sensory-related fear memories and communicates information regarding threat importance to memory and sensory processing elsewhere in the brain, such as the medial prefrontal cortex and sensory cortices. neurological structures traditionally appreciated for their roles in anxiety include the amygdala, insula and orbitofrontal cortex (ofc). it is broadly postulated that changes in one or more of these neurological structures are believed to allow greater amygdala response to emotional stimuli in individuals who have gad as compared to individuals who do not have gad. individuals with gad have been suggested to have greater amygdala and medial prefrontal cortex (mpfc) activation in response to stimuli than individuals who do not have gad. however, the exact relationship between the amygdala and the frontal cortex (e.g., prefrontal cortex or the orbitofrontal cortex (ofc)) is not fully understood because there are studies that suggest increased or decreased activity in the frontal cortex in individuals who have gad. consequently, because of the tenuous understanding of the frontal cortex as it relates to the amygdala in individuals who have gad, it's an open question as to whether individuals who have gad bear an amygdala that is more sensitive than an amygdala in an individual without gad or whether frontal cortex hyperactivity is responsible for changes in amygdala responsiveness to various stimuli. recent studies have attempted to identify specific regions of the frontal cortex (e.g., dorsomedial prefrontal cortex (dmpfc)) that may be more or less reactive in individuals who have gad or specific networks that may be differentially implicated in individuals who have gad. other lines of study investigate whether activation patterns vary in individuals who have gad at different ages with respect to individuals who do not have gad at the same age (e.g., amygdala activation in adolescents with gad). treatment traditional treatment modalities broadly fall into two categories, i.e., psychotherapeutic and pharmacological intervention. in addition to these two conventional therapeutic approaches, areas of active investigation include complementary and alternative medications (cams), brain stimulation, exercise, therapeutic massage and other interventions that have been proposed for further study. treatment modalities can, and often are, utilized concurrently so that an individual may pursue psychological therapy (i.e., psychotherapy) and pharmacological therapy. both cognitive behavioral therapy (cbt) and medications (such as ssris) have been shown to be effective in reducing anxiety. a combination of both cbt and medication is generally seen as the most desirable approach to treatment. use of medication to lower extreme anxiety levels can be important in enabling patients to engage effectively in cbt. psychotherapy psychotherapeutic interventions include a plurality of therapy types that vary based upon their specific methodologies for enabling individuals to gain insight into the working of the conscious and subconscious mind and which sometimes focus on the relationship between cognition and behavior. cognitive behavioral therapy (cbt) is widely regarded as the first-line psychological therapy for treating gad. additionally, many of these psychological interventions may be delivered in an individual or group therapy setting. while individual and group settings are broadly both considered effective for treating gad, individual therapy tends to promote longer-lasting engagement in therapy (i.e., lower attrition over time). psychodynamic therapy psychodynamic therapy is a type of therapy premised upon freudian psychology in which a psychologist enables an individual explore various elements in their subconscious mind to resolve conflicts that may exist between the conscious and subconscious elements of the mind. in the context of gad, the psychodynamic theory of anxiety suggests that the unconscious mind engages in worry as a defense mechanism to avoid feelings of anger or hostility because such feelings might cause social isolation or other negative attribution toward oneself. accordingly, the various psychodynamic therapies attempt to explore the nature of worry as it functions in gad in order to enable individuals to alter the subconscious practice of using worry as a defense mechanism and to thereby diminish gad symptoms. variations of psychotherapy include a near-term version of therapy, "short-term anxiety-provoking psychotherapy (stapp). behavioral therapy behavioral therapy is therapeutic intervention premised upon the concept that anxiety is learned through classical conditioning (e.g., in view of one or more negative experiences) and maintained through operant conditioning (e.g., one finds that by avoiding a feared experience that one avoids anxiety). thus, behavioral therapy enables an individual to re-learn conditioned responses (behaviors) and to thereby challenge behaviors that have become conditioned responses to fear and anxiety, and which have previously given rise to further maladaptive behaviors. cognitive therapy cognitive therapy (ct) is premised upon the idea that anxiety is the result of maladaptive beliefs and methods of thinking. thus, ct involves assisting individuals to identify more rational ways of thinking and to replace maladaptive thinking patterns (i.e., cognitive distortions) with healthier thinking patterns (e.g., replacing the cognitive distortion of catastrophizing with a more productive pattern of thinking). individuals in ct learn how to identify objective evidence, test hypotheses, and ultimately identify maladaptive thinking patterns so that these patterns can be challenged and replaced. acceptance and commitment therapy acceptance and commitment therapy (act) is a behavioral treatment based on acceptance-based models. act is designed with the purpose to target three therapeutic goals: (1) reduce the use of avoiding strategies intended to avoid feelings, thoughts, memories, and sensations; (2) decreasing a person's literal response to their thoughts (e.g., understanding that thinking "i'm hopeless" does not mean that the person's life is truly hopeless), and (3) increasing the person's ability to keep commitments to changing their behaviors. these goals are attained by switching the person's attempt to control events to working towards changing their behavior and focusing on valued directions and goals in their lives as well as committing to behaviors that help the individual accomplish those personal goals. this psychological therapy teaches mindfulness (paying attention on purpose, in the present, and in a nonjudgmental manner) and acceptance (openness and willingness to sustain contact) skills for responding to uncontrollable events and therefore manifesting behaviors that enact personal values. intolerance of uncertainty therapy intolerance of uncertainty (iu) refers to a consistent negative reaction to uncertain and ambiguous events regardless of their likelihood of occurrence. intolerance of uncertainty therapy (iut) is used as a stand-alone treatment for gad patients. thus, iut focuses on helping patients in developing the ability to tolerate, cope with and accept uncertainty in their life in order to reduce anxiety. iut is based on the psychological components of psychoeducation, awareness of worry, problem-solving training, re-evaluation of the usefulness of worry, imagining virtual exposure, recognition of uncertainty, and behavioral exposure. studies have shown support for the efficacy of this therapy with gad patients with continued improvements in follow-up periods. motivational interviewing a promising innovative approach to improving recovery rates for the treatment of gad is to combine cbt with motivational interviewing (mi). motivational interviewing is a strategy centered on the patient that aims to increase intrinsic motivation and decrease ambivalence about change due to the treatment. mi contains four key elements: (1) express empathy, (2) heighten dissonance between behaviors that are not desired and values that are not consistent with those behaviors, (3) move with resistance rather than direct confrontation, and (4) encourage self-efficacy. it is based on asking open-ended questions and listening carefully and reflectively to patients' answers, eliciting "change talk", and talking with patients about the pros and cons of change. some studies have shown the combination of cbt with mi to be more effective than cbt alone. cognitive behavioral therapy cognitive behavioral therapy (cbt) is an evidence-based type of psychotherapy that demonstrates efficacy in treating gad and which integrates the cognitive and behavioral therapeutic approaches. the objective of cbt is to enable individuals to identify irrational thoughts that cause anxiety and to challenge dysfunctional thinking patterns by engaging in awareness techniques such as hypothesis testing and journaling. because cbt involves the practice of worry and anxiety management, cbt includes a plurality of intervention techniques that enable individuals to explore worry, anxiety and automatic negative thinking patterns. these interventions include anxiety management training, cognitive restructuring, progressive relaxation, situational exposure and self-controlled desensitization. several modes of delivery are effective in treating gad, including internet-delivered cbt, or icbt. emotion-focused therapy emotion-focused therapy (eft) is a short-term psychotherapy that is focused on humanistic needs of emotions when treating individuals with gad. eft can incorporate numerous practices such as experimental therapy, systemic therapy, and elements of cbt to allow individuals to work through difficult emotional states. the primary goal of eft is assisting individuals in living with their vulnerable emotions and overcoming avoidance so that adaptive experiences such as compassion and protective anger can be generated in response to the emotional needs that are embedded in core emotional vulnerability. sandplay therapy sandplay therapy (spt) is an intervention based on nonverbal therapeutic practices. the main objective of spt is to allow the individual the ability to work through their emotional problems from childhood traumas (ct) through play using sand and toy figures. although the therapy is mainly focused on nonverbal cues, verbal cues are also observed and documented during the rehabilitation process of the individual. spt allows a multisensory experience through a safe and protected space allowing the individual the opportunity to regulate their mind and emotions. this therapeutic practice is offered in both adults and children. other forms of psychological therapy relaxation techniques (e.g., relaxing imagery, meditational relaxation) metacognitive therapy (mct): the objective of mct is to alter thinking patterns regarding worry so that worry is no longer used as a coping strategy. it has promising results in treatment of gad as well as other mental issues. mindfulness based stress reduction (mbsr) mindfulness based cognitive therapy (mbct) supportive therapy: this is a rogerian method of therapy in which subjects experience empathy and acceptance from their therapist to facilitate increasing awareness. variations of active supportive therapy include gestalt therapy, transactional analysis and counseling. internet-delivered interpretation training: the focus of this training is to reduce worry and anxiety while promoting positive outcomes and positive interpretations. pharmacotherapy medications that have been studied were reviewed in a recent network meta-analysis that compared all studied medications with placebo and also with each other and another compared the rates of remission between different medications. benzodiazepines (bzs) have been used to treat anxiety starting in the 1960s. there is a risk of dependence and tolerance to benzodiazepines. bzs have a number of effects that make them a good option for treating anxiety including anxiolytic, hypnotic (induce sleep), myorelaxant (relax muscles), anticonvulsant, and amnestic (impair short-term memory) properties. while bzs work well to alleviate anxiety shortly after administration, they are also known for their ability to promote dependence and are frequently used recreationally or non-medically. antidepressants (e.g., ssris / snris) have become a mainstay in treating gad in adults. first-line medications from any drug category often include those that have been approved by the food and drug administration (fda) or other similar regulatory body such as the ema or tga for treating gad because these drugs have been show to be safe and effective. fda-approved medications for treating gad fda-approved medications for treating gad include: ssris paroxetineescitalopramsnris venlafaxineduloxetinebenzodiazepines alprazolamazapirones buspirone non-fda approved medications while certain medications are not specifically fda approved for treatment of gad, there are a number of medications that historically have been used or studied for treating gad. other medications that have been used or evaluated for treating gad include: ssris (antidepressants) citalopram fluoxetine sertraline fluvoxamine benzodiazepines clonazepam lorazepam diazepam gaba analogs pregabalin tiagabine second-generation antipsychotics (sgas) olanzapine (evidence of effectiveness is merely a trend) ziprasidone risperidone aripiprazole (studied as an adjunctive measure in concert with other treatment) quetiapine (atypical antipsychotic studied as an adjunctive measure in adults and geriatric patients) antihistamines hydroxyzine (h1 receptor antagonist) vilazodone (atypical antidepressant) agomelatine (antidepressant, mt1/2 receptor agonist, 5ht2c antagoinst) clonidine (noted to cause decreased blood pressure and other aes) guanfacine (a2a receptor agonist, studied in pediatric patients with gad) mirtazapine (atypical antidepressant having 5ht2a and 5ht2c receptor affinity) vortioxetine (multimodal antidepressant) eszopiclone (non-benzodiazepine hypnotic) tricyclic antidepressants amitriptyline clomipramine doxepin imipramine trimipramine desipramine nortriptyline protriptyline opipramol (atypical tca) trazodone monamine oxidase inhibitors (maois) tranylcypromine phenelzine homeopathic preparations (discussed below, see complementary and alternative medications (cams)) selective serotonin reuptake inhibitors pharmaceutical treatments for gad include selective serotonin reuptake inhibitors (ssris). ssris increase serotonin levels through inhibition of serotonin reuptake receptors. fda approved ssris used for this purpose include escitalopram and paroxetine. however, guidelines suggest using sertraline