doi:10.1038/nn745 ccel1.2006.05.006 0422 van Os, J., & Kapur, S. (2009). Schizophrenia. Lan 0435 Blissitt, P. A. (2006b). Care of the critically ill cet, 374(9690), 635-45. doi:10.1016/50140-6736(0.9) patient with penetrating head injury. Critical care nursing 6O995-8 clinics of North America, 18(3), 321-32. doi:10.1016/j. 0423 Adler, L. A., & Cohen, J. (2004). Diagnosis and ccel1.2006.05.006 evaluation of adults with attention deficit hyperactivity 0436 Borg, E., & Counter, S.A. (1989). The middle-ear disorder. Psychiatry Clinic, 27, 187-214. muscles. Scientific American, 261(2), 74-80. Retrieved 0424 Arnott, W., Sali, L., & Copland, D. (2011). Impaired from http://www.ncbi.nlm.nih.gov/pubmed/2667133 reading comprehension in Schizophrenia: evidence for 0437 Brady, K., Pearlstein, T., Asnis, G. M., Baker, D., underlying phonological processing deficits. Psychiatry Rothbaum, B., Sikes, C. R., & Farfel, G. M. (2000). Effi research, 187(1-2), 6-10. Elsevier Ireland Ltd. doi:10. cacy and safety of Sertraline treatment of posttraumatic 1016/j.psychres.2010.11.025 stress disorder: a randomized controlled trial. JAMA: the journal of the American Medical Association, 283(14), 0425 Association, A. P. (2000). Diagnostic and Statistical 1837-44. Retrieved from http://www.ncbi.nlm.nih.gov/ Manual of Mental Disorders, Fourth Edition. DSM-IV pubmed/10770145 TRR) (p. 943). American Psychiatric Pub. Retrieved from http://books.google.com/books?id=w 0438 Bramlett, H. M., & Dietrich, W. D. (2007). Progres HajjMnjxwC&pgis=1 sive damage after brain and spinal cord injury: patho mechanisms and treatment strategies. Progress in brain 0426 Bales, J. Wagner, A., & Kline, A. (2009). Persistent research, 161, 125-41. doi:10.1016/S0079-6123(06) cognitive dysfunction after traumatic brain injury: A 61009-1 dopamine hypothesis. Neurosci Biobehav Rev., 33(7), 981 0439 Brekke, J., Kay, D. D., Lee, K. S., & Green, M. F. 1003. doi:10.1016/j.neubiorev.2009.03.011. Persistent (2005). Biosocial pathways to functional outcome in 0427 Basso, A., & Scarpa, M.T. (1990). Traumatic apha schizophrenia. Schizophrenia Research, 80(2-3), 213-225. sia in children and adults: a comparison of clinical features Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ and evolution. Cortex, a journal devoted to the study of the 16137859 nervous system and behavior; 26(4), 501-14. Retrieved 0440 Bremner, J. D., Mletzko, T., Welter, S., Quinn, S., from http://www.ncbi.nlm.nih.gov/pubmed/1706973 Williams, C., Brummer, M., Siddiq, S., et al. (2005). 0428 Bayly, P. V., Cohen, T. S. Leister, E. P., Ajo, D., Effects of phenyloin on memory, cognition and brainstruc Leuthardt, E. C., & Genin, G. M. (2005). Deformation of ture in post-traumatic stress disorder: a pilot study. Journal the human brain induced by mild acceleration. Journal of of psychopharmacology (Oxford, England), 19(2), 159-65. neurotrauma, 22(8), 845-56. doi:10.1089/neu.2005.22. doi:10.1177/O269881. 105048996 845 0441 Buckley, P. F., Miller, B.J., Lehrer, D. S., & Castle, 0429 Becker, T., & Kilian, R. (2006). Psychiatric services D.J. (2009). Psychiatric comorbidities and schizophrenia. for people with severe mental illness across western Schizophrenia bulletin, 35(2), 383-402. doi:10.1093/sch Europe: what can be generalized from current knowledge bulfsbn 135 about differences in provision, costs and outcomes of men 0442 Busch, R. M., McBride, A., Curtiss, G., & Vander tal health care? Acta psychiatrica Scandinavica. Supple ploeg, R. D. (2005). The components of executive func mentum, (429), 9-16. doi:10.1111/1600-0447.2005. tioning in traumatic brain injury. Journal of clinical and OO711X experimental neuropsychology, 27(8), 1022-32. doi:10. 0430 Bell, V., Halligan, P. W., & Ellis, H. D. (2006). 108Of 13803390490919263 Explaining delusions: a cognitive perspective. Trends in 0443 Cienfuegos, A., March, L., Shelley, A. M., & Javitt, cognitive sciences, 10(5), 219-26. doi:10.1016/j.tics.2006. D.C. (1999). Impaired categorical perception of synthetic O3.004 speech Sounds in Schizophrenia. Biological psychiatry, 0431 Bentall, R. P. Fernyhough, C., Morrison, A. P. 45(1), 82-8. Retrieved from http://www.ncbi.nlm.nih.gov/ Lewis, S., & Corcoran, R. (2007). Prospects for a cogni pubmed/98.94579 tive-developmental account of psychotic experiences. The 0444 Cohen, A. S., & Docherty, N. M. (2004). Affective British journal of clinical psychology/the British Psycho reactivity of speech and emotional experience in patients logical Society, 46(Pt 2), 155-73. doi:10.1348/ with schizophrenia. Schizophrenia research, 69(1), 7-14. O14466506X 123011 doi:10.1016/50920-9964(03)00069-0 0432 Betancur, C. (2011). Etiological heterogeneity in 0445 Committee on Child Abuse and Neglect. (2001). autism spectrum disorders: more than 100 genetic and Shaken Baby Syndrome: Rotational Cranial Injuries Tech genomic disorders and still counting. Brain research, nical Report. PEDIATRICS, 108(1), 206-210. doi:10. 1380, 42-77. doi:10.1016/j.brainres.2010.11.078 1542/peds. 108.1.206 0433 Biederman, J., Faraone, S.V., Monuteaux, M. C., & 0446 Costa, E., & Guidotti, A. (1996). Benzodiazepines Biederman, J., Faraone, S. V., & Monuteaux, M. (2002). on trial: a research strategy for their rehabilitation. Trends Differential effect of environmental adversity by gender: in pharmacological sciences, 17(5), 192-200. Retrieved Rutter's index of adversity in a sample of boys and girls from http://www.ncbi.nlm.nih.gov/pubmed/8669 126 with and without ADHD. American Journal of Psychiatry, 0447 Coyle, J.T., Tsai, G., & Goff, D. (2003). Converging 159(9), 1556-1563. American Psychiatric Assn. doi:10. evidence of NMDA receptor hypofunction in the patho 1176/appi.ajp. 159.9.1556 physiology of schizophrenia. Annals of the New York Acad US 2014/0142140 A1 May 22, 2014 29

emy of Sciences, 1003,318-27. Retrieved from http://www. America, 12(2), 175-87, vii. Retrieved from http://www. incbi.nlm.nih.gov/pubmed/14684455 neuroimaging...theclinics.com/article/S1052-5149(02) 0448 Cummings, J. L. (1993). Frontal-subcortical cir 00009-6/fulltext cuits and human behavior. Archives of neurology, 50(8), 0462 Hashimoto, T., Volk, D. W. Eggan, S. M., Mirnics, 873-80. Retrieved from http://www.ncbi.nlm.nih.gov/ K., Pierri, J. N., Sun, Z. Sampson, A.R., et al. (2003). Gene pubmed/8352676 expression deficits in a subclass of GABA neurons in the 0449 Davids, E., K is, B., Specka, M., & Gastpar, M. prefrontal cortex of subjects with schizophrenia. The Jour (2006). A pilot clinical trial of oxcarbazepine in adults with nal of neuroscience: the official journal of the Society for attention-deficit hyperactivity disorder: Progress in neu Neuroscience, 23(15), 6315-26. Retrieved from http:// ropsychopharmacology biological psychiatry (Vol. 30, pp. www.ncbi.nlm.nih.gov/pubmed/12867516 1033-1038). 0463 Heimberg, C., Gur, R. E., Erwin, R. J., Shtasel, D. 0450 Demb, J. B., Boynton, G.M., Best, M., & Heeger, D. L., & Gur, R. C. (1992). Facial emotion discrimination: III. J. (1998). Psychophysical evidence for a magnocellular Behavioral findings in schizophrenia. Psychiatry research, pathway deficit in dyslexia. Vision research, 38(11), 1555 42(3), 253-65. Retrieved from http://www.ncbi.nlm.nih. 9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ gov/pubmed/1496.057 97.47491 0464) Horan, W. P., & Blanchard, J.J. (2003). Emotional 0451 Erdmann, J. (2011). Broad collaborations bring new responses to psychosocial stress in Schizophrenia: the role energy to autism therapeutics. Chemistry & biology, 18(2), of individual differences in affective traits and coping. 142-3. doi:10.1016/j.chembiol.2011.02.006 Schizophrenia research, 60(2-3), 271-83. Retrieved from 0452 Faden, A., Demediuk, P., Panter, S., & Vink, R. http://www.ncbi.nlm.nih.gov/pubmed/12591589 (1989). The role of excitatory amino acids and NMDA 0465 Insel, T. R. (2010). Rethinking schizophrenia. receptors in traumatic brain injury. Science, 244(4906), Nature, 468(7321), 187-93. Nature Publishing Group. doi: 798-800. doi:10.1126/science. 2567056 10.1038/nature09552 0453 Faraone, S.V., Biederman, J., Spencer, T., Mick, E., 0466 Jackson, J. H. (1873). ON THE ANATOMICAL & Murray, K., Petty, C., Adamson, J. J., et al. (2006). Diag PHYSIOLOGICAL LOCALISATION OF MOVE nosing adult attention deficit hyperactivity disorder: are MENTS IN THE BRAIN. The Lancet, 101 (2581), 232 late onset and subthreshold diagnoses valid? The American 235. doi:10.1016/50140-6736(02)63385-9 journal of psychiatry, 163(10), 1720-9: quiz, 1859. doi:10. 0467 Javitt, DC, Doneshka, P. Grochowski, S., & Ritter, 1176/applajp. 163.10.1720 W. (1995). Impaired mismatch negativity generation 0454 Forde, I., Holloway, J., Healy, O., & Brosnan, J. reflects widespread dysfunction of working memory in (2011). A dyadic analysis of the effects of setting and schizophrenia. Archives of general psychiatry, 52(7), 550 communication partner on elicited and spontaneous com 8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ munication of children with Autism Spectrum Disorder 7598.631 and typically developing children. Research in Autism 0468 Javitt, Daniel C. Shelley, A.-M., Silipo, G., & Lie Spectrum Disorders, 5(4), 1471-1478. berman, J. A. (2000). Deficits in Auditory and Visual Con 0455 Freeman, D., Garety, P. A., Kuipers, E., Fowler, D., text-Dependent Processing in Schizophrenia. ARCH GEN Bebbington, P. E., & Dunn, G. (2007). Acting on persecu tory delusions: the importance of safety seeking. Behav PSYCHIATRY 57, 1131-1137. iour research and therapy, 45(1), 89-99. doi:10.1016/j. 0469 Jones, H. M., & Pilowsky, L. S. (2002). Dopamine brat.2006.01.014 and antipsychotic drug action revisited. The British journal 0456 Gomot, M., & Wicker, B. (2012). A challenging, of psychiatry: the journal of mental science, 181,271-5. unpredictable world for people with Autism Spectrum Dis Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ order. International journal of psychophysiology: official 1235665O journal of the International Organization of Psychophysi 0470 Kadhim, H. J., Duchateau, J., & Sébire, G. (2008). ology, 83(2), 240-7. doi:10.1016/j.ijpsycho.2011.09.017 Cytokines and brain injury: invited review. Journal of 0457 Granacher, R. P. (2007). Traumatic Brain Injury: intensive care medicine, 23(4), 236-49. doi:10.1177/ Methods for Clinical and Forensic Neuropsychiatric O885O666.083 18458 Assessment (Google eBook) (p. 560). CRC Press. 0471 Kessler, RC, Sonnega, A., Bromet, E., Hughes, M., 04.58 Green, M. F. Kern, R. S., Braff, D. L., & Mintz, J. & Nelson, C.B. (1995). Posttraumatic stress disorder in the (2000). Neurocognitive deficits and functional outcome in National Comorbidity Survey. Archives of general psy schizophrenia: are we measuring the “right stuff? Schizo chiatry, 52(12), 1048-60. Retrieved from http://www.ncbi. phrenia bulletin, 26(1), 119-36. Retrieved from http:// nlm.nih.gov/pubmed/7492257 www.ncbi.nlm.nih.gov/pubmed/10755673 0472 Kessler, Ronald C, Adler, L., Barkley, R., Bieder 0459 Green, Michael F. (2006). Cognitive impairment man, J., Conners, C. K., Demler, O., Faraone, S.V., et al. and functional outcome in Schizophrenia and bipolar dis (2006). The prevalence and correlates of adult ADHD in order. The Journal of clinical psychiatry, 67(10), e12. the United States: results from the National Comorbidity Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ Survey Replication. The American journal of psychiatry, 17107235 163(4), 716-23. doi:10.1176/appl.a.p. 1634.716 0460 Guastella, A. J., Mitchell, P. B., & Dadds, M. R. 0473 Kim, E. (2002). Agitation, aggression, and disinhi (2008). Oxytocin increases gaze to the eye region of human bition syndromes after traumatic brain injury. NeuroReha faces. Biological psychiatry, 63(1), 3-5. doi:10.1016/j.bi bilitation, 17(4), 297-310. Retrieved from http://www. opsych.2007.06.026 incbi.nlm.nih.gov/pubmed/12547978 0461 Hardman, J. M., & Manoukian, A. (2002). Pathol 0474 Kneisl, C. R., & Trigoboff, E. (2008). Contempo ogy of head trauma. Neuroimaging clinics of North rary Psychiatric-Mental Health Nursing (2nd Edition) (p. US 2014/0142140 A1 May 22, 2014 30

1024). Prentice Hall. Retrieved from http://www.amazon. 0486 Lux, W. E. (2007). A neuropsychiatric perspective com/Contemporary-Psychiatric-Mental-Health-Nursing on traumatic brain injury. The Journal of Rehabilitation Edition/dp/013243489X Research and Development, 44(7), 951-962. doi:10.1682/ 0475 Konradi, C., & Heckers, S. (2003). Molecular JRRD2007.O1.OOO9 aspects of glutamate dysregulation: implications for 0487. Maas, A.I.R., Stocchetti, N., & Bullock, R. (2008). Schizophrenia and its treatment. Pharmacology & thera Moderate and severe traumatic brain injury in adults. Lan peutics, 97(2), 153-79. Retrieved from http://www.ncbi. cet neurology, 7(8), 728-41. doi:10.1016/S1474-4422(08) nlm.nih.gov/pubmed/12559388 7O164-9 0488. Manuscript, A., Revheim, N., Butler, P. D., 0476 Kraus, M. F., Susmaras, T., Caughlin, B. P. Walker, Schechter, I., Jalbrzikowski, M., Silipo, G., & Javitt, D.C. C.J., Sweeney, J. A., & Little, D. M. (2007). White matter (2006). Reading impairment and visual processing deficits integrity and cognition in chronic traumatic brain injury: a in schizophrenia. Schizophrenia research, 87(1-3), 238-45. diffusion tensor imaging study. Brain: a journal of neurol doi:10.1016/j.schres.2006.06.022 ogy, 130(Pt 10), 2508-19. doi:10.1093/brain/awm216 0489. Matson, J. L., Kozlowski, A. M., Worley, J. A., 0477 Kuipers, E., Garety, P., Fowler, D., Freeman, D., Shoemaker, M.E., Sipes, M., & Horovitz, M. (2011). What Dunn, G., & Bebbington, P. (2006). Cognitive, emotional, is the evidence for environmental causes of challenging and Social processes in psychosis: refining cognitive behaviors in persons with intellectual disabilities and behavioral therapy for persistent positive symptoms. autism spectrum disorders? Research in developmental Schizophrenia bulletin, 32 Suppl 1, S24-31. doi:10.1093/ disabilities, 32(2), 693-8. doi:10.1016/j.ridd.2010.11.012 Schbulfsb1014 0490 Mattson, A.J., & Levin, H. S. (1990a). Frontal lobe 0478 Kumar, R. Husain, M., Gupta, R. K., Hasan, K. M., dysfunction following closed head injury. A review of the Haris, M., Agarwal, A. K. Pandey, C. M., et al. (2009). literature. The Journal of nervous and mental disease, 178 Serial changes in the white matter diffusion tensor imaging (5), 282-91. Retrieved from http://www.ncbi.nlm.nih.gov/ metrics in moderate traumatic brain injury and correlation pubmed/2187053 with neuro-cognitive function. Journal of neurotrauma, 0491. Mattson, A.J., & Levin, H. S. (1990b). Frontal lobe 26(4), 481-95. doi:10.1089/neu.2008.0461 dysfunction following closed head injury. A review of the 0479. Kurtz, M. M. (2005). Neurocognitive impairment literature. The Journal of nervous and mental disease, 178 across the lifespan in Schizophrenia: an update. Schizo (5), 282-91. Retrieved from http://www.ncbi.nlm.nih.gov/ phrenia research, 74(1), 15-26. doi:10.1016/j.schres.2004. pubmed/2187053 07.005 0492 McCrea, M.A. (2007). Mild Traumatic Brain Injury and Postconcussion Syndrome. The New Evidence Base for 0480 Kéri, S., Kiss, I., & Kelemen, O. (2009). Sharing Diagnosis and Treatment (Oxford Workshop Series: Secrets: oxytocin and trust in Schizophrenia. Social neuro American Academy of Clinical Neuropsychology) (p. 224). science, 4(4), 287-93. doi:10.1080/17470910802319710 Oxford University Press, USA. Retrieved from http:// 0481 Lahti, A. C., Weiler, M.A., Tamara Michaelidis, B. www.amazon.com/Traumatic-Brain-Injury-Postconcus A., Parwani, A., & Tamminga, C. A. (2001). Effects of sion-Syndrome/dp/0195328299 ketamine in normal and Schizophrenic Volunteers. Neurop 0493 McDonald, S., Flanagan, S. Rollins, J., & Kinch, J. sychopharmacology: official publication of the American (2003). TASIT: A new clinical tool for assessing social College of Neuropsychopharmacology, 25(4), 455-67. doi: perception after traumatic braininjury. The Journal of head 10.1016/S0893-133X(01)00243-3 trauma rehabilitation, 18(3), 219-38. Retrieved from 0482 Lai, J., Porreca, F., Hunter, J. C., & Gold, M. S. http://www.ncbi.nlm.nih.gov/pubmed/12802165 (2004). Voltage-gated Sodium channels and hyperalgesia. 0494 McNab, F., & Klingberg, T. (2008). Prefrontal cor Annual review of pharmacology and toxicology, 44, 371 tex and basal ganglia control access to working memory. 97. doi:10.1146/annurev.pharmtox.44.101802.121627 Nature neuroscience, 11(1), 103-7. doi:10.1038/nn2024 0483 Laruelle, M., Abi-Dargham, A., van Dyck, C. H., 0495 Mohr, J. P. Weiss, G. H., Caveness, W. F., Dillon, J. Gil, R., D'Souza, C. D., Erdos, J., McCance, E., et al. D., Kistler, J. P., Meirowsky, A. M., & Rish, B. L. (1980). (1996). Single photon emission computerized tomography Language and motor disorders after penetrating head imaging of amphetamine-induced dopamine release in injury in VietNam. Neurology, 30(12), 1273-9. Retrieved drug-free schizophrenic Subjects. Proceedings of the from http://www.ncbi.nlm.nih.gov/pubmed/71928.08 National Academy of Sciences of the United States of 0496 Morris, R. W., Weickert, C. S., & Loughland, C. M. America, 93(17), 9235-40. Retrieved from http://www. (2009). Emotional face processing in schizophrenia. Cur pubmedcentral.nih.gov/articlerender. rent opinion in psychiatry, 22(2), 140-6. doi:10.1097/ fegi?artid=38625&tool-pmcentrez&render type-abstract YCO.ObO13e328324f395 0497 Morrison, A. L., King, T. M., Korell, M. A. Smi 0484 Latalova, K., Prasko, J., Diveky, T., & Velartova, H. alek, J. E., & Troncoso, J. C. (1998). Acceleration-decel (2011). Cognitive impairment in bipolar disorder. Bio eration injuries to the brain in blunt force trauma. The medical Papers, 155(1), 19-26. doi:10.5507/bp.155.2011. American journal of forensic medicine and pathology, 19(2), 109-12. Retrieved from http://www.ncbi.nlm.nih. 0485 Lewis, D. a, Volk, D. W., & Hashimoto, T. (2004). gov/pubmed/9662103 Selective alterations in prefrontal cortical GABA neu 0498 Mula, M., & Trimble, M. R. (2009). Antiepileptic rotransmission in Schizophrenia: a novel target for the drug-induced cognitive adverse effects: potential mecha treatment of working memory dysfunction. Psychophar nisms and contributing factors. CNS drugs, 23(2), 121-37. macology, 174(1), 143-50. doi:10.1007/s00213-003 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 1673-X 19173372 US 2014/0142140 A1 May 22, 2014

0499 Murphy, K. R., & Barkley, R.A. (1996). Prevalence 0514 Porges, S. W. (2007). The polyvagal perspective. of DSM-IV symptoms of ADHD in adult licensed drivers: Biological psychology, 74(2), 116–43. doi:10.1016/j.biop Implications for clinical diagnosis. Journal of Attention sycho.2006.06.009 Disorders, 1(3), 147-161. Sage Publications. doi:10.1177/ 0515 Porges, S. W. (2009). The polyvagal theory: new 1087054796OO10O303 insights into adaptive reactions of the autonomic nervous (0500 Müller, R.-A. (2007). The study of autism as a dis system. Cleveland Clinic journal of medicine, 76 Suppl tributed disorder. Mental retardation and developmental 2(April), S86-90. doi:10.3949/ccjm.76.s2.17 disabilities research reviews, 13(1), 85-95. doi:10.1002/ 0516. Povlishock, J.T. (2008). The classification of trau mrdd.20141 matic brain injury (TBI) for targeted therapies. Journal of 0501 NINDA Traumatic Brain Injury Information Page. neurotrauma, 25(7), 717-8. doi:10.1089/neu.2008.9964 (2008). National Institute of Neurological Disorders and 0517 Professor, A. C. P. S. M. M. Frcp. F. & E. (2002). Stroke. Retrieved from http://www.ninds.nih.gov/disor Symptoms in the Mind: An Introduction to Descriptive derS/tbi/tbi.htm Psychopathology (p. 430). Saunders Ltd. Retrieved from 0502 Nahum, A. M., & Melvin, J. (2001). Accidental http://www.amazon.co.uk/Symptoms-Mind-Introduction Injury: Biomechanics and Prevention (Google eBook) Descriptive-Psychopathology/dp/0702026271 (Vol. 2001, p. 637). Springer. 0518 Reichenberg, A. (2005, January). Cognitive impair 0503 Neurotrauma: New Insights Into Pathology and ment as a risk factor for psychosis. Dialogues in clinical Treatment (Google eBook). (2007). (p. 443). Elsevier. neuroscience. Retrieved from http://www.ncbi.nlm.nih. 0504 Noggle, C. A. (2011). The Encyclopedia of Neurop gov/pubmed/21946.140 sychological Disorders (p. 804). Springer Publishing 0519 Ridder, W. H., Borsting, E., Cooper, M., McNeel, Company. Retrieved from http://books.google.com/ B., & Huang, E. (1997). Notall dyslexics are created equal. books?id=Q30 QeaGvLYC&pgis=1 Optometry and vision science: official publication of the 0505. Oblak A, Gibbs T.T., & Blatt G.J. (2009). Decreased American Academy of Optometry, 74(2), 99-104. GABAA receptors and benzodiazepine binding sites in the Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ anterior cingulate cortex in autism. Autism Research, 204), 90973.26 205-219. doi:10.1002/aur.88. Decreased 0520 Romani, A., Conte, S., Callieco, R., Bergamaschi, 0506. Ommaya, A. K., & Gennarelli, T. A. (1974). Cere R., Versino, M., Lanzi, G., Zambrino, C. A., et al. (2001). bral concussion and traumatic unconsciousness. Correla Visual evoked potential abnormalities in dyslexic children. tion of experimental and clinical observations of blunt head Functional neurology, 16(3), 219-29. Retrieved from injuries. Brain: a journal of neurology, 97(4), 633-54. http://www.ncbi.nlm.nih.gov/pubmed/11769867 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 0521. Rubenstein, J. L. R., & Merzenich, M. M. (2003). 4215541 Model of autism: increased ratio of excitation/inhibition in 0507 Picchioni, M. M., & Murray, R. M. (2007). Schizo key neural systems. Genes, brain, and behavior. 205), 255 phrenia. BMJ (Clinical research ed.), 335(7610), 91-5. 67. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ doi:10.1136/bmj.39227.616447.BE 14606691 0522 Russell, T. A., Green, M. J., Simpson, I., & Colth 0508 Poirier, M. P. (2003). Concussions: assessment, eart, M. (2008). Remediation of facial emotion perception management, and recommendations for return to activity. in Schizophrenia: concomitant changes in visual attention. Clinical Pediatric Emergency Medicine, 4(3), 179-185. Schizophrenia research, 103(1-3), 248-56. doi:10.1016/j. doi:10.1016/S1522-8401(03)00061-2 Schres.2008.04.033 0509 Ponsford, J., Draper, K.,& Schönberger, M. (2008). 0523 Silver, H., Goodman, C., Knoll, G., & Isakov, V. Functional outcome 10 years after traumatic brain injury: (2004). Brief emotion training improves recognition of its relationship with demographic, injury severity, and cog facial emotions in chronic schizophrenia. A pilot study. nitive and emotional status. Journal of the International Psychiatry research, 128(2), 147-54. doi:10.1016/j.psy Neuropsychological Society: JINS, 14(2), 233-42. doi:10. chres. 2004.06.002 101.7/S135561 7708080272 0524. Silverstein, S. M., Schenkel, L. S., Valone, C., & 0510 Porges, S.W. (1998). Love: an emergent property of Nuernberger, S.W. (1998). Cognitive deficits and psychi the mammalian autonomic nervous system. Psycho atric rehabilitation outcomes in schizophrenia. The Psychi neuroendocrinology, 23(8), 837-61. Retrieved from http:// atric quarterly, 69(3), 169-91. Retrieved from http://www. www.ncbi.nlm.nih.gov/pubmed/9924740 incbi.nlm.nih.gov/pubmed/9682284 0511 Porges, S.W. (2001). The polyvagal theory: phylo 0525) Smith, B., Fowler, D. G., Freeman, D., Bebbington, genetic Substrates of a Social nervous system. International P. Bashforth, H., Garety, P., Dunn, G., et al. (2006). Emo journal of psychophysiology: official journal of the Inter tion and psychosis: links between depression, self-esteem, national Organization of Psychophysiology, 42(2), 123 negative schematic beliefs and delusions and hallucina 46. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ tions. Schizophrenia research, 86(1-3), 181-8. doi:10. 11587772 1016/j.schres.2006.06.018 0512 Porges, S.W. (2003a). The Polyvagal Theory: phy 0526 Smith, D. H. Meaney, D. F., & Shull, W. H. (1989). logenetic contributions to Social behavior. Physiology & Diffuse axonal injury in head trauma. The Journal of head behavior; 79(3), 503-13. Retrieved from http://www.ncbi. trauma rehabilitation, 18(4), 307-16. Retrieved from nlm.nih.gov/pubmed/12954445 http://www.ncbi.nlm.nih.gov/pubmed/16222 127 0513 Porges, S. W. (2003b). Social engagement and 0527 Smith, T., Weston, C., & Lieberman, J. (2010). attachment: a phylogenetic perspective. Annals of the New Schizophrenia (maintenance treatment). American family York Academy of Sciences, 1008, 31-47. Retrieved from physician, 82(4), 338-9. Retrieved from http://www.ncbi. http://www.ncbi.nlm.nih.gov/pubmed/14998870 nlm.nih.gov/pubmed/20704164 US 2014/0142140 A1 May 22, 2014 32

0528 Solomon, M., Ozonoff, S.J., Ursu, S., Ravizza, S., injury: practicing in the absence of strong evidence. EURJ Cummings, N., Ly, S., & Carter, C. S. (2009). The neural PHYS REHABILMED, 46(4), 557-562. Substrates of cognitive control deficits in autism spectrum (0542 Willcutt, E. G., & Pennington, B. F. (2000). Comor disorders. Neuropsychologia, 47(12), 2515-26. doi:10. bidity of reading disability and attention-deficit/hyperac 1016/j.neuropsychologia 2009.04.019 tivity disorder: differences by gender and subtype. Journal 0529 Tager-Flusberg, H. (2010). The origins of social of Learning Disabilities, 33(2), 179-191. doi:10.1177/ impairments in autism spectrum disorder: Studies of OO222 194OOO33OO2O6 infants at risk. Neural networks: the official journal of the (0543 Williams, C., & Wood, R. L. (2010). Alexithymia International Neural Network Society, 23(8-9), 1072-6. and emotional empathy following traumatic brain injury. doi:10.1016/j.neunet.2010.07.008 Journal of clinical and experimental neuropsychology, 0530 Talcott J. B. Hansen PC, Willis-Owen C. McKinnell 32(3), 259-67. doi:10.1080/13803390902976940 I W. Richardson A. J. S. J. (1998). Visual magnocellular (0544 Wingo, A. P. Harvey, P. D., & Baldessarini, R. J. impairment in adult developmental dyslexics. Neuro-Oph (2009). Neurocognitive impairment in bipolar disorder thalmology, 20, 187-201. patients: functional implications. Bipolar disorders, 11(2), 0531 Tallal, P., Merzenich, M., Miller, S., & Jenkins, W. 113-25. doi:10.111141399-5618.2009.00665.X (1998). Language learning impairment: integrating (0545 Zhang, L.I., Bao, S., & Merzenich, M. M. (2001). research and remediation. Scandinavian journal of psy Persistent and specific influences of early acoustic environ chology, 39(3), 197-9. Retrieved from http://www.ncbi. ments on primary auditory cortex. Nature neuroscience, nlm.nih.gov/pubmed/98.00537 4(11), 1123-30. doi:10.1038/nn745 0532 Taylor, J. J. (1958). Selected Writings of John 0546 van Os, J., & Kapur, S. (2009). Schizophrenia. Lan Hughlings Jackson. (J. J. Taylor, Ed.) (pp. 45-118). Lon cet, 374(9690), 635-45. doi:10.1016/50140-6736(0.9) don: Staples Press. 6O995-8 0533 Textbook of Traumatic Brain Injury. (2004). (p. 0547 Adler, L. A., & Cohen, J. (2004). Diagnosis and 792). American Psychiatric Publishing, Inc. Retrieved evaluation of adults with attention deficit hyperactivity from http://www.amazon.com/Textbook-Traumatic-In disorder. Psychiatry Clinic, 27, 187-214. jury-Jonathan-Silver/dp/1585621056 0548 Arnott, W., Sali, L., & Copland, D. (2011). Impaired 0534. The Boundaries of Consciousness: Neurobiology reading comprehension in Schizophrenia: evidence for And Neuropathology (Google eBook). (2006). (p. 585). underlying phonological processing deficits. Psychiatry Elsevier. Retrieved from http://books.google.com/ research, 187(1-2), 6-10. Elsevier Ireland Ltd. doi:10. books?id=YHGacGKyVbYC&pgis=1 1016/j.psychres.2010.11.025 0535 The Practice of Forensic Neuropsychology. Meet 0549. Association, A.P. (2000). Diagnostic and Statistical ing Challenges in the Courtroom (Critical Issues in Neu Manual of Mental Disorders, Fourth Edition. DSM-IV ropsychology). (1996). (p. 240). Springer. TR(R) (p. 943). American Psychiatric Pub. Retrieved from 0536 Tucker, P. Zaninelli, R., Yehuda, R., Ruggiero, L., http://books.google.com/books?id=w Dillingham, K., & Pitts, C. D. (2001). Paroxetine in the HaMnjxwC&pgis=1 treatment of chronic posttraumatic stress disorder: results 0550 Bales, J. Wagner, A., & Kline, A. (2009). Persistent of a placebo-controlled, flexible-dosage trial. The Journal cognitive dysfunction after traumatic brain injury: A of clinical psychiatry, 62(11), 860-8. Retrieved from http:// dopamine hypothesis. Neurosci Biobehav Rev., 33 (7), 981 www.ncbi.nlm.nih.gov/pubmed/11775045 1003. doi:10.1016/j.neubiorev.2009.03.011. Persistent 0537 Tunnicliff, G. (1996). Basis of the antiseizure action 0551 Basso, A., & Scarpa, M.T. (1990). Traumatic apha of phenyloin. General pharmacology, 27(7), 1091-7. sia in children and adults: a comparison of clinical features Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ and evolution. Cortex, a journal devoted to the study of the 8981053 nervous system and behavior; 26(4), 501-14. Retrieved 0538 Tuominen, H. J., Tihonen, J., & Wahlbeck, K. from http://www.ncbi.nlm.nih.gov/pubmed/1706973 (2005). Glutamatergic drugs for Schizophrenia: a system 0552 Bayly, P. V., Cohen, T. S. Leister, E. P., Ajo, D., atic review and meta-analysis. Schizophrenia research, Leuthardt, E. C., & Genin, G. M. (2005). Deformation of 72(2-3), 225-34. doi:10.1016/j.schres.2004.05.005 the human brain induced by mild acceleration. Journal of 0539 Vicini, S., Alho, H., Costa, E., Mienville, J. M., neurotrauma, 22(8), 845-56. doi:10.1089/neu.2005.22. Santi, M. R., & Vaccarino, F. M. (1986). Modulation of 845 gamma-aminobutyric acid-mediated inhibitory synaptic 0553 Becker, T., & Kilian, R. (2006). Psychiatric services currents in dissociated cortical cell cultures. Proceedings for people with severe mental illness across western of the National Academy of Sciences of the United States of Europe: what can be generalized from current knowledge America, 83 (23), 9269-73. Retrieved from http://www. about differences in provision, costs and outcomes of men pubmedcentral.nih.gov/articlerender. tal health care? Acta psychiatrica Scandinavica. Supple fegi?artid=387117&tool-pmcentrez&rende mentum, (429), 9-16. doi:10.1111/j.1600-0447.2005. rtype=abstract OO711X 0540 Weiss, M., Safren, S. a, Solanto, M.V., Hechtman, 0554 Bell, V., Halligan, P. W., & Ellis, H. D. (2006). L., Rostain, A. L., Ramsay, J. R., & Murray, C. (2008). Explaining delusions: a cognitive perspective. Trends in Research forum on psychological treatment of adults with cognitive sciences, 10(5), 219-26. doi:10.1016/j.tics.2006. ADHD. Journal of attention disorders, 11(6), 642-51. doi: O3.004 10.1177/1087054708315063 0555. Bentall, R. P. Fernyhough, C., Morrison, A. P. (0541. Whyte, J. (2010). Pharmacological treatment of Lewis, S., & Corcoran, R. (2007). Prospects for a cogni cognitive and behavioural sequele of traumatic brain tive-developmental account of psychotic experiences. The US 2014/0142140 A1 May 22, 2014

British journal of clinical psychology/the British Psycho with schizophrenia. Schizophrenia research, 69(1), 7-14. logical Society, 46(Pt 2), 155-73. doi:10.1348/ doi:10.1016/SO920-9964(03)00069-0 O14466506X 123011 0569 Committee on Child Abuse and Neglect. (2001). 0556. Betancur, C. (2011). Etiological heterogeneity in Shaken Baby Syndrome: Rotational Cranial Injuries Tech autism spectrum disorders: more than 100 genetic and nical Report. PEDIATRICS, 108(1), 206-210. doi:10. genomic disorders and still counting. Brain research, 1542/peds. 108.1.206 1380, 42-77. doi:10.1016/j.brainres.2010.11.078 (0570 Costa, E., & Guidotti, A. (1996). Benzodiazepines 0557. Biederman, J., Faraone, S.V., Monuteaux, M. C., & on trial: a research strategy for their rehabilitation. Trends Biederman, J., Faraone, S. V., & Monuteaux, M. (2002). in pharmacological sciences, 17(5), 192-200. Retrieved Differential effect of environmental adversity by gender: from http://www.ncbi.nlm.nih.gov/pubmed/8669 126 Rutter's index of adversity in a sample of boys and girls (0571 Coyle, J.T., Tsai, G., & Goff, D. (2003). Converging with and without ADHD. American Journal of Psychiatry, evidence of NMDA receptor hypofunction in the patho 159(9), 1556-1563. American Psychiatric Assn. doi:10. physiology of schizophrenia. Annals of the New York Acad 1176/appi.ajp. 159.9.1556 emy of Sciences, 1003,318-27. Retrieved from http://www. 0558 Blissitt, P. A. (2006a). Care of the critically ill incbi.nlm.nih.gov/pubmed/14684455 patient with penetrating head injury. Critical care nursing 0572 Cummings, J. L. (1993). Frontal-subcortical cir clinics of North America, 18(3), 321-32. doi:10.1016/j. cuits and human behavior. Archives of neurology, 50(8), ccel1.2006.05.006 873-80. Retrieved from http://www.ncbi.nlm.nih.gov/ 0559 Blissitt, P. A. (2006b). Care of the critically ill pubmed/8352676 patient with penetrating head injury. Critical care nursing (0573 Davids, E., K is, B., Specka, M., & Gastpar, M. clinics of North America, 18(3), 321-32. doi:10.1016/j. (2006). A pilot clinical trial of oxcarbazepine in adults with ccel1.2006.05.006 attention-deficit hyperactivity disorder: Progress in neu 0560 Borg, E., & Counter, S.A. (1989). The middle-ear ropsychopharmacology biological psychiatry (Vol. 30, pp. muscles. Scientific American, 261 (2), 74-80. Retrieved 1033-1038). from http://www.ncbi.nlm.nih.gov/pubmed/2667133 (0574 Demb, J. B., Boynton, G. M., Best, M., & Heeger, D. 0561 Brady, K., Pearlstein, T., Asnis, G. M., Baker, D., J. (1998). Psychophysical evidence for a magnocellular Rothbaum, B., Sikes, C. R., & Farfel, G. M. (2000). Effi pathway deficit in dyslexia. Vision research, 38(11), 1555 cacy and safety of Sertraline treatment of posttraumatic 9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ stress disorder: a randomized controlled trial. JAMA: the 9.747491 journal of the American Medical Association, 283 (14), 0575 Erdmann, J. (2011). Broad collaborations bring new 1837-44. Retrieved from http://www.ncbi.nlm.nih.gov/ energy to autism therapeutics. Chemistry & biology, 18(2), pubmed/10770145 142-3. doi:10.1016/j.chembiol.2011.02.006 0562 Bramlett, H. M., & Dietrich, W. D. (2007). Progres 0576 Faden, A., Demediuk, P., Panter, S., & Vink, R. sive damage after brain and spinal cord injury: patho (1989). The role of excitatory amino acids and NMDA mechanisms and treatment strategies. Progress in brain receptors in traumatic brain injury. Science, 244(4906), research, 161, 125-41. doi:10.1016/S0079-6123(06) 798-800. doi:10.1126/science.2567056 61009-1 (0577. Faraone, S.V., Biederman, J., Spencer, T., Mick, E., 0563) Brekke, J., Kay, D. D., Lee, K. S., & Green, M. F. Murray, K., Petty, C., Adamson, J. J., et al. (2006). Diag (2005). Biosocial pathways to functional outcome in nosing adult attention deficit hyperactivity disorder: are schizophrenia. Schizophrenia Research, 80(2-3), 213-225. late onset and subthreshold diagnoses valid? The American Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ journal of psychiatry, 163(10), 1720-9: quiz, 1859. doi:10. 16137859 1176/applajp. 163.10.1720 0564 Bremner, J. D., Mletzko, T., Welter, S., Quinn, S., (0578. Forde, I., Holloway, J., Healy, O., & Brosnan, J. Williams, C., Brummer, M., Siddiq, S., et al. (2005). (2011). A dyadic analysis of the effects of setting and Effects of phenyloin on memory, cognition and brainstruc communication partner on elicited and spontaneous com ture in post-traumatic stress disorder: a pilot study. Journal munication of children with Autism Spectrum Disorder of psychopharmacology (Oxford, England), 19(2), 159-65. and typically developing children. Research in Autism doi:10.1177/O269881 105048996 Spectrum Disorders, 5(4), 1471-1478. 0565 Buckley, P. F., Miller, B.J., Lehrer, D.S., & Castle, (0579. Freeman, D., Garety, P. A., Kuipers, E., Fowler, D., D.J. (2009). Psychiatric comorbidities and schizophrenia. Bebbington, P. E., & Dunn, G. (2007). Acting on persecu Schizophrenia bulletin, 35(2), 383-402. doi:10.1093/sch tory delusions: the importance of safety seeking. Behav bulfsbn 135 iour research and therapy, 45(1), 89-99. doi:10.1016/j. 0566 Busch, R. M., McBride, A., Curtiss, G., & Vander brat.2006.01.014 ploeg, R. D. (2005). The components of executive func 0580 Gomot, M., & Wicker, B. (2012). A challenging, tioning in traumatic brain injury. Journal of clinical and unpredictable world for people with Autism Spectrum Dis experimental neuropsychology, 27(8), 1022-32. doi:10. order. International journal of psychophysiology: official 1080/13803390490919263 journal of the International Organization of Psychophysi 0567 Cienfuegos, A., March, L., Shelley, A. M., & Javitt, ology, 83(2), 240-7. doi:10.1016/j.ijpsycho.2011.09.017 D.C. (1999). Impaired categorical perception of synthetic 0581 Granacher, R. P. (2007). Traumatic Brain Injury: speech Sounds in Schizophrenia. Biological psychiatry, Methods for Clinical and Forensic Neuropsychiatric 45(1), 82-8. Retrieved from http://www.ncbi.nlm.nih.gov/ Assessment (Google eBook) (p. 560). CRC Press. pubmed/98.94579 0582 Green, M. F. Kern, R. S., Braff, D. L., & Mintz, J. 0568 Cohen, A. S., & Docherty, N. M. (2004). Affective (2000). Neurocognitive deficits and functional outcome in reactivity of speech and emotional experience in patients schizophrenia: are we measuring the “right stuff? Schizo US 2014/0142140 A1 May 22, 2014 34

phrenia bulletin, 26(1), 119-36. Retrieved from http:// 0596 Kessler, Ronald C, Adler, L., Barkley, R., Bieder www.ncbi.nlm.nih.gov/pubmed/10755673 man, J., Conners, C. K., Demler, O., Faraone, S.V., et al. 0583. Green, Michael F. (2006). Cognitive impairment (2006). The prevalence and correlates of adult ADHD in and functional outcome in Schizophrenia and bipolar dis the United States: results from the National Comorbidity order. The Journal of clinical psychiatry, 67(10), e12. Survey Replication. The American journal of psychiatry, Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 163(4), 716-23. doi:10.1176/appl.a.p. 1634.716 17107235 0597 Kim, E. (2002). Agitation, aggression, and disinhi 0584 Guastella, A. J., Mitchell, P. B., & Dadds, M. R. bition syndromes after traumatic brain injury. NeuroReha (2008). Oxytocin increases gaze to the eye region of human bilitation, 17(4), 297-310. Retrieved from http://www. faces. Biological psychiatry, 63(1), 3-5. doi:10.1016/j.bi incbi.nlm.nih.gov/pubmed/12547978 opsych.2007.06.026 0598. Kneisl, C. R., & Trigoboff, E. (2008). Contempo 0585 Hardman, J. M., & Manoukian, A. (2002). Pathol rary Psychiatric-Mental Health Nursing (2nd Edition) (p. ogy of head trauma. Neuroimaging clinics of North 1024). Prentice Hall. Retrieved from http://www.amazon. America, 12(2), 175-87. vii. Retrieved from http://www. com/Contemporary-Psychiatric-Mental-Health-Nursing neuroimaging...theclinics.com/article/S1052-5149(02) Edition/dp/013243489X 00009-6/fulltext 0599 Konradi, C., & Heckers, S. (2003). Molecular 0586 Hashimoto, T., Volk, D. W. Eggan, S. M., Mirnics, aspects of glutamate dysregulation: implications for K., Pierri, J. N., Sun, Z. Sampson, A.R., et al. (2003). Gene Schizophrenia and its treatment. Pharmacology & thera expression deficits in a subclass of GABA neurons in the peutics, 97(2), 153-79. Retrieved from http://www.ncbi. prefrontal cortex of subjects with schizophrenia. The Jour nlm.nih.gov/pubmed/12559388 nal of neuroscience: the official journal of the Society for 0600 Kraus, M. F., Susmaras, T., Caughlin, B. P. Walker, Neuroscience, 23(15), 6315-26. Retrieved from http:// C.J., Sweeney, J. A., & Little, D. M. (2007). White matter www.ncbi.nlm.nih.gov/pubmed/12867516 integrity and cognition in chronic traumatic brain injury: a 0587 Heimberg, C., Gur, R. E., Erwin, R. J., Shtasel, D. diffusion tensor imaging study. Brain. a journal of neurol L., & Gur, R. C. (1992). Facial emotion discrimination: III. ogy, 130(Pt 10), 2508-19. doi:10.1093/brain?awm216 Behavioral findings in schizophrenia. Psychiatry research, 0601 Kuipers, E., Garety, P., Fowler, D., Freeman, D., 42(3), 253-65. Retrieved from http://www.ncbi.nlm.nih. Dunn, G., & Bebbington, P. (2006). Cognitive, emotional, gov/pubmed/1496057 and social processes in psychosis: refining cognitive 0588 Horan, W. P., & Blanchard, J.J. (2003). Emotional responses to psychosocial stress in Schizophrenia: the role behavioral therapy for persistent positive symptoms. of individual differences in affective traits and coping. Schizophrenia bulletin, 32 Suppl 1, S24-31. doi:10.1093/ Schizophrenia research, 60(2-3), 271-83. Retrieved from Schbulfsb1014 http://www.ncbi.nlm.nih.gov/pubmed/12591589 0602 Kumar, R. Husain, M., Gupta, R. K., Hasan, K. M., 0589 Insel, T. R. (2010). Rethinking schizophrenia. Haris, M., Agarwal, A. K., Pandey, C. M., et al. (2009). Nature, 468(7321), 187-93. Nature Publishing Group. doi: Serial changes in the white matter diffusion tensor imaging 10.1038/nature09552 metrics in moderate traumatic brain injury and correlation 0590 Jackson, J. H. (1873). ON THE ANATOMICAL & with neuro-cognitive function. Journal of neurotrauma, PHYSIOLOGICAL LOCALISATION OF MOVE 26(4), 481-95. doi:10.1089/neu.2008.0461 MENTS IN THE BRAIN. The Lancet, 101 (2581), 232 0603 Kurtz, M. M. (2005). Neurocognitive impairment 235. doi:10.1016/50140-6736(02)63385-9 across the lifespan in Schizophrenia: an update. Schizo 0591 Javitt, DC, Doneshka, P., Grochowski, S., & Ritter, phrenia research, 74(1), 15-26. doi:10.1016/j.schres.2004. W. (1995). Impaired mismatch negativity generation 07.005 reflects widespread dysfunction of working memory in 0604 Kéri, S., Kiss, I., & Kelemen, O. (2009). Sharing schizophrenia. Archives of general psychiatry, 52(7), 550 secrets: oxytocin and trust in Schizophrenia. Social neuro 8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ science, 4(4), 287-93. doi:10.1080/17470910802319710 7598.631 0605 Lahti, A. C., Weiler, M.A., Tamara Michaelidis, B. 0592 Javitt, Daniel C. Shelley, A.-M., Silipo, G., & Lie A., Parwani, A., & Tamminga, C. A. (2001). Effects of berman, J. A. (2000). Deficits in Auditory and Visual Con ketamine in normal and Schizophrenic Volunteers. Neurop text-Dependent Processing in Schizophrenia. ARCH GEN sychopharmacology: official publication of the American PSYCHIATRY 57, 1131-1137. College of Neuropsychopharmacology, 25(4), 455-67. doi: 0593 Jones, H. M., & Pilowsky, L. S. (2002). Dopamine 10.1016/50893-133X(01)00243-3 and antipsychotic drug action revisited. The British journal 0606 Lai, J., Porreca, F., Hunter, J. C., & Gold, M. S. of psychiatry: the journal of mental science, 181, 271-5. (2004). Voltage-gated Sodium channels and hyperalgesia. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ Annual review of pharmacology and toxicology, 44, 371 1235.665O 97. doi:10.1146/annurev.pharmtox.44. 101802.121627 0594) Kadhim, H. J., Duchateau, J., & Sebire, G. (2008). 0607 Laruelle, M., Abi-Dargham, A., van Dyck, C. H., Cytokines and brain injury: invited review. Journal of Gil, R., D'Souza, C. D., Erdos, J., McCance, E., et al. intensive care medicine, 23(4), 236-49. doi:10.1177/ (1996). Single photon emission computerized tomography O885O666.083 18458 imaging of amphetamine-induced dopamine release in 0595 Kessler, RC, Sonnega, A., Bromet, E., Hughes, M., drug-free schizophrenic Subjects. Proceedings of the & Nelson, C.B. (1995). Posttraumatic stress disorder in the National Academy of Sciences of the United States of National Comorbidity Survey. Archives of general psy America, 93(17), 9235-40. Retrieved from http://www. chiatry, 52(12), 1048-60. Retrieved from http://www.ncbi. pubmedcentral.nih.gov/articlerender. nlm.nih.gov/pubmed/7492257 fcgi?artid=38625&tool-pmcentrez&render type-abstract US 2014/0142140 A1 May 22, 2014

0608 Latalova, K., Prasko, J., Diveky, T., & Velartova, H. 0621 Morrison, A. L., King, T. M., Korell, M. A. Smi (2011). Cognitive impairment in bipolar disorder. Bio alek, J. E., & Troncoso, J. C. (1998). Acceleration-decel medical Papers, 155(1), 19-26. doi:10.5507/bp.155.2011. eration injuries to the brain in blunt force trauma. The OO3 American journal of forensic medicine and pathology, 0609 Lewis, D. a, Volk, D. W., & Hashimoto, T. (2004). 19(2), 109-12. Retrieved from http://www.ncbi.nlm.nih. Selective alterations in prefrontal cortical GABA neu gov/pubmed/9662103 rotransmission in Schizophrenia: a novel target for the 0622 Mula, M., & Trimble, M. R. (2009). Antiepileptic treatment of working memory dysfunction. Psychophar drug-induced cognitive adverse effects: potential mecha macology, 174(1), 143-50. doi:10.1007/s00213-003 nisms and contributing factors. CNS drugs, 23(2), 121-37. 1673-X Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 0610 Lux, W. E. (2007). A neuropsychiatric perspective 19173372 on traumatic brain injury. The Journal of Rehabilitation 0623 Murphy, K. R., & Barkley, R. A. (1996). Prevalence Research and Development, 44(7), 951-962. doi:10.1682/ of DSM-IV symptoms of ADHD in adult licensed drivers: JRRD2007.O1.OOO9 Implications for clinical diagnosis. Journal of Attention 0611 Maas, A.I.R., Stocchetti, N., & Bullock, R. (2008). Disorders, 1(3), 147-161. Sage Publications. doi:10.1177/ Moderate and severe traumatic brain injury in adults. Lan 1087054796OO1 OO303 cet neurology, 7(8), 728-41. doi:10.1016/S1474-4422(08) 0624 Müller, R.-A. (2007). The study of autism as a dis 701 64-9 tributed disorder. Mental retardation and developmental 0612 Manuscript, A., Revheim, N., Butler, P. D., disabilities research reviews, 13(1), 85-95. doi:10.1002/ Schechter, I., Jalbrzikowski, M., Silipo, G., & Javitt, D.C. mrdd.20141 (2006). Reading impairment and visual processing deficits 0625 NINDA Traumatic Brain Injury Information Page. in schizophrenia. Schizophrenia research, 87(1-3), 238-45. (2008). National Institute of Neurological Disorders and doi:10.1016/j.schres.2006.06.022 Stroke. Retrieved from http://www.ninds.nih.gov/disor 0613 Matson, J. L., Kozlowski, A. M., Worley, J. A., derS/tbi/tbi.htm Shoemaker, M. E., Sipes, M., & Horovitz, M. (2011). What 0626. Nahum, A. M., & Melvin, J. (2001). Accidental is the evidence for environmental causes of challenging Injury. Biomechanics and Prevention (Google eBook) behaviors in persons with intellectual disabilities and (Vol. 2001, p. 637). Springer. autism spectrum disorders? Research in developmental 0627 Neurotrauma: New Insights Into Pathology and disabilities, 32(2), 693-8. doi:10.1016/j.ridd.2010.11.012 Treatment (Google eBook). (2007). (p. 443). Elsevier. 0614 Mattson, A.J., & Levin, H. S. (1990a). Frontal lobe 0628 Noggle, C. A. (2011). The Encyclopedia of Neurop dysfunction following closed head injury. A review of the sychological Disorders (p. 804). Springer Publishing literature. The Journal of nervous and mental disease, 178 Company. Retrieved from http://books.google.com/ (5), 282-91. Retrieved from http://www.ncbi.nlm.nih.gov/ books?id=Q30 QeaGVLYC&pgis=1 pubmed/2187053 0629 Oblak A, Gibbs T.T. & Blatt G.J. (2009). Decreased 0615 Mattson, A.J., & Levin, H. S. (1990b). Frontal lobe GABAA receptors and benzodiazepine binding sites in the dysfunction following closed head injury. A review of the anterior cingulate cortex in autism. Autism Research, 204), literature. The Journal of nervous and mental disease, 178 205-219. doi:10.1002/aur.88. Decreased (5), 282-91. Retrieved from http://www.ncbi.nlm.nih.gov/ 0630 Ommaya, A. K., & Gennarelli, T. A. (1974). Cere pubmed/2187053 bral concussion and traumatic unconsciousness. Correla 0616) McCrea, M.A. (2007). Mild Traumatic Brain Injury tion of experimental and clinical observations of blunt head and Postconcussion Syndrome. The New Evidence Base for injuries. Brain: a journal of neurology, 97(4), 633-54. Diagnosis and Treatment (Oxford Workshop Series: Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ American Academy of Clinical Neuropsychology) (p. 224). 4215541 Oxford University Press, USA. Retrieved from http:// 0631 Picchioni, M. M., & Murray, R. M. (2007). Schizo www.amazon.com/Traumatic-Brain-Injury-Postconcus phrenia. BMJ (Clinical research ed.), 335(7610), 91-5. sion-Syndrome/dp/0195328299 doi:10.1136/bmj.39227.616447.BE 0617 McDonald, S., Flanagan, S. Rollins, J., & Kinch, J. 0632 Poirier, M. P. (2003). Concussions: assessment, (2003). TASIT: A new clinical tool for assessing social management, and recommendations for return to activity. perception after traumatic braininjury. TheJournal of head Clinical Pediatric Emergency Medicine, 4(3), 179-185. trauma rehabilitation, 18(3), 219-38. Retrieved from doi:10.1016/S1522-8401(03)00061-2 http://www.ncbi.nlm.nih.gov/pubmed/128021.65 0633 Ponsford, J., Draper, K.,& Schönberger, M. (2008). 0618. McNab, F., & Klingberg, T. (2008). Prefrontal cor Functional outcome 10 years after traumatic brain injury: tex and basal ganglia control access to working memory. its relationship with demographic, injury severity, and cog Nature neuroscience, 11(1), 103-7. doi:10.1038/nn2024 nitive and emotional status. Journal of the International 0619. Mohr, J. P. Weiss, G. H., Caveness, W. F., Dillon, J. Neuropsychological Society. JINS, 14(2), 233-42. doi:10. D., Kistler, J. P., Meirowsky, A. M., & Rish, B. L. (1980). 101.7/S135561 7708080272 Language and motor disorders after penetrating head 0634 Porges, S.W. (1998). Love: an emergent property of injury in Viet Nam. Neurology, 30(12), 1273-9. Retrieved the mammalian autonomic nervous system. Psycho from http://www.ncbi.nlm.nih.gov/pubmed/71928.08 neuroendocrinology, 23(8), 837-61. Retrieved from http:// 0620. Morris, R. W., Weickert, C. S., & Loughland, C. M. www.ncbi.nlm.nih.gov/pubmed/9924740 (2009). Emotional face processing in schizophrenia. Cur 0635 Porges, S.W. (2001). The polyvagal theory: phylo rent opinion in psychiatry, 22(2), 140-6. doi:10.1097/ genetic Substrates of a Social nervous system. International YCO.ObO13e328324f&95 journal of psychophysiology: official journal of the Inter US 2014/0142140 A1 May 22, 2014 36

national Organization of Psychophysiology, 42(2), 123 negative schematic beliefs and delusions and hallucina 46. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ tions. Schizophrenia research, 86(1-3), 181-8. doi:10. 11587772 1016/j.schres.2006.06.018 0636 Porges, S.W. (2003a). The Polyvagal Theory: phy 0650 Smith, D. H. Meaney, D. F., & Shull, W. H. (1989). logenetic contributions to Social behavior. Physiology & Diffuse axonal injury in head trauma. The Journal of head behavior; 79(3), 503-13. Retrieved from http://www.ncbi. trauma rehabilitation, 18(4), 307-16. Retrieved from nlm.nih.gov/pubmed/12954445 http://www.ncbi.nlm.nih.gov/pubmed/16222 127 0637 Porges, S. W. (2003b). Social engagement and 0651 Smith, T., Weston, C., & Lieberman, J. (2010). attachment: a phylogenetic perspective. Annals of the New Schizophrenia (maintenance treatment). American family York Academy of Sciences, 1008, 31-47. Retrieved from physician, 82(4), 338-9. Retrieved from http://www.ncbi. http://www.ncbi.nlm.nih.gov/pubmed/14998870 nlm.nih.gov/pubmed/20704164 0638 Porges, S. W. (2007). The polyvagal perspective. 0652 Solomon, M., Ozonoff, S.J., Ursu, S., Ravizza, S., Biological psychology, 74(2), 116-43. doi:10.1016/j.biop Cummings, N., Ly, S., & Carter, C. S. (2009). The neural sycho.2006.06.009 Substrates of cognitive control deficits in autism spectrum 0639 Porges, S. W. (2009). The polyvagal theory: new disorders. Neuropsychologia, 47(12), 2515-26. doi:10. insights into adaptive reactions of the autonomic nervous 1016/j.neuropsychologia. 2009.04.019 system. Cleveland Clinic journal of medicine, 76 Suppl 0653 Tager-Flusberg, H. (2010). The origins of social 2(April), S86-90. doi:10.3949/ccjm.76.s2.17 impairments in autism spectrum disorder: Studies of (0640 Povlishock, J.T. (2008). The classification of trau infants at risk. Neural networks: the official journal of the matic brain injury (TBI) for targeted therapies. Journal of International Neural Network Society, 23(8-9), 1072-6. neurotrauma, 25(7), 717-8. doi:10.1089/neu.2008.9964 doi:10.1016/j.neunet.2010.07.008 (0641) Professor, A. C. P. S. M. M. Frcp. F. & E. (2002). 0654 Talcott JB, Hansen PC, Willis-Owen C. McKinnell Symptoms in the Mind: An Introduction to Descriptive I W. Richardson A. J. S. J. (1998). Visual magnocellular Psychopathology (p. 430). Saunders Ltd. Retrieved from impairment in adult developmental dyslexics. Neuro-Oph http://www.amazon.co.uk/Symptoms-Mind-Introduction thalmology, 20, 187-201. Descriptive-Psychopathology/dp/0702026271 0655 Tallal, P., Merzenich, M., Miller, S., & Jenkins, W. 0642 Reichenberg, A. (2005, January). Cognitive impair (1998). Language learning impairment: integrating ment as a risk factor for psychosis. Dialogues in clinical research and remediation. Scandinavian journal of psy neuroscience. Retrieved from http://www.ncbi.nlm.nih. chology, 39(3), 197-9. Retrieved from http://www.ncbi. gov/pubmed/21946.140 nlm.nih.gov/pubmed/98.00537 (0643 Ridder, W. H., Borsting, E., Cooper, M., McNeel, 0656 Taylor, J. J. (1958). Selected Writings of John B., & Huang, E. (1997). Not all dyslexics are created equal. Hughlings Jackson. (J.J. Taylor, Ed.) (pp. 45-118). Lon Optometry and vision science: official publication of the don: Staples Press. American Academy of Optometry, 74(2), 99-104. 0657 Textbook of Traumatic Brain Injury. (2004). (p. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 792). American Psychiatric Publishing, Inc. Retrieved 90973.26 from http://www.amazon.com/Textbook-Traumatic-In 0644 Romani, A., Conte, S., Callieco, R., Bergamaschi, jury-Jonathan-Silver/dp/1585621056 R., Versino, M., Lanzi, G., Zambrino, C. A., et al. (2001). 0658. The Boundaries of Consciousness: Neurobiology Visual evoked potential abnormalities in dyslexic children. And Neuropathology (Google eBook). (2006). (p. 585). Functional neurology, 16(3), 219-29. Retrieved from Elsevier. Retrieved from http://books.google.com/ http://www.ncbi.nlm.nih.gov/pubmed/11769867 books?id=YHGacGKyVbYC&pgis=1 (0645 Rubenstein, J. L. R., & Merzenich, M. M. (2003). 0659. The Practice of Forensic Neuropsychology. Meet Model of autism: increased ratio of excitation/inhibition in ing Challenges in the Courtroom (Critical Issues in Neu key neural systems. Genes, brain, and behavior, 205), 255 ropsychology). (1996). (p. 240). Springer. 67. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 0660 Tucker, P. Zaninelli, R., Yehuda, R., Ruggiero, L., 14606691 Dillingham, K., & Pitts, C. D. (2001). Paroxetine in the 0646 Russell, T. A., Green, M. J., Simpson, I., & Colth treatment of chronic posttraumatic stress disorder: results eart, M. (2008). Remediation of facial emotion perception of a placebo-controlled, flexible-dosage trial. The Journal in Schizophrenia: concomitant changes in visual attention. of clinical psychiatry, 62(11), 860-8. Retrieved from http:// Schizophrenia research, 103(1-3), 248-56. doi:10.1016/j. www.ncbi.nlm.nih.gov/pubmed/11775045 Schres.2008.04.033 0661 Tunnicliff, G. (1996). Basis of the antiseizure action 0647 Silver, H., Goodman, C., Knoll, G., & Isakov, V. of phenyloin. General pharmacology, 27(7), 1091-7. (2004). Brief emotion training improves recognition of Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ facial emotions in chronic schizophrenia. A pilot study. 8981053 Psychiatry research, 128(2), 147-54. doi:10.1016/j.psy 0662 Tuominen, H. J., Tihonen, J., & Wahlbeck, K. chres. 2004.06.002 (2005). Glutamatergic drugs for Schizophrenia: a system 0648 Silverstein, S. M., Schenkel, L. S., Valone, C., & atic review and meta-analysis. Schizophrenia research, Nuernberger, S.W. (1998). Cognitive deficits and psychi 72(2-3), 225-34. doi:10.1016/j.schres.2004.05.005 atric rehabilitation outcomes in schizophrenia. The Psychi 0663 Vicini, S., Alho, H., Costa, E., Mienville, J. M., atric quarterly, 69(3), 169-91. Retrieved from http://www. Santi, M. R., & Vaccarino, F. M. (1986). Modulation of incbi.nlm.nih.gov/pubmed/9682284 gamma-aminobutyric acid-mediated inhibitory synaptic (0649. Smith, B., Fowler, D. G., Freeman, D., Bebbington, currents in dissociated cortical cell cultures. Proceedings P. Bashforth, H., Garety, P., Dunn, G., et al. (2006). Emo of the National Academy of Sciences of the United States of tion and psychosis: links between depression, self-esteem, America, 83(23), 9269-73. Retrieved from http://www. US 2014/0142140 A1 May 22, 2014 37

pubmedcentral.nih.gov/articlerender. (2007). Mental disorders among persons with chronic back fegi?artid=387117&tool-pmcentrez&rende or neck pain: Results from the world mental health surveys. rtype=abstract Pain, 129, 332-342. 0664 Weiss, M., Safren, S. a, Solanto, M.V., Hechtman, 0678 Lai, J., Porreca, F., Hunter, J. C., & Gold, M. S. L., Rostain, A. L., Ramsay, J. R., & Murray, C. (2008). (2004). Voltage gated Sodium channels and hyperalgesia. Research forum on psychological treatment of adults with Annual Review of Pharmacology and Toxicology, 44, 371 ADHD. Journal of attention disorders, 11(6), 642-51. doi: 397. 10.1177/1087054708315063 0679 Rogers, B. A. Diagnosis and management of degen 0665 Whyte, J. (2010). Pharmacological treatment of erative neck pain clinical practice. (2010). British Jour cognitive and behavioural sequele of traumatic brain nal of Hospital Medicine, 71, 137-142. injury: practicing in the absence of strong evidence. EURJ 0680 Townsend, C. O., Sletten, C. D., Bruce, B. K., PHYS REHABILMED, 46(4), 557-562. Rome, J. D., Luedtke, C. A., & Hodgson, J. E. (2005). 0666 Willcutt, E. G., & Pennington, B. F. (2000). Comor Physical and emotional functioning of adult patients with bidity of reading disability and attention-deficit/hyperac chronic abdominal pain: Comparison with patients with chronic back pain. The Journal of Pain, 6, 75-83. tivity disorder: differences by gender and subtype. Journal 0681 Von Korff, M., Crane, P., Lane, M., Miglioretti, D. of Learning Disabilities, 33(2), 179-191. doi:10.1177/ L., Simon, G., Saunders, K., Stang, P., Brandenburg, & OO222 194OOO33OO2O6 Kessler, R. (2005). Chronic spinal pain and physical-men 0667 Williams, C., & Wood, R. L. (2010). Alexithymia tal comorbidity in the United States: results from the and emotional empathy following traumatic brain injury. national comorbidity survey replication. Pain, 113, 331 Journal of clinical and experimental neuropsychology, 339. 32(3), 259-67. doi:10.1080/13803390902976940 0682 Von Korff, M., & Dunn, K. M. (2008). Chronic pain 0668 Wingo,9. A. P., Harvey,y P. D., & Baldessarini, R. J. reconsidered. Pain, 138, 267-276. (2009). Neurocognitive impairment in bipolar disorder 0683 Young Casey, C., Greenberg, M.A., Nicassio, P.M., patients: functional implications. Bipolar disorders, 11(2), Harpin, R. N., & Hubbard, D. (2008). Transition from 113-25. doi:10.111141399-5618.2009.00665.X acute to chronic pain and disability: A model including 0669 Zhang, L.I., Bao, S., & Merzenich, M. M. (2001). cognitive, affective and trauma factors. Pain, 134, 69-79. Persistent and specific influences of early acoustic environ 0684. The following examples are included to demon ments on primary auditory cortex. Nature neuroscience, strate preferred embodiments of the invention. It should be 4(11), 1123-30. doi:10.1038/nn745 appreciated by those of skill in the art that the techniques 0670 van Os, J., & Kapur, S. (2009). Schizophrenia. Lan disclosed in the examples that follow represent techniques cet, 374(9690), 635-45. doi:10.1016/50140-6736(0.9) discovered by the inventor to function well in the practice of 6O995-8 the invention, and thus can be considered to constitute pre 0671 Burmeister, R., Hannay, H. J., Copeland, K., ferred modes for its practice. However, those of skill in the art Fletcher, J. M., Boudousquie, A & Dennis, M. (2005). should, in light of the present disclosure, appreciate that many Attention problems and executive functions in children changes can be made in the specific embodiments which are with spina bifida and hydrocephalus. Child Neuropsychol disclosed and still obtain a like or similar result without ogy, 11, 265-283. departing from the spirit and scope of the invention. 0685 So that the invention may be readily understood and 0672 Fletcher, J. M., & Brei, T. J. (2010). Introduction: put into practical effects, reference is made to the following Spina Bifida-A multidisciplinary perspective. Develop non-limiting examples: mental Disabilities Research Reviews, 16, 1-5. 0673 Holmbeck, G. N., Essner, B., Kelly, L., Friedman, EXAMPLE 1. D., DeLucia, C., Zebracki, K & Jandasek, B. (2010). Tra jectories of psychosocial adjustment in adolescents with Mild Cognitive Impairment (MCI) and Dementia spina bifida: a six year, four-wave longitudinal follow-up. Journal of Consulting and Clinical Psychology, 78, 511 0686 Patient 1A was an elderly woman with history of 525. impairment of cognitive function. Presumptive diagnosis of possible dementia of Alzheimers type. Commenced on 25 mg 0674) Holmbeck, G. N., Westhoven, V.C., Phillips, W. S., of Phenyloin with some improvement but benefit was lost on Bowers, R., Gruse, C., Nikolopoulos, T., Wienke Totura, C. continuation of this dose. Withdrawal of medication resulted M., & Davison, K. (2003). A multimethod, a multi-infor in transient improvement followed by a return to pre-pheny mant, and multidimensional perspective on psychosocial loin functioning. Assumption made that the regular dose of 25 adjustment in preadolescents with spina bifida. Journal of mg was too high. Phenyloin dose was gradually reduced until Consulting and Clinical Psychology, 71, 782-796. Sustained improvement obtained at a daily dose of 3 mg in 0675 Oakeshott, P., Hunt, G. M., Poulton, A., & Reid, F. divided doses orally with significant improvement. This ben (2009). Expectation of life and unexpected death in open efit has been sustained for over 24 months. spina bifida: a 40-year complete, non-selective, longitudi 0687 Patient 1B was an elderly retired male with a 7 year nal cohort study. Developmental Medicine & Child Neu history of Alzheimer's type dementia treated with the cho rology, 52, 749-753. linesterase inhibitor Donepezil. He experienced a significant 0676 Rose, B. M., & Holmbeck, G. N. (2007). Attention improvement in his subjective cognitive functioning and as and executive functions in adolescents with spina bifida. measured with the ADAS-cog (Alzheimer's Disease Assess Journal of Pediatric Psychology, 32,983-994. ment Scale-cognitive subscale). His cognitive function has 0677 Demyltenaere, K., Bruffaerts, R., Lee, S. Posada gradually deteriorated since this time. On commencement of Villa, J., Kovess, V., Angermeyer, M. C., Von Korff, M. a test dose of the phenyloin 1 mg Sublingual dose he demon US 2014/0142140 A1 May 22, 2014

strated a significant improvement in his ability to read a the words simultaneously. Patient also described a reduction standard text within 10 min of the dose. His reading was more in the instability or movement of the words on the page which fluent being better able to follow the meaning of the text. had always been experienced when reading. Also further There was also improvement in his Stroop Test particularly in commented on the Subjective improvement in vision, with an part three, the more cognitively demanding where his accu apparent improved depth perception. These beneficial effects racy improved from 50 to 90%. The following day after this were lost when the dose of the phenyloin was increased to 50 single dose he was more able to initiate activities which he ng. had not undertaken for several months beforehand and did not 0692 Patient 2C commenced on a trial of Ultra Low need the frequent rests during the day which he had been Dosephenyloin, 1 mg daily. Patient noted that her visual acu taking. ity had appeared to improve. Patient noticed greater contrast 0688. It is postulated that the use of a very low dose anti in the text when reading and this had reduced her dependency epileptic drug has enabled an improvement in cognitive pro upon spectacles which she had relied on formany years. As in cessing and higher executive functioning. The usually well previous examples these benefits were not sustained at a developed and Sophisticated ability to maintain social rela higher dose. Patient 2D had a history of learning difficulties tionships is one of the last systems to reach maturity in ado since childhood. The patient has been able to sustain employ lescence. It would seem therefore reasonable to expect this ment with considerable effort. Reading had always been system to be the most sensitive to any cognitive decline. If effortful and largely unrewarding. Patient had described dif treatment were available that could reverse or stabilise the ficulties tracking along the text being frequently distracted by decline, it would have a profound impact and benefit both for the lines above and below becoming lost on the page as well the individual’s mental health and independence, as well as a as having little recall or comprehension of what he had read. delay in the need for more intensive and costly residential On commencing a 0.5 mg dose of phenyloin, the patient care. The benefits seen in this clinical situation would not be described a significant improvement in his ability to read with expected from the normal and excepted use of an anti-epilep less effort, able to process and understand the text and noted tic drug, which normally acts as a general cerebral depressant a significant improvement in his ability to track the written or mood stabiliser and at a dose that would normally be text. expected to result in exacerbation of any cognitive impair 0693. The clinical improvement observed in both reading ment, in contrast to the compositions and methods of the and verbal communication have both relied on enhanced invention. effortless processing. This in turn enhances the understanding 0689. It has also been noted in other types of dementia for of the content of either forms of communication. In Social example in multiple Sclerosis there is a slowing of processing interactionifengagement does not occur the process becomes even before the dementia is evident. This can be measured exhausting and unrewarding, the same is true with writing or relatively early in the illness and the individual may be oth reading. The latter engagement can be conceptualised as erwise asymptomatic. It is hypothesised that as the inventor being able to establish the picture in one's mind of the story. has noted improvement in the processing of individuals with If this does not occur there is little benefit and thus a lack of MCI and dementia and with a low dose of the AEDs together motivation to read fiction, with the reader quickly becoming with or without a psychoStimulant may improve the cognitive fatigued, disengaged and disinterested. These two processes impairment associated with multiple Sclerosis and may also can be seen in association; parallel improvements in both enhance overall processing leading to improved psycho literacy and communication have been noted in the clinic social function. We have also noted that the clinical tool used in Some research studies to analyse processing speed in mul EXAMPLE 3 tiple sclerosis is the The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically Attention Deficit Hyperactivity Disorder assesses auditory information processing speed and flexibil 0694 Patient 3A: diagnosed with ADHD and generalised ity, we have used this tool experimentally in individuals with anxiety disorder. Treated for five years on a combination of a ADHD and cognitive impairment and demonstrated improve tricyclic antidepressant and dexamphetamine. Persistent ment following treatment with low-dose AEDs. symptoms of ADHD, in particular difficulties with organisa tion, selective attention, Sustained attention and ability to EXAMPLE 2 sustain social interaction without effort. Unsuccessful attempts at withdrawal of stimulant and antidepressant with Reading Disorder worsening of symptoms. 0690 Patient 2A, a middle-aged adult who commenced a 0695 Trial of phenyloin 30 mg capsule temporarily asso trial of ultra low dose phenyloin, 1 mg daily had noted that her ciated with improvement in clarity of thoughts and eye con visual acuity had appeared to improve. She noticed greater tact during conversation both when listening and speaking. contrast when reading. This had reduced her dependency Phenyloin withdrawn, this was associated with an initial upon spectacles which she had relied on for many years. As in improvement then later worsening to the pre-phenyloin func previous examples these benefits were not sustained at a tioning. Medication reintroduced at a lower dose again with higher dose. initial benefit that associated with rapid loss of efficacy. The 0691 Patient 2B, had a history of learning and social dif improvement on ceasing the phenyloin lasted up to 7 days ficulties. Following a 1 mg Sublingual dose of phenyloin, the before the subsequent deterioration was noted. Ultra low patient described improved ability to read with pseudo word doses of phenyloin were found to be most efficacious with a component of WAIT (Wechsler Individual Achievement test). dose of 0.1 mg daily. At this dose the phenyloin was associ Patient described an unexpected improvement in the clarity ated with the following improvements: and contrast of the words and letters, further commenting on 0696 greater attention to details the improvement in her ability to both see and comprehend 0697 sustained attention US 2014/0142140 A1 May 22, 2014 39

0698 less effortful listening during conversation ment which correlated to this lower but more efficacious 0699 improved self organisation and sequencing of therapeutic range. Finally the medication levels dropped Suf tasks ficiently for there to be no residual therapeutic benefit. 0700 less distracted and forgetful 0710 Since this initial trial of the sublingual dose it has 0701 subjective improvement in clarity of thought been repeated on many occasions the changes have been 0702) enhanced ability to ignore negative and intrusive consistent with the above hypothesis. Repeated audio and thoughts Video assessments of social interaction and of reading aloud (0703 less effortful reading standardised texts has provided additional clinical data to 0704 improved social engagement and enjoyment of confirm these findings. The assessments have also included conversation testing using measures of rapid automised naming using the developmental Eye Movement Test and the Stroop test. These EXAMPLE 4 have also been consistent with the improved cognitive func tioning. Both a neuropsychological and an occupational Acquired Brain Injury assessment have been consistent with the improvements on Two Cases Both in Middle-Aged Men: Ultra low phenyloin described above. (0705 1. Patient 4A had an 18 month history of closed Patient 4B: head injury following a fall. (0706 2. Patient 4B had a 10 year history of closed head 0711 Premorbidly a successful businessman, following injury following a motor vehicle accident the motor vehicle accident he became estranged from his family, he isolated himself and after many years obtained Patient 4A: part-time unskilled employment. He was initially com 0707. The patient had suffered no loss of consciousness at menced on a low dose of dexamphetamine with limited the time of injury. Following the injury, he experienced sig improvement in his concentration and attention. On a test nificant cognitive deficits and personality change. His com dose of a Sublingual dose 1 mg he noted a reduction in the munication had deteriorated and he had become Socially effort required for communication. He also spontaneously withdrawn. He was increasing reliant on his wife to provide commented about the apparent enhanced clarity of vision. He all Support. described the subjective visual experience of being betterable 0708. He developed repetitive motor tics and vocalisa to focus on the examiners face during the assessment instead tions. The Vocalizations he would experience as an increasing of being consistently distracted by the background of the internal desire to do these which he could not control. Only room. There was no previous history of ADHD either in when he was very distracted could he resist and he became childhood or in adult life. worse when he was fatigued. The motor tics consisted of 0712 Commenced on a trial of phenyloin initial dose of 3 repetitive tapping with his thumb against his fingers. These mg he described an unexpected and dramatic improvement in symptoms commenced soon after his accident. He was the ability to organise and undertake tasks. He was able the treated with a combination of pharmacotherapy without sig first time since the accident to focus on and follow conversa nificant benefit; he remained impaired and unable to cope in tion. Following the accident he was unable to read this was in Social situations. His coordination and ability to sequence contrast to his premorbid functioning where from childhood thoughts was impaired which contributed to his inability he had a read frequently and widely. Previously was unable to undertake simple activities or repairs at home. This was in retain information he was reading Sufficient for understand complete contrast to his premorbid functioning. He was a ing. Following commencement of the phenyloin he began gifted athlete and worked as a skilled manual worker. reading for the first time in 10 years both fiction and non 0709. He was initiated on a test dose of very low phenyloin fiction texts. He was also able to recall details of previous using a fragment of a commercially available tablet approxi conversations and information which had taken place prior to mately equivalent to less than 3 mg. This was dissolved in the the accident. For the intervening years he had no recollection mouth and absorbed through the buccal mucosa. He of these details and surprise both himself and his family about described a dramatic and unexpected improvement in his the depth and accuracy of his recall. This would appear to ability to focus, his repetitive chanting and hand movements Suggest an improvement or reduction in his retrograde ceased. He was more able to structure his conversation which memory loss. He was able to attend and participate in Social he was able to undertake with improved ability to sustain eye gatherings. This was effortless and enjoyable and was able to contact which he had not done since the accident had Sustain attention equivalent to that of his peers. Improvement occurred. The dose was increased and repeated the following is sufficient to begin to return to a similar level of functioning day on this occasion unlike on the first is there was no dra that he was able to prior to the accident. matic improvement. One the third day the same dose was 0713. It is clinically observed that the improvements repeated with a noticeable deterioration in his ability to focus observed in reading in the cases of acquired brain injury are and organize his thinking. Following this the phenyloin was possibly more significant than in other conditions where there ceased. Over the following next five days there was a gradual is a developmental disorder which may have contributed to improvement in his functioning to a level that he experienced the reading difficulty. We hypothesise that in the acquired after the first test dose followed by a deterioration to his brain injury the individual had an essentially normal reading pre-phenyloin functioning. The hypothesis was generated system prior to the injury. Whereas in a developmental disor that the initial dose was in the correct therapeutic range. der the origin of the reading difficulties may be more complex However, following the second and third dose the efficacy of and would have been present during the acquisition of read the medication was lost. It was possible following the reduc ing, therefore the deficit may have been compounded by the tion in the available phenyloin there was a transient improve lack of exposure to effortless reading. US 2014/0142140 A1 May 22, 2014 40

0714. In both cases the improvements have been sustained Patient 5e for over 12 months. The severe fatigue which used to be associated with any cognitive demand has decreased, but still 0720. An adult females noted that on commencement of can occur after demanding and Sustained concentration. On low dose phenyloin an improvement in her ability to accu occasions symptoms of irritability and sense of being over rately identify distances when playing lawn bowls. whelmed still occur. Although, these symptoms can be partly Patient 5f reversed by the administration of a further dose of ULP which can provide temporary relief. 0721. An adult noted that on commencement of low dose 0715. It is clinically observed that the improvements phenyloin improvement in visual judgement was also noted observed in reading in the cases of acquired brain injury are in a young man playing Soccer with an enhanced ability to possibly more significant than in other conditions where there judge distances and coordinate the kicking of a soccer ball. is a developmental disorder which may have contributed to This was also associated with a reduction in the distraction he the reading difficulty. We hypothesise that in the acquired usually experienced while playing soccer. He attributed this brain injury the individual had an essentially normal reading to being overwhelmed by the other players on the field which system prior to the injury. Whereas in a developmental disor reduced his ability to think clearly enough to play himself. der the origin of the reading difficulties may be more complex Whilst training alone he was able to develop reasonable ball and would have been present during the acquisition of read skills. Unfortunately these were lost when playing in a team ing, therefore the deficit may have been compounded by the situation. This was not dissimilar to the Social anxiety he lack of exposure to effortless reading. However, these are experienced, commonly describing the sense of being early observations and will require further investigation. watched by so many people on the Soccer field. On taking the Ultra low dose phenyloin he was more able to effortlessly EXAMPLE 5 focus on his own game and be aware of the others, both the opposition and his own team. Visual fatigue EXAMPLE 6 Patient 5a 0716 Adult male with a history of ADHD stabilised on a Autism and other Pervasive Development Disorders combination of a psychoStimulant and Sodium Valproate. 0722 Patient 6A: Adult, diagnosed in childhood with Phenyloin 4 mg was added to his treatment regime with a autism and ADHD. Along history of behavioural disturbance further improvement in his overall functioning. Generally felt with frequent episodes of violence despite treatment with more mentally alert and able to focus on tasks with less effort. high-dose antipsychotic medication. A single test dose of the Patient had previously been aware of deterioration in his Sublingual phenyloin 1 mg was administered with an imme vision towards the end of each day and he reported that his diate improvement noted in his ability to Socially interact and optometrist had confirmed that the symptoms were consistent Sustain limited conversation. Following this, a regular dose of with visual fatigue and recommended the use of spectacles. phenyloin was commenced at 4 mg. Sustained release daily. He unexpectedly reported that on the commencement of the This improvement was consistently noted both in the home phenyloin his visual fatigue no longer occurred and he was no environment and at the day respite centre where he attended. longer reliant on his glasses which he had been previously. The high-dose antipsychotic medication has been reduced without any associated loss of recent benefit. Following a Patient 5b withdrawal of the phenyloin there was a return of the behav 0717 Adult diagnosed with ADHD and stable on treat ioural disturbance which abated on recommencement ment with psychoStimulants. Noted a significant improve 0723 Patient 6B was an adult, diagnosed in childhood ment in function when therapy augmented with a very low with autism and ADHD. A history of behavioural disturbance dose of phenyloin, 2 mg daily. Previously always relied on and educational impairment. Initiated on 1 mg phenyloin glasses to read because of an astigmatism. He was Surprised daily. Gradually increased to 3 mg individed doses daily. The by an apparent improvement in his visual acuity when he commencement of ULDP was associated with sustained could unexpectedly complete a reading test without wearing improvement in communication and family relationships his corrective glasses. He was unable to describe similar together with a reduction in behavioural disturbance. These recent episodes consistent with an improvement in his visual Improvements were lost when either the phenyloin was at a acuity as this had not occurred previously. higher dose or withdrawn. 0724 Patient 6C was an adult, diagnosed in childhood Patient 5c with autism and ADHD with a history of behavioural distur bance and educational impairment. The patient was initiated 0718. Adult previously diagnosed with ADHD and no on 1 mg phenyloin daily which was gradually increased to 3 longer taking stimulant medication. Commenced on 1 mg mg in divided doses daily. The commencement of the ultra phenyloin and noticed an immediate and unexpected low dose phenyloin was associated with Sustained improve improvement in visual acuity whilst reading. ment in communication and family relationships together with a reduction in behavioural disturbance. These improve Patient 5d ments were lost when either a higher dose of phenyloin was 0719. Adult male, noted that his ability to undertake three administered or when medication was withdrawn. dimensional delicate work requiring both visual acuity and 0725 Patient 6D: Adult, diagnosed in childhood with depth perception improved on the commencement of ultra autism, ADHD and antisocial personality traits. Significant low dose phenyloin 2 mg. Although this dose beneficial 1 mg improvement in behaviour, Verbal and non-verbal communi associated with the most consistent improvement. cation with the introduction of 2 mg phenyloin daily. Patient US 2014/0142140 A1 May 22, 2014

C’s conversation became more appropriate and consistent cant psychosocial impairment. This has been considered in together with reported improvements in significant relation the diagnosis of Social Communication Disorder. The spec ships. No additional benefit on increased dose of 4 mg. trum impairments are not dissimilar to that identified with 0726 Patient 6E was an adult, diagnosed with communi ASD's but are of a lesser severity. Using this description we cation disorder and major depression. A significant improve have noted significant improvements in many patients dem ment in communication was observed on initiation of 50 mg onstrating these symptoms with the treatment with ultra low sodium valproate. The initial benefits were lost when medi dose phenyloin. cation was ceased. Following reintroduction with a dose of 25 0732 A new diagnostic category Social communication mg daily, a Sustained improvement in the ability to commu disorder, is likely to be included in the Diagnostic and Statis nicate with less effort and the absence of negative internal tical Manual of the American Psychiatric Association version dialogue and relentless preplanning of conversations were 5 (DSMV). We have noted in many cases improvements in observed. the symptoms which are likely to be included in this diagno 0727 Patient 6F was an adult with ASD. A significant S1S improvement in behaviour, Verbal and non-verbal communi 0733 A. Persistent difficulties in pragmatics or the cation was observed with the introduction of 50 mg sodium Social uses of Verbal and nonverbal communication in valproate daily. The patients conversation became more naturalistic contexts, which affects the development of appropriate and consistent and improvements in significant Social reciprocity and Social relationships that cannot be relationships were reported. A reduction in the reliance on explained by low abilities in the domains of word struc alcohol to alleviate anxiety in Social situations was observed. ture and grammar or general cognitive ability. Within three days, an increasing cognitive slowing, general 0734. Many patients demonstrating difficulties in the malaise and tiredness were observed. Sodium valproate was normal use of Verbal and non-verbal communication withdrawn and improvement was noted. Sodium valproate leading to clumsy and awkward interaction. These dose of 25 mg daily was successfully reintroduced. difficulties are improved by the use of low dose phe 0728 Patient 6G was as adult, diagnosed in childhood nyloin and other low dose antiepileptic medications with ASD. Patient exhibited chronic impairment with motor 0735 B. Persistent difficulties in the acquisition and use tics, repetitive behaviour and social withdrawal. Previous of spoken language, written language, and other modali improvement in communication and other symptoms of ASD ties of language (e.g., sign language) for narrative, on introduction of sodium valproate 50 mg daily were noted, expository and conversational discourse. Symptoms although the patient developed side-effects including low may affect comprehension, production, and awareness mood and irritability. Sodium valproate was withdrawn. at a discourse level individually or in any combination Reintroduction of sodium valproate 25 mg on alternate days that are likely to endure into adolescence and adulthood, was associated with a Sustained improvement in the commu although the symptoms, domains, and modalities nication, eye contact during dialogue, reduction in motor tics involved may shift with age. and greater Social engagement and independently motivated 0736 Spoken and written language is often very activity. effortful leading to fatigue and disengagement, these 0729. In addition to these individual examples we have impairments are specifically improved by the use of observed on multiple occasions similar improvements in low dose phenyloin and other low dose antiepileptic Social cognition, behaviour and empathy on the low dose of medications. phenyloin. This has also been associated with improvements 0737 C. Rule out Autism Spectrum Disorder. Autism in reading and verbal understanding. These benefits have spectrum disorder by definition encompasses pragmatic been Sustained in some situations for three years. Although communication problems, but also includes restricted, difficult to be objective, there seems to be good evidence of repetitive patterns of behavior, interests or activities as ongoing improvement. In other words these benefits do not part of the autism spectrum. Therefore, Autism Spec represent a stationary reflection of an enhanced ability to trum Disorder needs to be ruled out for Social Commu learn. Improvements in coordination, in fine and gross motor nication Disorder to be diagnosed. Social Communica control have been reported and improvement in gait which tion Disorder can occur as a primary impairment or frequently is a significant issue for individuals with autistic co-exist with disorders other than Autism Spectrum Dis disorders. order (e.g., Speech Disorders Learning Disorder, Intel 0730. A much higher dose of phenyloin has been used with lectual Disorders). good effect in patients we have treated with bipolar spectrum 0738. D. Symptoms must be present in early childhood disorders. Although uncertain of the precise mechanism of (but may not become fully manifest until speech, lan action, it would appear that individuals with autistic spectrum guage, or communication demands exceed limited disorders benefit from the Ultra Low Dose Phenyloin in con capacities). trast to those with a more affective illnesses. If the dose of 0739 These difficulties are long-term frequently dat phenyloin is increased above the Ultra low dose level in those ing back to childhood, there is on occasions evidence with bipolar spectrum disorders, a loss of efficacy is described of any environmental compensation although this fre together with a sensitivity of his which was not seen in those quently leads to a rigid coping strategies which can be with bipolar spectrum disorders. The increased sensitivity in seen as maladaptive in other situations. autistic spectrum disorders to psychotropic agents has been 0740 E. The low social communication abilities result observed previously with selective serotonin reuptake inhibi in functional limitations in effective communication, tOrS. Social participation, academic achievement, or occupa 0731. It is important to consider the diagnosis of ASD is a tional performance, alone or in any combination. spectrum disorder rather than a categorical condition. There 0741. These poor social communication difficulties are fore varying degrees of Social dysfunction can cause signifi spectrum conditions but are associated often with severe and US 2014/0142140 A1 May 22, 2014 42 disabling impairments and frequently are associated with EXAMPLE 9 psychiatric morbidities. The deficits which are characterised by these symptoms are often pervasive and disabling. PTSD Improvement in these areas of poor communication often (0750 Patient 9A: Two year history of PTSD & Major results in a significant recovery in Social academic and occu Depression, unable to work for nine months. Little consistent pational performance They may be associated with other improvement despite 15 months poly-psycho-pharmaco comorbidities result in considerable disability. With success therapy including antidepressants and antipsychotic medica ful treatment with the low dose antiepileptic medications tion. Eight months specialist psychiatric treatment including these impairments often quickly resolve leading to improve specific PTSD therapy program. Recently assessed as Global ments in overall psychosocial functioning. Assessment of Functioning (GAF) of 30. No history of pre morbid ASD or ADHD, possible mild reading difficulties. EXAMPLE 7 Commenced on ultra low dose phenyloin (ULDP) 2 mg daily and within 24 hours reported the following improvements: Schizophrenia (0751 Clarity of thoughts 0752 A return of his ability to sustain eye contact dur 0742 Patient 7A: Adult, initially diagnosed with schizo ing conversation which had been absent since the onset phrenia in adolescence. Long history of impairment with of his symptoms of PTSD predominant paranoid delusions controlled with antipsy 0753 Improved concentration chotic medication although still experiencing significant 0754) Able to control intrusive thoughts relapses despite consistent adherence to the pharmacotherapy (0755 Reduced cognitive fatigue regime. Significant social impairment, unable to Sustain 0756 Reduced hypervigilance and startle reflex employment and requires Support. Prominent negative symp 0757. More patient, confident and consistent in inter toms and Social deficits, unable to Sustain eye contact when personal interactions speaking. Speech slow, effortful and fatiguing. Patient com 0758. These changes confirmed by partner menced on 2 mg phenyloin daily; family and patient reported 0759 During treatment dose reduced to 1 mg and significant improvement in ability to communicate with less increased to 4 mg both resulting in a reduction in efficacy. Improvements have been maintained over three months now effort. Prosody and rate of speech both improved. actively initiating a return to work program. 0743 Patient 7B: Adult initially diagnosed with schizo 0760 Patient 9B: 40 year history of severe PTSD associ phrenia during adolescence, following many years of promi ated with severe re-experiencing phenomena, absence of any nent positive symptoms with severe behavioural disturbances family relationships and Social withdrawal, anger outbursts, and violence requiring periods of hospitalisation. Patient has chronic sleep disturbance exaggerated startle reflex and never been able to Sustain employment and requires signifi hypervigilance. Comorbid conditions including chronic cant Social Support to maintain functioning. Prominent major depression, alcohol dependence. Attended regular psy thought disorder and general Social disengagement. On ini chiatric treatment for in excess of five years. Treated with a tiation of 1 mg of Sublingual phenyloin significant improve combination of regular outpatient psychotherapy and phar ment in speech and ability to read aloud a standard text was macotherapy including antidepressants and antipsychotic noted. Following this, the patient is more able to initiate medications. Remained significantly impaired and the Symp activities such as spontaneously assisting repairs on motor toms in excess of those required to diagnose PTSD according vehicle. Able to Sustain and enjoy social interaction in a to DSM IV. Weight gain associated with antipsychotic medi sheltered workshop which had never occurred previously. cation. Trial of phenyloin 2 mg compounded capsule twice Positive effects abated when phenyloin withdrawn. daily, within one week the following improvements were reported: EXAMPLE 8 0761 Enhanced communication 0762. Thoughts were better paced making speech less effortful Bipolar Case 0763 Distressing and intrusive thoughts less intense and easier to dismiss 0744 Patient 8A: Adult with a diagnosis of bipolar mood 0764. Thoughts were clearer disorder with limited benefit on combination of antidepres 0765 Improved sleep with less awakenings and dis sant therapy and lithium carbonate, unable to work as a con tressing dreams. sequence of illness. Trial dose of phenyloin compounded 2 0766 Speaking described as less rushed with improved mg capsule resulted in a significant improvement in function capacity and reduction in the amount of Stuttering. this was confirmed by friends and family. This was described 0767 Reduced exaggerated startle reflex and hyper as the single most beneficial treatment in many years of Vigilance. pharmcotherapy. 0768. Overall described a 50% improvement on com 0745. The following were noted, mencement of the low dose phenyloin 0769 Patient 9C:40 year history of PTSD associated with 0746 enhanced organisation and planning chronic impairment in previous alcohol dependence. Previ 0747 reduced effort required for social interaction ous psychiatric admissions as a consequence of condition. Long-term antidepressant therapy together with intermittent 0748 enhanced clarity of thought use of antipsychotic medication. Trial of 3 mg phenyloin 0749 a sense of being psychologically more normal associated with initial improved ability to dismiss and ignore Improvements have enabled a return to part-time work. distressing, intrusive thoughts to mood Stability and concen US 2014/0142140 A1 May 22, 2014

tration. However, became irritable and experienced word rary relief. Narcotic analgesics had not produced Sustained finding difficulties. Over nine months dose gradually reduced improvement. The patient described intense pain character including periods of complete withdrawal which were asso ised by sharp stabbing pain, becoming worse on movement ciated with a return to his pre-phenyloin functioning includ together with chronic and unremitting headaches. Within 3 to ing a worsening of his symptoms of PTSD. The most stable 4 min of administration of a Sublingual dose of 1 mg pheny and efficacious dose was identified as phenyloin 0.5 mg daily. loin, the patient experienced a significant reduction in the (0770 Stable improvements included: intensity of the pain from 10/10(being the most severe) to 0771 reduction of intrusive and negative thoughts 5/10(manageable). The relief lasted for approximately 10 0772 Enhanced interpersonal communication min, during which time the patient also unexpectedly (0773) Reduced effort of reading described an enhancement in his vision, which was described 0774) Enhanced quality of sleep as being both brighter and clearer. Subsequently, there was a return of the more severe pain but not to the pre-dose level. A EXAMPLE 10 further Sublingual dose of phenyloin 1 mg was taken 15 mins after the first dose. A similar reduction in the severity of the Tardive Dyskinesia pain was noted. (0775 Patient 10A was an elderly man with a history of 0784 The improvement was characterised as being simi post-dramatic stress disorder treated with long-term antipsy lar to the relief he had experienced when undergoing a nerve chotic medication. He had over 12 months developed abnor block. Following the sublingual doses of phenyloin the mal movements consistent with symptoms of tardive dyskin patient, described an absence of the more chronic pain as well sia. He was given a test dose of 1 mg phenyloin and these as greater mobility in his movement and a reduction in the abnormal facial movements ceased. After a later withdraw of severity of the intense stabbing pain. Whilst the pain was still the phenyloin he was rechallenged with the same dose of evident he was more able to ignore and distract himself from phenyloin a similar benefit was observed and maintained on a the noxious experience. The control of the chronic pain was regular dose of the ULDP. maintained after the initial improvement on taking a daily dose of phenyloin 3 mg modified release capsule. A further EXAMPLE 11 acute improvement in the freedom of movement without pain was noted on taking an additional dose of Sublingual dose of Spina Bifida phenyloin 1 mg. (0776 Patient 11A presented with spina bifida, ADHD, EXAMPLE 13 learning difficulties and Social anxiety treated for many years on low dose methylphenidate. Throughout Schooling the Tinnitus patient required educational Support and demonstrated impairment in executive functioning and emotional dysregu 0785 Tinnitus is the perception of sound within the human lation. These difficulties contributed to poor social skills and ear in the absence of corresponding external Sound. Tinnitus emotional lability especially when attempting to communi is common; about 20% of people between 55 and 65 years old cate. On commencement of ultra low Sublingual dose pheny report symptoms on a general health questionnaire, and loin 1 mg there was a significant improvement in: 11.8% on more detailed tinnitus-specific questionnaires) 0777 Social interaction as observed during the consul 0786 The ability to control intrusive and unpleasant tation and reported in other situations. stimuli should be as automatic as possible enabling active 0778 Sustain conversation with less effort and greater attention to be focused on new and potentially more important engagement information. This habituation of repetitive noise from either (0779) Ability to actively contribute noted by extended internal, Such as tinnitus or external background noise family members. enables this process of discrimination to occur. If there are 0780 Ability to read aloud improved with enhanced impairments in the processing of information this can lead to prosody, pacing, speed and accuracy. an inability to selectively control these stimuli. Thus the 0781 Fine motor control and handwriting both perception of tinnitus can be overwhelming and distracting. described and reported by tutors We have noted benefits in individuals with tinnitus on com 0782. These improvements were sustained for over 12 mencement of low dose antiepileptic medications. This is months and were confirmed by tutors. A loss of efficacy was also frequently associated with improved social cognition. observed after the dose was increased to 2 mg. The optimal We hypothesise that the ability to discriminate and control the response was associated with 1.5 mg phenyloin daily in two relevant stimuli is associated with enhanced neuronal func divided doses. The improvements continued to improve over tion which may occur from the improved neuronal modula 12 months on a stable dose of the phenyloin and appeared to tion. reflect an improved retention of new learning and then build 1. An anti-epileptic agent for use in the treatment of a on this experience. This is possibly reflecting the normalising neurological disorder other than epilepsy characterised in that of the learning process by the ultra low dose phenyloin. the anti-epileptic agent is the sole active agent and that the daily dose of the anti-epileptic is less than 20% of the mini EXAMPLE 12 mum daily dose which is effective for mood stabilisation or treatment of epileptic symptoms. Chronic Pain 2. An anti-epileptic agent according to claim 1, wherein the 0783 Patient 8A presented with a 20 year history of daily dose is less than 2.5% of the minimum daily dose of the chronic neck pain following a traumatic injury. Multiple Sur anti-epileptic agent which is effective for mood stabilisation gical procedures and nerve blocks had provided only tempo or treatment of epileptic symptoms. US 2014/0142140 A1 May 22, 2014 44

3. A pharmaceutical composition comprising a Sub-thera erase inhibitor, wherein the daily dose of the anti-epileptic peutic dose of an anti-epileptic agent as the Sole active agent agent is less than 2.5% of the minimum daily dose which is within the composition, together with a pharmaceutically effective for mood stabilisation or the treatment of epileptic acceptable carrier, diluent and/or excipient, wherein the Sub symptoms. therapeutic dose is less than 20% of the minimum daily dose of the anti-epileptic agent which is effective for mood stabi 17. A pharmaceutical composition according to claim 10, lisation or treatment of epileptic symptoms. wherein the antiepileptic agent is selected from brivaracetam, 4. A pharmaceutical composition according to claim 3, carbamazepine, clobazam, clonazepam, ethoSuximide, fel wherein the composition is for use in the treatment of a bamate, gabapentin, lacosamide, lamotrigine, levetiracetam, neurological disorder other than epilepsy. oXcarbazepine, phenobarbital, phenyloin, pregabalin, primi 5. A pharmaceutical composition according to claim 3, done, retigabine, rufinamide, Safinamide, seletracetam, wherein the composition is adapted for transdermal adminis talampanel, tiagabine, topiramate, Valproate, vigabatrin, tration. Zonisamide, benzodiazepines, barbiturates and sedative hyp 6. A pharmaceutical composition according to claim 5. notics. wherein the transdermal administration is via the oral mucosa and the composition is in the form of powders, a capsule, a 18. A pharmaceutical composition according to claim 10, tablet, a lozenge, a troche or a pastille. wherein the stimulant is selected from Adrafinil, Amantadine, 7. A pharmaceutical composition according to claim 3, Armodafinil, Carphedon, Modafinil, 4-Fluoroamphetamine, wherein the composition comprises a formulation which pro 4-Fluoromethamphetamine, 4-Methylmethcathinone, vides a controlled release or a sustained release of at least one 4-MTA, C.-PPP, Amphechloral, Amphetamine, Dextroam active present in the composition. phetamine. Adderall, Amphetaminil, BenZphetamine, Bupro 8. A method of treating a neurological disorder other than pion, Cathinone, Chlorphentermine, Clobenzorex, Clorter epilepsy in a Subject in need thereof, including the step of mine, Cypena mine, Diethyl propion, Dimethoxyampheta administering to the Subject an anti-epileptic agent as the sole mine, Dimethylampheta mine, Dimethylcathinone, Diphe active agent, wherein the daily dose of the anti-epileptic agent nyl prolinol, Ephedrine, Epinephrine, Ethcathinone, Ethy is less than 20% of the minimum daily dose which is effective lamphetamine, Fencamfamine, Fenethylline, Fenfluramine, for mood stabilisation or treatment of epileptic symptoms. Fenproporex, Feprosidnine, Furfenorex, Levomethamphet 9. An agent according to claim 1, wherein the antiepileptic amine, Lisdexamfetamine, L-lysine-damphetamine, agent is selected from brivaracetam, carbamazepine, cloba MDMA, Mefenorex, Methamphetamine, Methcathinone, Zam, clonazepam, ethoSuximide, felbamate, gabapentin, Methoxyphedrine, Methylone, Octopamine, Parahy lacosamide, lamotrigine, levetiracetam, oXcarbazepine, phe droxyamphetamine, PMA, PMEA, PMMA, PPAP. Phen nobarbital, phenyloin, pregabalin, primidone, retigabine, dimetrazine, Phenmetrazine, Phentermine, Phenylephrine, rufinamide, Safinamide, seletracetam, talampanel, tiagabine, Phenylpropanolamine, Prolintane, Propylamphetamine, topiramate, Valproate, vigabatrin, Zonisamide, benzodiaz Pseudoephedrine, Selegiline, Synephrine, Tenamphetamine, epines, barbiturates and sedative hypnotics. Xylopropamine; piperazines, BZP, MeOPP, MBZP, mCPP, 10. A pharmaceutical composition according to claim 3, 2C-B-BZP, Tropanes, Brasofensine, CFT, Cocaethylene, further comprising: Cocaine, Dimethocaine, Lometopane, PIT, PTI, RTI-121, an active selected from a stimulant, an anti-Parkinson's Tesofensine, Troparil, WF-23, WF-33, Cholinergics, agent, an analgesic and an acetylcholinesterase inhibi Arecoline, Cotinine, Convulsants, Bicuculline, Gabazine, tOr. Pentetrazol, Picrotoxin, Strychnine, Thujone; Phenylami 11. A pharmaceutical composition according to claim 10, nooxazoles, 4-Methyl-aminorex, Aminorex, Clominorex, wherein: Fenozolone, Fluminorex, Pemoline, Thozalinone, Aminept the sub-therapeutic dose is less than 2.5% of the minimum ine, Bemegride, BPAP. Clenbuterol, Clofenciclan, Cyclopen daily dose which is effective for mood stabilisation or tamine, Cyprodenate, Desoxypipradrol, Ethylphenidate, treatment of epileptic symptoms. Ethamivan, Gilutensin, GYKI-52895, Hexacyclonate, Indian 12. A pharmaceutical composition according to claim 10, orex, lndatraline, 1sometheptene, Mazindol, MDPV. Meso wherein the composition is for use in the treatment of a carb, methylphenidate, Dexmethylphenidate, Naphthyliso neurological disorder other than epilepsy. propylamine, Nikethamide, Nocaine, Nomifensine, 13. A pharmaceutical composition according to claim 10, Phacetoperane, Phthalimidopropiophenone, Pipradrol, Pro wherein the composition is adapted for transdermal adminis lintane, Propylhexedrine, Pyrovalerone, Tuamine, Vanox tration. erine, Yohimbine, Zylofuramine, Deanol, Diethylaminoetha 14. A pharmaceutical composition according to claim 13, nol, Dimefline Hydrochloride, Etilamfetamine wherein the composition is adapted for administration via the Hydrochloride, Fencamfamin Hydrochloride, Fenetylline oral mucosa and is in the form of powders, a capsule, a tablet, Hydrochloride, Fenfluramine Hydrochloride, Fenproporex a lozenge, a troche or a pastille. Hydrochloride, Lobeline Hydrochloride, Pentetrazol, and 15. A pharmaceutical composition according to claim 10, Propylhexedrine. wherein the composition comprises a formulation which pro 19. A pharmaceutical composition according to claim 10, vides a controlled release or a sustained release of at least one wherein the anti-Parkinson's agent is selected from apomor active present in the composition. phine, benserazide, benZatropine, bromocriptine, caber 16. A method of treating a neurological disorder other than goline, carbidopa, clozapine, domperidone, entacapone, epilepsy in a Subject in need thereof, including the step of levodopa, lisuride, orphenadrine, pergolide, piribedil, prami administering to the Subject a combination of (a) an anti pexole, procyclidine, quetiapine, rasagiline, rivastigmine, epileptic agent, and (b) an active selected from a stimulant, an ropinirole, rotigotine, selegiline, tolcapone, trihexyphenidyl, anti-Parkinson's agent, an analgesic and an acetylcholinest a dopamine agonist, a dopamine decarboxylase inhibitor, a US 2014/0142140 A1 May 22, 2014

catechol O methyl transferase (COMT) enzyme inhibitor, a amfetamine, L-lysine-damphetamine, MDMA, Mefenorex, monoamine oxidase-B inhibitor and an N-methyl-D-aspar Methamphetamine, Methcathinone, Methoxyphedrine, tate blocker. Methylone, Octopamine, Parahydroxyamphetamine, PMA, 20. A pharmaceutical composition according to claim 10, PMEA, PMMA, PPAP, Phendimetrazine, Phenmetrazine, wherein the acetylcholinesterase inhibitor is selected from Phentermine, Phenylephrine, Phenylpropanolamine, Prolin tacrine, donepezil, galantamine and rivastigmine. tane, Propylamphetamine, Pseudoephedrine, Selegiline, 21. The composition according to claim 3, wherein the Synephrine, Tenamphetamine, Xylopropamine; piperazines, antiepileptic agent is selected from brivaracetam, carbam BZP, MeOPP, MBZP, mCPP, 2C-B-BZP, Tropanes, Bra azepine, clobazam, clonazepam, ethoSuximide, felbamate, sofensine, CFT, Cocaethylene, Cocaine, Dimethocaine, gabapentin, lacosamide, lamotrigine, levetiracetam, Oxcarba Lometopane, PIT, PTI, RTI-121, Tesofensine, Troparil, Zepine, phenobarbital, phenyloin, pregabalin, primidone, WF-23, WF-33, Cholinergics, Arecoline, Cotinine, Convul retigabine, rufinamide, Safinamide, seletracetam, talampanel, sants, Bicuculline, Gabazine, Pentetrazol, Picrotoxin, Strych tiagabine, topiramate, valproate, vigabatrin, Zonisamide, nine, Thujone; Phenylaminooxazoles, 4-Methyl-aminorex, benzodiazepines, barbiturates and sedative hypnotics. Aminorex, Clominorex, Fenozolone, Fluminorex, Pemoline, 22. The composition according to claim 8, wherein the Thozalinone, Amineptine, Bemegride, BPAP. Clenbuterol, antiepileptic agent is selected from brivaracetam, carbam Clofenciclan, Cyclopentamine, Cyprodenate, Desoxyp azepine, clobazam, clonazepam, ethoSuximide, felbamate, ipradrol, Ethylphenidate, Ethamivan, Gilutensin, GYKI gabapentin, lacosamide, lamotrigine, levetiracetam, Oxcarba 52895, Hexacyclonate, lindanorex, lndatraline, 1somethep Zepine, phenobarbital, phenyloin, pregabalin, primidone, tene, Mazindol, MDPV. Mesocarb, methylphenidate, retigabine, rufinamide, Safinamide, seletracetam, talampanel, Dexmethylphenidate, Naphthylisopropylamine, Niketha tiagabine, topiramate, valproate, vigabatrin, Zonisamide, mide, Nocaine, Nomifensine, Phacetoperane, Phthalimi benzodiazepines, barbiturates and sedative hypnotics. dopropiophenone, Pipradrol, Prolintane, Propylhexedrine, 23. The method according to claim 16, wherein the anti Pyrovalerone, Tuamine, Vanoxerine, Yohimbine, Zylo epileptic agentis selected from brivaracetam, carbamazepine, furamine, Deanol, Diethylaminoethanol, Dimefline Hydro clobazam, clonazepam, ethoSuximide, felbamate, gabapen chloride, Etilamfetamine Hydrochloride, Fencamfamin tin, lacosamide, lamotrigine, levetiracetam, oXcarbazepine, Hydrochloride, Fenetyline Hydrochloride, Fenfluramine phenobarbital, phenyloin, pregabalin, primidone, retigabine, Hydrochloride, Fenproporex Hydrochloride, Lobeline rufinamide, Safinamide, seletracetam, talampanel, tiagabine, Hydrochloride, Pentetrazol, and Propylhexedrine. topiramate, valproate, vigabatrin, Zonisamide, benzodiaz 25. The method according to claim 16, wherein the anti epines, barbiturates and sedative hypnotics. Parkinson's agent is selected from apomorphine, benser 24. The method according to claim 16, wherein the stimu azide, benzatropine, bromocriptine, cabergoline, carbidopa, lant is selected from Adrafinil, Amantadine, Armodafinil, clozapine, domperidone, entacapone, levodopa, lisuride, Carphedon, Modafinil, 4-Fluoroamphetamine, 4-Fluo orphenadrine, pergolide, piribedil, pramipexole, procyclid romethamphetamine, 4-Methylmethcathinone, 4-MTA, ine, quetiapine, rasagiline, rivastigmine, ropinirole, rotigo C.-PPP, Amphechloral, Amphetamine, Dextroamphetamine, tine, Selegiline, tolcapone, trihexyphenidyl, a dopamine ago Adderall, Amphetaminil, BenZphetamine, Bupropion, Cathi nist, a dopamine decarboxylase inhibitor, a catechol Omethyl none, Chlorphentermine, Clobenzorex, Clortermine, Cypena transferase (COMT) enzyme inhibitor, a monoamine oxi mine, Diethyl propion, Dimethoxyampheta mine, Dim dase-B inhibitor and an N-methyl-D-aspartate blocker. ethylampheta mine, Dimethylcathinone, Diphenyl prolinol, 26. The method according to claim 16, wherein the acetyl Ephedrine, Epinephrine, Ethcathinone, Ethylamphetamine, cholinesterase inhibitor is selected from tacrine, donepezil, Fencamfamine, Fenethylline, Fenfluramine, Fenproporex, galantamine and rivastigmine. Feprosidinine, Furfenorex, Levomethamphetamine, Lisdex k k k k k